Cloned genome of infectious hepatitis C virus of genotype 2A and uses thereof

Abstract

The present invention discloses nucleic acid sequence which encodes infectious hepatitis C virus of strain HC-J6.sub.CH, genotype 2a, and the use of the sequence, and polypeptides encoded by all or part of the sequence, in the development of vaccines and diagnostics for HCV and in the development of screening assays for the identification of antiviral agents for HCV.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application is a continuation of U.S. application Ser. No.: 09/980,559, filed May 14, 2002, which is the U.S. National Phase of International Application No.: PCT/US00/15446, filed Jun. 2, 2000, designating the United States of America and published in English on Dec. 14, 2000 as WO 00/75338, which claims the benefit of U.S. Provisional Application No. 60/137,693 filed Jun. 4, 1999, all of which are hereby expressly incorporated by reference in their entireties.

FIELD OF THE INVENTION

[0002] The present invention relates to molecular approaches to the production of nucleic acid sequence which comprises the genome of infectious hepatitis C virus. In particular, the invention provides a nucleic acid sequence which comprises the genome of an infectious hepatitis C virus of genotype 2a. The invention therefore relates to the use of the nucleic acid sequence and polypeptides encoded by all or part of the sequence in the development of vaccines and diagnostic assays for HCV and in the development of screening assays for the identification of antiviral agents for HCV.

BACKGROUND OF THE INVENTION

[0003] Hepatitis C virus (HCV) has a positive-sense single-strand RNA genome and is a member of the genus Hepacivirus within the Flaviviridae family of viruses (Rice, C. M. 1996 Flaviviridae: The viruses and their replication, In Fields Virolog (B. N. Fields, D. M. Knipe, P. M. Howley, et al., Eds.), Third ed., pp. 931-959. Lippincott-Raven Publishers, Philadelphia). As for all positive-stranded RNA viruses, the genome of HCV functions as mRNA from which all viral proteins necessary for propagation are translated.

[0004] The viral genome of HCV is approximately 9600 nucleotides (nts) in length and consists of a highly conserved 5' untranslated region (UTR), a single long open reading frame (ORF) of approximately 9,000 nts and a complex 3' UTR. The 5' UTR contains an internal ribosomal entry site (Tsukiyama-Kohara, K. et al. 1992 J. Virol. 66:1476-1483; Honda, M., et al. 1996 RNA 2:955-968). The 3' UTR consists of a short variable region, a polypyrimidine tract of variable length and, at the 3' end, a highly conserved region of approximately 100 nucleotides (Kolykhalov, A. A. et al. 1996 J. Virol. 70:3363-3371; Tanaka, T et al. 1995 Biochem. Biophys. Res. Commun. 215:744-749; Tanaka, T. et al. 1996 J. Virol. 70:3307-3312; Yamada, N. et al. 1996 Virology 223:255-261). The last 46 nucleotides of this conserved region were predicted to form a stable stem-loop structure thought to be critical for viral replication (Blight, K. J. and Rice, C. M. 1997 J. Virol. 71:7345-7352; Ito, T. and Lai, M. M. C. 1997 J. Virol. 71:8698-8706; Tsuchihara, K. et al. 1997 J. Virol. 71:6720-6726). The ORF encodes a large polypeptide precursor that is cleaved into at least 10 proteins by host and viral proteinases (Rice, C. M. 1996 Flaviviridae: The viruses and their replication, In Fields Virology (B. N. Fields, D. M. Knipe, P. M. Howley, et al., Eds.), Third ed., pp. 931-959. Lippincott-Raven Publishers, Philadelphia). The predicted envelope proteins contain several conserved N-linked glycosylation sites and cysteine residues (Okamoto, H. et al. 1992 Virology 188:331-341). The NS3 gene encodes a serine protease and an RNA helicase and the NS5B gene encodes an RNA-dependent RNA polymerase.

[0005] A remarkable characteristic of HCV is its genetic heterogeneity, which is manifested throughout the genome (Bukh, J. et al. 1995 Semin. Liver Dis. 15:41-63). The most heterogeneous regions of the genome are found in the envelope genes, in particular the hypervariable region 1 (HVR1) at the N-terminus of E2 (Hijikata, M. et al. 1991 Biochem. Biophys. Res. Commun. 175:220-228; Weiner, A. J. et al. 1991 Virology 180:842-848). HCV circulates as a quasispecies of closely related genomes in an infected individual. Globally, six major HCV genotypes (genotypes 1-6) and multiple subtypes (a, b, c, etc.) have been identified (Bukh, J. et al. 1993 PNAS USA 90:8234-8238; Simmonds, P. et al. 1993 J. Gen. Virol. 74:2391-2399).

[0006] The nucleotide and deduced amino acid sequences among isolates within a quasispecies generally differ by <2%, whereas those between isolates of different genotypes vary by as much as 35%. Genotypes 1, 2 and 3 are found worldwide and constitute more than 90% of the HCV infections in North and South America, Europe, Russia, China, Japan and Australia (Foms, X. and Bukh, J. 1998 Viral Hepatit. is Reviews 4:1-19). Throughout these regions genotype 1 accounts for the majority of HCV infections but genotypes 2 and 3 each account for 5-15%.

[0007] At present, more than 80% of individuals infected with HCV become chronically infected and these chronically infected individuals have a relatively high risk of developing chronic hepatitis, liver cirrhosis and hepatocellular carcinoma (Hoofnagle, J. H. 1997 Hepatology 26:15S-20S). The only effective therapy for chronic hepatitis C, interferon (IFN), alone or in combination with ribavirin, induces a sustained response in less than 50% of treated patients (Davis, G. L. et al. 1998 N. Engl. J. Med. 339:1493-1499; McHutchison, J. G. et al. 1998 N. Engl. J. Med. 339:1485-1492). Consequently, HCV is currently the most common cause of end stage liver failure and the reason for about 30% of liver transplants performed in the U.S. (Hoofnagle, J. H. 1997 Hepatology 26:15S-20S). In addition, a number of recent studies suggested that the severity of liver disease and the outcome of therapy may be genotype-dependent (reviewed in Bukh, J. et al. 1997 In "Viral Hepatitis and Liver Disease, Proceedings of IX Triennial International Symposium on Viral Hepatitis and Liver Disease, Rome, Italy, 1996" (M. Rizzetto, R. H. Purcell, J. L. Gerin and G. Verme, Eds.), pp. 167-175. Edizioni Minerva Medica, Turin). In particular, these studies suggested that infection with HCV genotype 1b was associated with more severe liver disease (Brechot, C. 1997 Hepatology 25:772-774) and a poorer response to IFN therapy (Fried, M. W. and Hoofnagle, J. H. 1995 Semin. Liver Dis. 15:82-91). As a result of the inability to develop a universally effective therapy against HCV infection, it is estimated that there are still more than 25,000 new infections yearly in the U.S. (Alter, M. J. 1997 Hepatology 26:62S-65S) Moreover, since there is no vaccine for HCV, HCV remains a serious public health problem.

[0008] Despite the intense interest in the development of vaccines and therapies for HCV, progress has been hindered by the absence of a useful cell culture system and the lack of any small animal model for laboratory study. For example, while replication of HCV in several cell lines has been reported, such observations have turned out not to be highly reproducible. In addition, the chimpanzee is the only animal model, other than man, for this disease.

[0009] Consequently, HCV has been studied only by using clinical materials obtained from patients or experimentally infected chimpanzees, an animal model whose availability is very limited.

[0010] However, several researchers have recently reported the construction of infectious cDNA clones of HCV, the identification of which would permit a more effective search for susceptible cell lines and facilitate molecular analysis of the viral genes and their function. For example, Yoo, B. J. et al. 1995 J. Virol. 69:32-38, and Dash, S. et al. 1997 Am. J. Pathol. 151:363-373 reported that RNA transcripts from cDNA clones of HCV-1 (genotype 1a) and HCV-N (genotype 1b), respectively, resulted in viral replication after transfection into human hepatoma cell lines.

[0011] Unfortunately, the viability of these clones was not tested in vivo and concerns were raised about the infectivity of these cDNA clones in vitro (Fausto, N. 1997 Am. J. Pathol. 151:361). In addition, both clones did not contain the terminal 98 conserved nucleotides at the very 3' end of the UTR.

[0012] Kolykhalov, A. A. et al. (1997 Science 277:570-574) and Yanagi et al. (1997 PNAS USA 94:8738-8743 and 1998 Virology 244:161-172) reported the derivation from HCV strains H77 (genotype 1a) and HC-J4 (genotype 1b) of cDNA clones of HCV that are infectious for chimpanzees. However, while these infectious clones will aid in studying HCV replication and pathogenesis and will provide an important tool for development of in vitro replication and propagation systems, it is important to have infectious clones of more than one genotype, given the extensive genetic heterogeneity of HCV and the potential impact of such heterogeneity on the development of effective therapies and vaccines for HCV.

[0013] In addition, synthetic chimeric viruses can be used to map the functional regions of viruses with different phenotypes. In flaviviruses and pestiviruses, infectious chimeric viruses have been successfully engineered to express different functional units of related viruses (Bray, M. and Lai, C.-J. 1991 PNAS USA 88:10342-10346; Pletnev, A. G. 1992 PNAS USA 89:10532-10536; Pletnev, A. G. and Men, R. 1998 PNAS USA 95:1746-175; Vassilev, V. B. et al. 1997 J. Virol. 71:471-478) and in some cases it has been possible to make chimeras between non-related or distantly related viruses. For instance, the IRES element of poliovirus or bovine viral diarrhea virus has been replaced with IRES sequences from HCV (Frolov, I. et al. 1998 RNA 4:1418-1435; Lu, H.-H. and Wimmer, E. 1996 PNAS USA 93:1412-1417; Zhao, W. D. et al. 1999 J. Virol. 73:1546-1554).

[0014] Recently, the construction of an infectious chimera of two closely related HCV subtypes has been reported. The chimera contained the complete ORF of a genotype 1b strain but had the 5' and 3' termini of a genotype 1a strain (Yanagi, M. et al. 1998 Virology 244:161-172).

[0015] It is important to determine whether chimeras constructed from more divergent HCV strains are infectious because such chimeras could be used to define the functions of viral units and to dissect the immune response.

SUMMARY OF THE INVENTION

[0016] The present invention relates to nucleic acid sequence which comprises the genome of infectious hepatitis C virus and in particular, nucleic acid sequence which comprises the genome of infectious hepatitis C virus of genotype 2a. It is therefore an object of the invention to provide nucleic acid sequence which encodes infectious hepatitis C virus. Such nucleic acid sequence is referred to throughout the application as "infectious nucleic acid sequence".

[0017] For the purposes of this application, nucleic acid sequence refers to RNA, DNA, cDNA or any variant thereof-capable of directing host organism synthesis of a hepatitis C virus polypeptide. It is understood that nucleic acid sequence encompasses nucleic acid sequences, which due to degeneracy, encode the same polypeptide sequence as the nucleic acid sequences described herein.

[0018] The invention also relates to the use of the infectious nucleic acid sequences to produce chimeric genomes consisting of portions of the open reading frames of nucleic acid sequences of other genotypes (including, but not limited to, genotypes 1, 2, 3, 4, 5 and 6) and subtypes (including, but not limited to, subtypes 1a, 1b, 2a, 2b, 2c, 3a, 4a-4f, 5a and 6a) of HCV. For example, infectious nucleic acid sequence of the 2a strain HC-J6, described herein can be used to produce chimeras with sequences from the genomes of other strains of HCV from different genotypes or subtypes. Nucleic acid sequences which comprise sequences from two or more HCV genotypes or subtypes are designated "chimeric nucleic acid sequences".

[0019] The invention further relates to mutations of the infectious nucleic acid sequence of the invention where mutation includes, but is not limited to, point mutations, deletions and insertions. In one embodiment, a gene or fragment thereof can be deleted to determine the effect of the deleted gene or genes on the properties of the encoded virus such as its virulence and its ability to replicate. In an alternative embodiment, a mutation may be introduced into the infectious nucleic acid sequences to examine the effect of the mutation on the properties of the virus.

[0020] The invention also relates to the introduction of mutations or deletions into the infectious nucleic acid sequence in order to produce an attenuated hepatitis C virus suitable for vaccine development.

[0021] The invention further relates to the use of the infectious nucleic acid sequence to produce attenuated viruses via passage in vitro or in vivo of the viruses produced by transfection of a host cell with the infectious nucleic acid sequence.

[0022] The present invention also relates to the use of the nucleic acid sequence of the invention or fragments thereof in the production of polypeptides where "nucleic acid sequence of the invention" refers to infectious nucleic acid sequence, mutations of infectious nucleic acid sequence, chimeric nucleic acid sequence and sequences which comprise the genome of attenuated viruses produced from the infectious nucleic acid sequence of the invention. In one embodiment, said polypeptide or polypeptides are fully or partially purified from hepatitis C virus produced by cells transfected with nucleic acid sequence of the invention.

[0023] In another embodiment, the polypeptide or polypeptides are produced recombinantly from a fragment of the nucleic acid sequences of the invention. In yet another embodiment, the polypeptides are chemically synthesized.

[0024] The polypeptides of the invention especially structural polypeptides, can serve as immunogens in the development of vaccines or as antigens in the development of diagnostic assays for detecting the presence of HCV in biological samples.

[0025] The invention therefore also relates to vaccines for use in immunizing mammals especially humans against hepatitis C. In one embodiment, the vaccine comprises one or more polypeptides made from the nucleic acid sequence of the invention or fragment thereof. In a second embodiment, the vaccine comprises a hepatitis C virus produced by transfection of host cells with the nucleic acid sequences of the invention.

[0026] The present invention therefore relates to methods for preventing hepatitis C in a mammal. In one embodiment the method comprises administering to a mammal a polypeptide or polyp6ptides encoded by the nucleic acid sequence of the invention in an amount effective to induce protective immunity to hepatitis C. In another embodiment, the method of prevention comprises administering to a mammal a hepatitis C virus of the invention in an amount effective to induce protective immunity against hepatitis C. In yet another embodiment, the method of protection comprises administering to a mammal the nucleic acid sequence of the invention or a fragment thereof in an amount effective to induce protective immunity against hepatitis C. The invention also relates to hepatitis C viruses produced by host cells transfected with the nucleic acid sequence of the present invention.

[0027] The invention therefore also provides pharmaceutical compositions comprising the nucleic acid sequence of the invention and/or the encoded hepatitis C viruses. The invention further provides pharmaceutical compositions comprising polypeptides encoded by the nucleic acid sequence of the invention or fragments thereof. The pharmaceutical compositions of the invention may be used prophylactically or therapeutically.

[0028] The invention also relates to antibodies to the hepatitis C virus of the invention or their encoded polypeptides and to pharmaceutical compositions comprising these antibodies.

[0029] The invention also relates to the use of the nucleic acid sequences of the invention to identify cell lines capable of supporting the replication of HCV in vitro.

[0030] The invention further relates to the use of the nucleic acid sequences of the invention or their encoded viral enzymes (e.g. NS3 serine protease, NS3 helicase, NS5B RNA polymerase) to develop screening assays to identify antiviral agents for HCV.

BRIEF DESCRIPTION OF THE DRAWINGS

[0031] FIG. 1 shows the amplification and cloning of hepatitis C virus genotype 2a (strain HC-J6.sub.Ch). The nucleotide positions correspond to the sequence of PJ6CF, a full length cDNA clone of hepatitis C virus, genotype 2a, strain HC-J6.sub.CH. Products from polymerase chain reaction are also shown. The names of the clones obtained from these products are indicated (number of clones sequenced are shown in parenthesis). The composition of the full-length cDNA clone is shown at the bottom. The restriction enzymes used for cloning are indicated. An XbaI site in HC-J6.sub.CH was eliminated by a silent substitution at position 5494.

[0032] FIG. 2 shows tree analysis of clones amplified from an infectious acute phase plasma pool generated in a chimpanzee inoculated with human plasma containing strain HC-J6 (Okamoto, H. et al. 1991 J. Gen. Virol. 72:2697-2704) as well as a tree of the predicted polyprotein sequence of HC-J6CH and the infectious HC-J6CH cDNA clone (pJ6CF).

[0033] The nucleotide positions with deletions or insertions were stripped in the analysis of the clones. Multiple sequence alignments and tree analyses were performed with GeneWorks (Oxford Molecular Group) (Bukh, J. et al. 1995 Semin. Liver Dis. 15:41-63). Genotype designations are indicated. Other sequences included in the analysis are HC-J8 (Okamoto, H. et al. 1992 Virology 188:331-341), genotype 1a infectious clone BEBE1 (Nakao, H. et al. 1996 Arch. Virol. 141:701-704), H77C (Yanagi, M. et al. 1997 PNAS USA 94:8738-8743); genotype 1b infectious clone J4L6S (Yanagi, M. et al. 1998 Virology 244:161-172). The scale in each tree indicates the calculated genetic distance.

[0034] FIG. 3 shows the alignment of the hypervariable region 1 sequences from 8 J6S clones of strain HC-J6.sub.CH =l (J6S1--SEQ ID NO: 39; J6S2--SEQ ID NO: 40; J6S3--SEQ ID NO: 41; J6S5--SEQ ID NO: 42; J6S6--SEQ ID NO: 43; J6S7--SEQ ID NO: 44; D J6S8--SEQ ID NO: 45; J6S4--SEQ ID NO: 46). HC-J6.sub.CH (SEQ ID NO: 47) represents the consensus amino acid sequence of the infectious plasma pool from an experimentally infected chimpanzee. HC-J6 (SEQ ID NO: 48) is the published amino acid sequence of the original inoculum (Okamoto, H. et al. 1991 J. Gen. Virol. 72:2697-2704).

[0035] FIG. 4 shows the construction of four intertypic chimeric cDNA clones. White boxes are sequences derived from genotype 2a clone pJ6CF, and black boxes are sequences derived from genotype la clone pCV-H77C (Yanagi, M. et al. 1997 PNAS USA 94:8738-8743). An NdeI site (mutation at position 9158 of pCV-H77C) was eliminated and an artificial NdeI site (mutation at position 2765 of pCV-H77C) was created by site-directed mutagenesis; silent mutations are underlined.

[0036] FIGS. 5A and 5B show the alignment of the nucleotide sequences of the 5' (H77CV-J6S--SEQ ID NO: 50; H77(p7)CV-J6S--SEQ ID NO: 51; H77-J6S--SEQ ID NO: 52; H77(p7)-J6S--SEQ ID NO: 53) (FIG. 5A) and 3' UTRs (H77C--SEQ ID NO: 55; H77CV-J6S--SEQ ID NO: 56; H77(p7)CV-J6S--SEQ ID NO: 57; H77-J6S--SEQ ID NO: 58; H77(p7)-J6S--SEQ ID NO: 59; J6CF--SEQ ID NO: 60) (FIG. 5B) and the amino acid sequences of E2/p7/NS2 junctions (H77C--SEQ ID NO: 61; H77CV-J6S--SEQ ID NO: 62; H77(p7)CV-J6S--SEQ ID NO: 63; H77-J6S--SEQ ID NO: 64; H77(p7)-J6S--SEQ ID NO: 65; J6CF--SEQ ID NO: 66) (FIG. 5B) in the intertypic 1a, 2a chimeric cDNA clones. In the 5' UTR alignment, the first 39 nts of core believed to be important for the IRES function were included (Lemon, S. M and Honda, M. 1997 Semin. Virol. 8:274-288). Top line: the sequence of the infectious genotype 1a clone pCV-H77C (Yanagi, M. et al. 1997 PNAS USA 94:8738-8743) (SEQ ID NO: 49). Bottom line: the sequence of the infectious genotype 2a clone pJ6CF (SEQ ID NO: 54). Dot: identity with the sequence of H77C. Capital letter: different from the sequence of H77C. Dash: deletion. Bold face: initiation or stop codon of the ORF. Underlined: AgeI cleavage site. Arrow: putative sites in the HCV polyprotein cleaved by host signal peptidases. Numbering corresponds to the sequence of pCV-H77C.

[0037] FIGS. 6A-6F show the nucleotide sequence of the infectious hepatitis C virus clone of genotype 1a strain H77C (SEQ ID NO: 67) and FIGS. 6G-6H show the amino acid sequence encoded by the clone (SEQ ID NO: 68).

[0038] FIGS. 7A-7F show the nucleotide sequence of the infectious hepatitis C virus clone of genotype 1b strain HC-J4 (SEQ ID NO: 69) and

[0039] FIGS. 7G-H show the amino acid sequence encoded by the clone (SEQ ID NO: 70).

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

[0040] The present invention relates to nucleic acid sequence which comprises the genome of an infectious hepatitis C virus. More specifically, the invention relates to nucleic acid sequence which encodes infectious hepatitis C virus of strain HC-J6.sub.CH, genotype 2a. The infectious nucleic acid sequence of the invention is shown in SEQ ID NO: 1 and is contained in a plasmid construct deposited with the American Type Culture Collection (ATCC) on May 28, 1999 and having ATCC accession number PTA-153.

[0041] The invention also relates to "chimeric nucleic-acid sequences" where the chimeric nucleic acid sequences consist of open-reading frame sequences and/or 5' and/or 3' untranslated sequences taken from nucleic acid sequences of hepatitis C viruses of different genotypes or subtypes.

[0042] In one embodiment, the chimeric nucleic acid sequence consists of sequence from the genome of infectious HCV of genotype 2a which encodes structural polypeptides and sequence from the genome of a HCV of a different genotype or subtype which encodes nonstructural polypeptides.

[0043] Alternatively, the nonstructural region of infectious HCV of genotype 2a and structural region of a HCV of a different genotype or subtype may be combined.

[0044] This will result in a chimeric nucleic acid sequence consisting of sequence from the genome of infectious HCV of genotype 2a which encodes nonstructural polypeptides and sequence from the genome of a HCV of a another genotype or subtype which encodes structural polypeptides.

[0045] Preferably, the nucleic acid sequence from the genome of the infectious HCV clone of genotype 1a (deposited with the ATCC on Jun. 2, 1999; FIGS. 6A-6F), or the nucleic acid sequence from the genome of the infectious HCV clone of genotype 1b (ATCC accession number 209596; FIGS. 7A-7F) is used to construct the chimeric nucleic acid sequence with the HCV of genotype 2a of the invention.

[0046] It is believed that the construction of such chimeric nucleic acid sequences will be of importance in studying the growth and virulence properties of hepatitis C virus and in the production of candidate hepatitis C virus vaccines suitable to confer protection against multiple genotypes of HCV. For example, one might produce a "multivalent" vaccine by putting epitopes from several genotypes or subtypes into one clone. Alternatively one might replace just a single gene from an infectious sequence with the corresponding gene from the genomic sequence of a strain from another genotype or subtype or create a chimeric gene which contains portions of a gene from two genotypes or subtypes. Examples of genes which could be replaced or which could be made chimeric, include, but are not limited to, the E1, E2 and NS4 genes.

[0047] The invention further relates to mutations of the infectious nucleic acid sequences where "mutations" include, but are not limited to, point mutations, deletions and insertions. Of course, one of ordinary skill in the art would recognize that the size of the insertions would be limited by the ability of the resultant nucleic acid sequence to be properly packaged within the virion. Such mutations could be produced by techniques known to those of skill in the art such as site-directed mutagenesis, fusion PCR, and restriction digestion followed by religation.

[0048] In one embodiment, mutagenesis might be undertaken to determine sequences that are important for viral properties such as replication or virulence. For example, one may introduce a mutation into the infectious nucleic acid sequence which eliminates the cleavage site between the NS4A and NS4B polypeptides to examine the effects on viral replication and processing of the polypeptide.

[0049] Alternatively, one may delete all or part of a gene or part of the 5' or 3' nontranslated region contained in an infectious nucleic acid sequence and then transfect a host cell (animal or cell culture) with the mutated sequence and measure viral replication in the host by methods known in the art such as RT-PCR. Preferred genes include, but are not limited to, the P7, NS4B and NS5A genes. Of course, those of ordinary skill in the art will understand that deletion of part of a gene, preferably the central portion of the gene, may be preferable to deletion of the entire gene in order to conserve the cleavage site boundaries which exist between proteins in the HCV polyprotein and which are necessary for proper processing of the polyprotein.

[0050] In the alternative, if the transfection is into a host animal such as a chimpanzee, one can monitor the virulence phenotype of the virus produced by transfection of the mutated infectious nucleic acid sequence by methods known in the art such as measurement of liver enzyme levels (alanine aminotransferase (ALT) or isocitrate dehydrogenase (ICD)) or by histopathology of liver biopsies. Thus, mutations of the infectious nucleic acid sequences may be useful in the production of attenuated HCV strains suitable for vaccine use.

[0051] The invention also relates to the use of the infectious nucleic acid sequence of the present invention to produce attenuated viral strains via passage in vitro or in vivo of the virus produced by transfection with the infectious nucleic acid sequence.

[0052] The present invention therefore relates to the use of the nucleic acid sequence of the invention to identify cell lines capable of supporting the replication of HCV.

[0053] In particular, it is contemplated that the mutations of the infectious nucleic acid sequence of the invention and the production of chimeric sequences as discussed above may be useful in identifying sequences critical for cell culture adaptation of HCV and hence, may be useful in identifying cell lines capable of supporting HCV replication.

[0054] Transfection of tissue culture cells with the nucleic acid sequences of the invention may be done by methods of transfection known in the art such as electroporation, precipitation with DEAE-Dextran or calcium phosphate or liposomes.

[0055] In one such embodiment, the method comprises the growing of animal cells, especially human cells, in vitro and transfecting the cells with the nucleic acid of the invention, then determining if the cells show indicia of HCV infection. Such indicia include the detection of viral antigens in the cell, for example, by immunofluorescence procedures well known in the art; the detection of viral polypeptides by Western blotting using antibodies specific therefor; and the detection of newly transcribed viral RNA within the cells via methods such as RT-PCR. The presence of live, infectious virus particles following such tests may also be shown by injection of cell culture medium or cell lysates into healthy, susceptible animals, with subsequent exhibition of the signs and symptoms of HCV infection.

[0056] Suitable cells or cell lines for culturing HCV include, but are not limited to, lymphocyte and hepatocyte cell lines known in the art.

[0057] Alternatively, primary hepatocytes can be cultured, and then infected with HCV; or, the hepatocyte cultures could be derived from the livers of infected chimpanzees. In addition, various immortalization methods known to those of ordinary skill in the art can be used to obtain cell lines derived from hepatocyte cultures. For example, primary hepatocyte cultures may be fused to a variety of cells to maintain stability.

[0058] The present invention further relates to the in vitro and in vivo production of hepatitis C viruses from the nucleic acid sequences of the invention.

[0059] In one embodiment, the sequences of the invention can be inserted into an expression vector that functions in eukaryotic cells. Eukaryotic expression vectors suitable for producing high efficiency gene transfer in vivo are well known to those of ordinary skill in the art and include, but are not limited to, plasmids, vaccinia viruses, retroviruses, adenoviruses and adeno-associated viruses.

[0060] In another embodiment, the sequences contained in the recombinant expression vector can be transcribed in vitro by methods known to those of ordinary skill in the art in order to produce RNA transcripts which encode the hepatitis C viruses of the invention. The hepatitis C viruses of the invention may then be produced by transfecting cells by methods known to those of ordinary skill in the art with either the in vitro transcription mixture containing the RNA transcripts or with the recombinant expression vectors containing the nucleic acid sequences described herein.

[0061] The hepatitis C viruses produced from the sequences of the invention may be purified or partially purified from the transfected cells by methods known to those of ordinary skill in the art. In a preferred embodiment, the viruses are partially purified prior to their use as immunogens in the pharmaceutical compositions and vaccines of the present invention.

[0062] The present invention therefore relates to the use of the hepatitis C viruses produced from the nucleic acid sequences of the invention as immunogens in live or killed (e.g., formalin inactivated) vaccines to prevent hepatitis C in a mammal.

[0063] In an alternative embodiment, the immunogen of the present invention may be an infectious nucleic acid sequence, a chimeric nucleic acid sequence, or a mutated infectious nucleic acid sequence which encodes a hepatitis C virus. Where the sequence is a cDNA sequence, the cDNAs and their RNA transcripts may be used to transfect a mammal by direct injection into the liver tissue of the mammal as described in the Examples.

[0064] Alternatively, direct gene transfer may be accomplished via administration of a eukaryotic expression vector containing a nucleic acid sequence of the invention.

[0065] In yet another embodiment, the immunogen may be a polypeptide encoded by the nucleic acid sequences of the invention. The present invention therefore also relates to polypeptides produced from the nucleic acid sequences of the invention or fragments thereof. In one embodiment, polypeptides of the present invention can be recombinantly produced by synthesis from the nucleic acid sequences of the invention or isolated fragments thereof, and purified, or partially purified, from transfected cells using methods already known in the art. In an alternative embodiment, the polypeptides may be purified or partially purified from viral particles produced via transfection of a host cell with the nucleic acid sequences of the invention. Such polypeptides might, for example, include either capsid or envelope polypeptides prepared from the sequences of the present invention.

[0066] When used as immunogens, the nucleic acid sequences of the invention, or the polypeptides or viruses produced therefrom, are preferably partially purified prior to use as immunogens in pharmaceutical compositions and vaccines of the present invention.

[0067] When used as a vaccine, the sequences and the polypeptide and virus products thereof, can be administered alone or in a suitable diluent, including, but not limited to, water, saline, or some type of buffered medium. The vaccine according to the present invention may be administered to an animal, especially a mammal, and most especially a human, by a variety of routes, including, but not limited to, intradermally, intramuscularly, subcutaneously, or in any combination thereof.

[0068] Suitable amounts of material to administer for prophylactic and therapeutic purposes will vary depending on the route selected and the immunogen (nucleic acid, virus, polypeptide) administered. One skilled in the art will appreciate that the amounts to be administered for any particular treatment protocol can be readily determined without undue experimentation.

[0069] The vaccines of the present invention may be administered once or periodically until a suitable titer of anti-HCV antibodies appear in the blood. For an immunogen consisting of a nucleic acid sequence, a suitable amount of nucleic acid sequence to be used for prophylactic purposes might be expected to fall in the range of from about 100 .mu.g to about 5 mg and most preferably in the range of from about 500 .mu.g to about 2 mg. For a polypeptide, a suitable amount to use for prophylactic purposes is preferably 100 ng to 100 .mu.g and for a virus 10.sup.2 to 10.sup.6 infectious doses. Such administration will, of course, occur prior to any sign of HCV infection.

[0070] A vaccine of the present invention may be employed in such forms as capsules, liquid solutions, suspensions or elixirs for oral administration, or sterile liquid forms such as solutions or suspensions. An inert carrier is preferably used, such as saline or phosphate-buffered saline, or any such carrier in which the HCV of the present invention can be suitably suspended. The vaccines may be in the form of single dose preparations or in multi-dose flasks which can be utilized for mass-vaccination programs of both animals and humans. For purposes of using the vaccines of the present invention reference is made to Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa., Osol (Ed.) (1980); and New Trends and Developments in Vaccines, Voller et al. (Eds.), University Park Press, Baltimore, Md. (1978), both of which provide much useful information for preparing and using vaccines. Of course, the polypeptides of the present invention, when used as vaccines, can include, as part of the composition or emulsion, a suitable adjuvant, such as alum (or aluminum hydroxide) when humans are to be vaccinated, to further stimulate production of antibodies by immune cells. When nucleic acids, viruses or polypeptides are used for vaccination purposes, other specific adjuvants such as CpG motifs (Krieg, A. K. et al. (1995) and (1996)), may prove useful.

[0071] When the nucleic acids, viruses and polypeptides of the present invention are used as vaccines or inocula, they will normally exist as physically discrete units suitable as a unitary dosage for animals, especially mammals, and most especially humans, wherein each unit will contain a predetermined quantity of active material calculated to produce the desired immunogenic effect in association with the required diluent. The dose of said vaccine or inoculum according to the present invention is administered at least once. In order to increase the antibody level, a second or booster dose may be administered at some time after the initial dose. The need for, and timing of, such booster dose will, of course, be determined within the sound judgment of the administrator of such vaccine or inoculum and according to sound principles well known in the art. For example, such booster dose could reasonably be expected to be advantageous at some time between about 2 weeks to about 6 months following the initial vaccination. Subsequent doses may be administered as indicated.

[0072] The nucleic acid sequences, viruses and polypeptides of the present invention can also be administered for purposes of therapy, where a mammal, especially a primate, and most especially a human, is already infected, as shown by well known diagnostic measures. When the nucleic acid sequences, viruses or polypeptides of the present invention are used for such therapeutic purposes, much of the same criteria will apply as when it is used as a vaccine, except that inoculation will occur post-infection. Thus, when the nucleic acid sequences, viruses or polypeptides of the present invention are used as therapeutic agents in the treatment of infection, the therapeutic agent comprises a pharmaceutical composition containing a sufficient amount of said nucleic acid sequences, viruses or polypeptides so as to elicit a therapeutically effective response in the organism to be treated. Of course, the amount of pharmaceutical composition to be administered will, as for vaccines, vary depending on the immunogen contained therein (nucleic acid, polypeptide, virus) and on the route of administration.

[0073] The therapeutic agent according to the present invention can thus be administered by subcutaneous, intramuscular or intradermal routes. One skilled in the art will certainly appreciate that the amounts to be administered for any particular treatment protocol can be readily determined without undue experimentation. Of course, the actual amounts will vary depending on the route of administration as well as the sex, age, and clinical status of the subject which, in the case of human patients, is to be determined with the sound judgment of the clinician.

[0074] The therapeutic agent of the present invention can be employed in such forms as capsules, liquid solutions, suspensions or elixirs, or sterile liquid forms such as solutions or suspensions. An inert carrier is preferably used, such as saline, phosphate-buffered saline, or any such carrier in which the HCV of the present invention can be suitably suspended. The therapeutic agents may be in the form of single dose preparations or in the multi-dose flasks which can be utilized for mass-treatment programs of both animals and humans. Of course, when the nucleic acid sequences, viruses or polypeptides of the present invention are used as therapeutic agents they may be administered as a single dose or as a series of doses, depending on the situation as determined by the person conducting the treatment.

[0075] The nucleic acids, polypeptides and viruses of the present invention can also be utilized in the production of antibodies against HCV. The term "antibody" is herein used to refer to immunoglobulin molecules and immunologically active portions of immunoglobulin molecules. Examples of antibody molecules are intact immunoglobulin molecules, substantially intact immunoglobulin molecules and portions of an immunoglobulin molecule, including those portions known in the art as Fab, F(ab')2 and F(v) as well as chimeric antibody molecules.

[0076] Thus, the polypeptides, viruses and nucleic acid sequences of the present invention can be used in the generation of antibodies that immunoreact (i.e., specific binding between an antigenic determinant-containing molecule and a molecule containing an antibody combining site such as a whole antibody molecule or an active portion thereof) with antigenic determinants on the surface of hepatitis C virus particles.

[0077] The present invention therefore also relates to antibodies produced following immunization with the nucleic acid sequences, viruses or polypeptides of the present invention. These antibodies are typically produced by immunizing a mammal with an immunogen or vaccine to induce antibody molecules having immunospecificity for polypeptides or viruses produced in response to infection with the nucleic acid sequences of the present invention. When used in generating such antibodies, the nucleic acid sequences, viruses, or polypeptides of the present invention may be linked to some type of carrier molecule. The resulting antibody molecules are then collected from said mammal.

[0078] Antibodies produced according to the present invention have the unique advantage of being generated in response to authentic, functional polypeptides produced according to the actual cloned HCV genome.

[0079] The antibody molecules of the present invention may be polyclonal or monoclonal. Monoclonal antibodies are readily produced by methods well known in the art. Portions of immunoglobin molecules, such as Fabs, as well as chimeric antibodies, may also be produced by methods well known to those of ordinary skill in the art of generating such antibodies.

[0080] The antibodies according to the present invention may also be contained in blood, plasma, serum, hybridoma supernatants, and the like. Alternatively, the antibody of the present invention is isolated to the extent desired by well known techniques such as, for example, using DEAE Sephadex. The antibodies produced according to the present invention may be further purified so as to obtain specific classes or subclasses of antibody such as IgM, IgG, IgA, and the like.

[0081] Antibodies of the IgG class are preferred for purposes of passive protection.

[0082] The antibodies of the present invention are useful in the prevention and treatment of diseases caused by hepatitis C virus in animals, especially mammals, and most especially humans.

[0083] In providing the antibodies of the present invention to a recipient mammal, preferably a human, the dosage of administered antibodies will vary depending on such factors as the mammal's age, weight, height, sex, general medical condition, previous medical history, and the like.

[0084] In general, it will be advantageous to provide the recipient mammal with a dosage of antibodies in the range of from about 1 mg/kg body weight to about 10 mg/kg body weight of the mammal, although a lower or higher dose may be administered if found desirable.

[0085] Such antibodies will normally be administered by intravenous or intramuscular route as an inoculum. The antibodies of the present invention are intended to be provided to the recipient subject in an amount sufficient to prevent, lessen or attenuate the severity, extent or duration of any existing infection.

[0086] The antibodies prepared by use of the nucleic acid sequences, viruses or polypeptides of the present invention are also highly useful for diagnostic purposes. For example, the antibodies can be used as in vitro diagnostic agents to test for the presence of HCV in biological samples taken from animals, especially humans. Such assays include, but are not limited to, radioimmunoassays, EIA, fluorescence, Western blot analysis and ELISAs. In one such embodiment, the biological sample is contacted with antibodies of the present invention and a labeled second antibody is used to detect the presence of HCV to which the antibodies are bound.

[0087] Such assays may be, for example, direct where the labeled first antibody is immunoreactive with the antigen, such as, for example, a polypeptide on the surface of the virus; indirect where a labeled second antibody is reactive with the first antibody; a competitive protocol such as would involve the addition of a labeled antigen; or sandwich where both labeled and unlabeled antibody are used, as well as other protocols well known and described in the art.

[0088] In one embodiment, an immunoassay method would utilize an antibody specific for HCV envelope determinants and would further comprise the steps of contacting a biological sample with the HCV-specific antibody and then detecting the presence of HCV material in the test sample using one of the types of assay protocols as described above. Polypeptides and antibodies produced according to the present invention may also be supplied in the form of a kit, either present in vials as purified material, or present in compositions and suspended in suitable diluents as previously described.

[0089] In a preferred embodiment, such a diagnostic test kit for detection of HCV antigens in a test sample comprises in combination a series of containers, each container a reagent needed for such assay. Thus, one such container would contain a specific amount of HCV-specific antibody as already described, a second container would contain a diluent for suspension of the sample to be tested, a third container would contain a positive control and an additional container would contain a negative control. An additional container could contain a blank.

[0090] For all prophylactic, therapeutic and diagnostic uses, the antibodies of the invention and other reagents, plus appropriate devices and accessories, may be provided in the form of a kit so-as to facilitate ready availability and ease of use.

[0091] The, present invention also relates to the use of nucleic acid sequences and polypeptides of the present invention to screen potential antiviral agents for antiviral activity against HCV. Such screening methods are known by those of skill in the art.

[0092] Generally, the antiviral agents are tested at a variety of concentrations, for their effect on preventing viral replication in cell culture systems which support viral replication, and then for an inhibition of infectivity or of viral pathogenicity (and a low level of toxicity) in an animal model system.

[0093] In one embodiment, animal cells (especially human cells) transfected with the nucleic acid sequences of the invention are cultured in vitro and the cells are treated with a candidate antiviral agent (a chemical, peptide etc.) by adding the candidate agent to the medium. The treated cells are then exposed, possibly under transfecting or fusing conditions known in the art, to the nucleic acid sequences of the present invention. A sufficient period of time would then be allowed to pass for infection to occur, following which the presence or absence of viral replication would be determined versus untreated control cells by methods known to those of ordinary skill in the art. Such methods include, but are not limited to, the detection of viral antigens in the cell, for example, by immunofluorescence procedures well known in the art; the detection of viral polypeptides by Western blotting using antibodies specific therefor; the detection of newly transcribed viral RNA within the cells by RT-PCR; and the detection of the presence of live, infectious virus particles by injection of cell culture medium or cell lysates into healthy, susceptible animals, with subsequent exhibition of the signs and symptoms of HCV infection. A comparison of results obtained for control cells (treated only with nucleic acid sequence) with those obtained for treated cells (nucleic acid sequence and antiviral agent) would indicate, the degree, if any, of antiviral activity of the candidate antiviral agent.

[0094] Of course, one of ordinary skill in the art would readily understand that such cells can be treated with the candidate antiviral agent either before or after exposure to the nucleic acid sequence of the present invention so as to determine what stage, or stages, of viral infection and replication said agent is effective against.

[0095] In an alternative embodiment, viral enzyme such as NS3 protease, NS2-NS3 protease, NS3 helicase or NS5B RNA polymerase may be produced from a nucleic acid sequence of the invention and used to screen for inhibitors which may act as antiviral agents. The structural and nonstructural regions of the HCV genome, including nucleotide and amino acid locations, have been determined, for example, as depicted in Houghton, M. 1996 Hepatitis C viruses. In Fields Virology (B. N. Fields, D. M. Knipe, P. M. Howley, et al., Eds.), Third ed., pp. 1035-1058. Lippincott-Raven Publishers, Philadelphia, FIG. 1; and Major, M. E. et al. (1997), Table 2.

[0096] Such above-mentioned protease inhibitors may take the form of chemical compounds or peptides which mimic the known cleavage sites of the protease and may be screened using methods known to those of skill in the art (Houghton, M. 1996 Hepatitis C viruses. In Fields Virology (B. N. Fields, D. M. Knipe, P. M. Howley, et al., Eds.), Third ed., pp. 1035-1058. Lippincott-Raven Publishers, Philadelphia; and Major, M.E. et al. 1997).

[0097] For example, a substrate may be employed which mimics the protease's natural substrate, but which provides a detectable signal (e.g., by fluorimetric or colorimetric methods) when cleaved. This substrate is then incubated with the protease and the candidate protease inhibitor under conditions of suitable pH, temperature etc. to detect protease activity. The proteolytic activities of the protease in the presence or absence of the candidate inhibitor are then determined.

[0098] In yet another embodiment, a candidate antiviral agent (such as a protease inhibitor) may be directly assayed in vivo for antiviral activity by administering the candidate antiviral agent to a chimpanzee transfected with a nucleic acid sequence of the invention or infected with a virus of the invention and then measuring viral replication in vivo via methods such as RT-PCR. Of course, the chimpanzee may be treated with the candidate agent either before or after transfection with the infectious nucleic acid sequence or infected with a virus of the invention so as to determine what stage, or stages, of viral infection and replication the agent is effective against.

[0099] The invention also provides that the nucleic acid sequences, viruses and polypeptides of the invention may be supplied in the form of a kit, alone or in the form of a pharmaceutical composition.

[0100] All scientific publication and/or patents cited herein are specifically incorporated by reference.

[0101] The following examples illustrate various aspects of the invention but are in no way intended to limit the scope thereof.

EXAMPLES

Materials and Methods

Source of HCV.

[0102] An infectious plasma pool of HCV genotype 2a (HC-J6.sub.CH) prepared from acute phase plasma of a chimpanzee experimentally inoculated with plasma from a Japanese patient infected with strain HC-J6 (Okamoto, H. et al. 1991 J. Gen. Virol. 72:2697-2704) was used for cloning. An infectious cDNA clone of HCV strain H77, genotype 1a was also used (pCV-H77C; Yanagi, M. et al. 1997 PNAS USA 94:8738-8743).

Amplification, Cloning and Sequence Analysis.

[0103] Viral RNA was extracted from 100 .mu.l aliquots of the HC7J6CH Plasma pool with the TRIzol system (GIBCO/BRL) (Yanagi, M. et al. 1997 PNAS USA 94:8738-8743). Primers used in cDNA synthesis and PCR amplification were based on the genomic sequence of strain HC-J6 (Okamoto, H. et al. 1991 J. Gen. Virol. 72:2697-2704) and from the conserved region (3'X) of the 3' UTR of HCV genotype 2a (Tanaka, T. et al. 1996 J. Virol. 70:3307-3312) (Table 1). The RNA was denatured at 65.degree. C. for 2 min, and cDNA was synthesized at 42.degree. C. for 1 hour with Superscript II reverse transcriptase (GIBCO/BRL) and specific reverse primers in 20 .mu.l reaction volumes. The cDNA mixtures 5- were treated with RNase H and RNase T1 (GIBCO/BRL) at 37.degree. C. for 20 min. TABLE-US-00001 TABLE 1 Oligonucleotides used for amplification and cloning of strain HC-J6.sub.CH, genotype 2a Designation Sequence (5'--> 3').sup.a 2427S-H77 ACTGGACACGGAGGTGGCCGCGTC (SEQ ID NO: 11) 2426S-H77 TTGTTCTTGTCGGGTTAATGGCGC (SEQ ID NO: 12) 2645R-H77 GGGTGTACTACACACATGAGTAAG (SEQ ID NO: 13) 2832R-H77 AAGCGCCCCTAACTGATGATG (SEQ ID NO: 14) H2751SII CGTCATCGATACCTCAGCGGGCATATGCACTGGACACGGA (SEQ ID NO: 15) H2786R GTCCAGTGCATATGCCCGCTGAGG (SEQ ID NO: 16) H2870R CATGCACCAGCTGATATAGCGCTTGTAATATG (SEQ ID NO: 17) H7851S TCCGTAGAGGAAGCTTGCAGCCTGACGGCC (SEQ ID NO: 18) H9140S (M) CAGAGGAGGCAGGGTGCTATATGTGGCAAGTAC (SEQ ID NO: 19) H9173R (M) GTACTTGCCACATATAGCAGCCCTGCCTCCTCTG (SEQ ID NO: 20) H9471R CGTCTCTAGACAGGAAATGGCTTAAGAGGCCGGAGTGTTTACC (SEQ ID NO: 21) J6-H2556S TTATGGATGCTCATCTTGTTGGGCCAGGCCGAAGCAGCTTTGGAGAACCTC (SEQ ID NO: 22) GTAATACT CAATGC 356RF-J6H AGGATTTGTGCTCATGGTGCACGGTCTACGAG (SEQ ID NO: 23) 1S-J6F.sup.b TTTTTTTTGCGGCCGCACCCGCCCCTAATAGG (SEQ ID NO: 24) 333S-J6 CCGTGCACCATGAGCACAAATCCTAAACCTC (SEQ ID NO: 25) 753R-J6 GGATGTACCCCATGAGGTCGGCAAAG (SEQ ID NO: 26) 2543S-J6F GTTTGCGCCTGCTTATGGATGCTCATCTTG (SEQ ID NO: 27) 2787R-J6(26) GCGTCATAAGCATATGCCTGTTGGGG (SEQ ID NO: 28) 3329R-J6 CCCTCAGCACTGGAGTACATCTG (SEQ ID NO: 29) 5487-J6F CGTCATGCATACCCCTAGGGCGGCTCTCATTGAAGAGGG (SEQ ID NO: 30) 5518R-J6F CGT6CCCTCTTCAATGAGAGCCGCTCTAGA (SEQ ID NO: 31) 9251S-J6F GCGGTGAAGACCAAGCTCAAACTCACTC (SEQ ID NO: 32) 9305R-J6F AATCTAGAAGGCGCGCTTCCGGCAATGGAGTGAGTTTGAGC (SEQ ID NO: 33) 9310R-J6F CGTCTCTAGAGGATAAATCCAGGAGGCGCGCTTCCGGC (SEQ ID NO: 34) 9399S-J6F TACTTTTTGTAGGGGTAGGCCTTTTCC (SEQ ID NO: 35) 9464-J6F CGTCTCTAGAGTGTAGCTAATGTGTGCCGCTCTA (SEQ ID NO: 36) 9470(24)-J6 CTATGGAGTGTAGCTAATGTGTGC (SEQ ID NO: 37) J6-3' XR CGTCTCTAGACATGATCTGCAGAGAGACCAGTTACGGCACTCTCTGFCAGT (SEQ ID NO: 38) CATGCGGCTCACGGACCTTTCACAGCTAGCCGTGACTAGGGCTAAGATGGA GCCACC .sup.aHCV-specific sequences are shown in plain text, non HCV-specific sequences are shown in bold face, and cleavage sites used for cDNA cloning are underlined. .sup.bThe core seciuence of the T7 promotor is shown in italics.

[0104] The strategy used to amplify and clone the full-length HC-J6.sub.CH sequence is shown in FIG. 1.

[0105] Nucleotide positions correspond to those of the 2a infectious clone (pJ6CF) that is described herein. The 5' end of HC-J6.sub.CH (nts. 17-297, excluding primer sequences) was amplified from 2 .mu.l of cDNA synthesized with primer a-2 (Yanagi, M. et al. 1996 J. Infect. Dis. 174:1324-1327). PCR was performed with AmpliTaq Gold DNA polymerase (Perkin-Elmer) as described previously (Yanagi, M. et al. 1996 J. Infect. Dis. 174:1324-1327) using primers 1S-J6F and a-2. After purification, the amplified products were cloned into pGEM-T Easy vector (Promega) using standard procedures and 5 clones (pJ6-5'UTR) were sequenced.

[0106] The 3' end of HC-J6.sub.CH was amplified in 3 overlapping pieces. RT-PCR of a short fragment of NS5B (nts. 9279-9439) was performed with primers 9251 S-J6F and 9464R-J6F as described above. The PCR products were cloned into pGEM-T Easy vector and sequence analysis was performed from 5 pJ6-3'F clones. A second region spanning from NS5B to the conserved region of the 3' UTR (nts. 9376-9629) was amplified in RT-nested PCR (external primers H9261F and H3'X58R, internal primers H9282F and H3'X45R) (Yanagi, M. et al. 1997 PNAS USA 94:8738-8743). The amplified products were cloned into pGEM-9zf(-) by using HindIII and XbaI sites and 14 pJ6-3'VR clones were sequenced. The third fragment, which included the 3' terminal sequence was amplified with primers 9399S-J6F and J6-3'XR from one of the pJ6-3'VR clones, and cloned into one of the pJ6-3'F clones by using StuI and XbaI sites (pJ6-3'X).

[0107] The ORF of HCV HC-J6.sub.CH was amplified by long RT-PCR in 3 overlapping pieces. The amplification was performed on 2 .mu.l of the cDNA mixtures with the Advantage cDNA polymerase mix (Clontech) (Yanagi, M. et al. 1997 PNAS USA 94:8738-8743). The J6S fragment (nts. 86-2761) was amplified--with primers a-1 (Yanagi, M. et al. 1996 J. Infect. Dis. 174:1324-1327) and J6-2787R from cDNA synthesized with primer J6-3329R. A single PCR round was performed in a Robocycler thermal cycler (Stratagene), and consisted of denaturation at 99.degree. C. for 35 sec, annealing at 67.degree. C. for 30 sec and elongation at 68.degree. C. for 4 min 30 sec during the first 5 cycles, 5 min during the next 10 cycles, 5 min 30 sec during the following 10 cycles and 6 min during the last 10 cycles.

[0108] The J6B fragment (nts. 2573-5488) was amplified with primers 2543S-J6F and 5518R-J6F from cDNA synthesized with primer 5518R-J6F. Finally, the J6A fragment (nts. 5515-9282) was amplified with primers 5487S-J6F and 9310R-J6F from cDNA synthesized with primer 9470R(24)-J6F. PCR amplifications of fragments J6B and J6A consisted of denaturation at 99.degree. C. for 35 sec, annealing at 67.degree. C. for 30 sec and elongation at 68.degree. C. for 6 min during the first 5 cycles, 7 min during the next 10 cycles, 8 min during the following 10 cycles and 9 min during the last 10 cycles.

[0109] After purification of the long PCR products with QIAquick PCR purification kit (QIAGEN), A-tailing reactions were performed with AmpliTaq DNA polymerase (Perkin Elmer) at 72.degree. C. for 1 hour. The gel-purified A-tailed PCR products were cloned into pCR2.1 vector (Invitrogen) or pGEM-T Easy vector (Promega). DH5-alpha competent cells (GIBCO BRL) were transformed and selected on LB agar plates containing 100 .mu.g/ml ampicillin (SIGMA) and amplified in LB liquid cultures at 30.degree. C. for 18-20 hrs (Yanagi, M. et al. 1997 PNAS USA 94:8738-8743) Midiprep was performed using Wizard Plus Midipreps DNA Purification System (Promega). Multiple clones of the J6S, J6A and the J6B fragments were sequenced.

[0110] The consensus sequence of strain HC-J6CH (nts. 17-9629) was determined by direct sequencing of PCR products (nts. 297-3004 and nts. 4893-5762) and by sequence analysis of the TA clones (nts. 17-5488 and nts. 5515-9629) (FIG. 1). Both strands of DNA were sequenced in all cases. Analyses of genomic sequences, including multiple sequence alignments and tree analyses, were performed with GeneWorks (Oxford Molecular Group) (Bukh, J. et al. 1995 Semin. Liver Dis. 15:41-63).

Construction of Chimeric cDNA Clones of Genotypes 1a & 2a.

[0111] Four full-length intertypic chimeric cDNA clones were constructed (FIGS. 4, 5A, 5B). In each clone the C, E1 and E2 genes encoded the consensus amino acid sequence of HC-J6.sub.CH. The p7 protein was encoded either by the HC-J6.sub.CH or pCV-H77C consensus sequence, and the NS proteins were all encoded by pCV-H77C genes. To engineer these cDNA clones, an NdeI site from pCV-H77C was first eliminated by a silent substitution (C to T) at position 9158. In brief, two fragments were amplified from pCV-H77C with primers H7851S and H9173R(M) and with primers H9140S(M) and H9417R (Table 3), gel-purified and used for fusion PCR with primers H7851S and H9417R. The fusion PCR products were cloned into pCV-H77C by using HindIII and AflII sites. A new artificial NdeI site was introduced by a silent substitution (C to T) at position 2765. PCR products, which were amplified from pCV-H77C with primer H2751SII containing artificial ClaI and NdeI sites and primer H2870R, were cloned into the modified pCV-H77C by using ClaI and Eco47111 sites. The final construct (pH77CV) was used as a cassette vector to construct the intertypic chimeric HCV cDNA clones.

[0112] The four chimeric cDNA clones were constructed as follows. pH77CV-J6S (nucleotide sequence shown in SEQ ID NO: 3 and amino acid sequence shown in SEQ ID NO: 4): The AgeI/BsmI fragment of clone J6S2 and the BsmI/NdeI fragment of clone J6S1, were cloned into pH77CV by using AgeI and NdeI sites; pH77 (p7)CV-J6S (nucleotide sequence shown in SEQ ID NO: 5 and amino acid sequence shown in SEQ ID NO: 6): A fragment of pH77CV-J6S was replaced with a fragment amplified from pCV-H77C with primers J6-H2556S and H2786R by using BsaBI and NdeI sites; J6S (nucleotide sequence shown in SEQ ID NO: 7 and amino acid sequence shown in SEQ ID NO: 8): A fragment amplified from pH77pCV-H77C with primers a-1 and 356RF-J6H77 and another fragment amplified from pH77CV-J6S with primers 333S-J6 and 753R-J6 were gel-purified and a fusion-PCR was performed with primers a-1 and 753R-J6. The AgeI/ClaI fragment of the subcloned fusion PCR products and the ClaI/NdeI fragment of pH77CV-J6S were cloned into pH77CV-J6S by using AgeI and NdeI sites; pH77(p7)-J6S (nucleotide sequence shown in SEQ ID NO: 9 and amino acid sequence shown in SEQ ID NO: 10). The AgeI/ClaI fragment of J6S and the ClaI/NdeI fragment of (p7)CV-J6S were cloned into pH77(p7)CV-J6S by using AgeI and NdeI sites.

[0113] Each intertypic chimeric cDNA clone was retransformed to select a single clone, and large-scale preparation of plasmid DNA was performed with a QIAGEN plasmid Maxi kit as described previously (Yanagi, M. et al. 1997 PNAS USA 94:8738-8743). Each of the four cDNA clones was completely sequenced before inoculation. Each clone was genetically stable since the digestion pattern was as expected following retransformation and the complete sequence was the expected one.

Construction of Full-Length cDNA Clone HC-J6.sub.CH.

[0114] An overview of the full-length HC-J6.sub.CH clone is presented in FIG. 1. In the final construct pJ6CF, which encodes the consensus polyprotein of HC-J6.sub.CH, an XbaI site was eliminated by a silent substitution (A to G) at position 5494. Digested fragments containing the consensus sequence were purified from the appropriate subclones and ligated using the sites indicated. The full-length cDNA clone (pJ6CF) was retransformed to select a single clone, and large-scale preparation of plasmid DNA followed by the complete sequence analysis was performed. Clone pJ6CF was genetically stable.

Intrahepatic Transfection of Chimpanzee with Transcribed RNA.

[0115] In duplicate 100 .mu.l reactions, RNA was transcribed in vitro with T7 RNA polymerase (Promega) from 10 .mu.g of template plasmid linearized with XbaI (Promega) as described previously (Yanagi, M. et al. 1997 PNAS USA 94:8738-8743).

[0116] The integrity of the RNA was checked by electrophoresis through agarose gel stained with ethidium bromide (Yanagi, M. et al. 1997 PNAS USA 94:8738-8743). Each transcription mixture was diluted with 400 .mu.l of ice-cold phosphate-buffered saline without calcium or magnesium and then immediately frozen on dry ice and stored at -80.degree. C. Within 24 hours, both transcription mixtures were injected into the same chimpanzee by percutaneous intrahepatic injection guided by ultrasound (Yanagi, M. et al. 1998 Virology 244:161-172; Yanagi, M. et al. 1999 PNAS USA 96:2291-2295). If the chimpanzee did not become infected, the same transfection was repeated once. After two negative results, the next clone was inoculated into the same chimpanzee following the same protocol. Injections were performed at weeks 0 and 2 with pH77CV-J6S, at weeks 5 and 8 with pH77(p7) CV-J6S, at weeks 14 and 16 with pH77-J6S, at weeks 19 and 23 with pH77(p7)-J6S, at week 28 with pJ6CF, and finally at week 34 with pCV-H77C.

[0117] The chimpanzee was maintained under conditions that met or exceeded all requirements for its use in an approved facility.

[0118] Serum samples were collected weekly from the chimpanzee and monitored for liver enzyme levels by standard procedures, anti-HCV antibodies by the second-generation ELISA (Abbott) and HCV RNA by a sensitive RT-nested PCR assay with AmpliTaq Gold DNA polymerase using primers from the 5' UTR (Yanagi, M. et al. 1996 J. Infect. Dis. 174:1324-1327). Samples were scored as negative for HCV RNA if two independent tests on 100 .mu.l of serum were negative.

[0119] The genome equivalent (GE) titer of HCV in positive samples was determined by RT-nested PCR on 10-fold serial dilutions of the extracted RNA (Bukh, J. et al. 1998 J. Infect. Dis. 178:1193-1197). The consensus sequence of the complete ORF from the chimpanzee infected with RNA transcripts of pJ6CF was determined by direct sequencing of overlapping PCR products obtained by long RT-nested PCR as previously described (Yanagi, M. et al. 1997 PNAS USA 94:8738-8743) with HC-J6 specific primers. After the intrahepatic transfection with RNA transcripts of pCV-H77C, we performed H77 (genotype 1a)-specific RT-nested PCR with primers 2427S-H77 and 2832R-H77 for the 1st round and with primers 2462S-H77 and 2645R-H77 for the 2nd round (Table 3). The sensitivity of this assay was equivalent to that of the assay using 5' UTR primers when testing serum containing only H77, genotype 1a. The genome titer of genotype 1a was determined by using this specific RT-nested PCR on 10-fold serial dilutions of the extracted RNA.

Example 1

Sequence Analysis of HCV Strain HC-J6.sub.CH

[0120] As minor deviations from the consensus amino acid sequence were found previously to render full-length HCV cDNA clones noninfectious (Yanagi, M. et al. 1997 PNAS USA 94:8738-8743; Yanagi, M. et al. 1998 Virology 244:161-172), the consensus sequence of the cloning source of genotype 2a (strain HC-J6.sub.CH) was determined prior to constructing any full-length clones. In brief, a plasma pool containing strain HC-J6.sub.CH was prepared from acute phase plasmapheresis units collected from a chimpanzee experimentally infected with HC-J6 (Okamoto, H. et al. 1991 J. Gen. Virol. 72:2697-2704). The HCV genome titer of this pool was 10.sup.5.4 genome equivalents (GE)/ml (Quantiplex HCV RNA bDNA 2.0, Chiron) and the infectivity titer was 10.sup.4 chimpanzee infectious doses/ml.

[0121] The consensus sequence of the 5' UTR of HC-J6.sub.CH (nts. 17-340) was deduced from 5 clones containing nts. 17-297 and 8 clones containing nts. 86-340. The 5' UTR of the various clones was highly conserved, but the consensus sequence of HC-J6.sub.CH differed by 2 nucleotides from that published previously for HC-J6 (Okamoto, H. et al. 1991 J. Gen. Virol. 72:2697-2704: C to T at position 36 and T to C at position 222).

[0122] The consensus sequence of 14 clones of the 3' UTR of HC-J6.sub.CH indicated that the 39 nucleotide long variable region was highly conserved in this strain and was identical to that previously published for HC-J6 (Okamoto, H. et al. 1991 J. Gen. Virol. 72:2697-2704). The polypyrimidine tract varied greatly in length (84-164 nucleotides), and contained some conserved A residues. In the conserved region, the proximal 16 nucleotides were identical to those previously published for isolates of different HCV genotypes (Kolykhalov, A. A. et al. 1996 J. Virol. 70:3363-3371; Tanaka, T. et al. 1996 J. Virol. 70:3307-3312; Yamada, N. et al. 1996 Virology 223:255-261). The remaining 82 nucleotides of the conserved region were determined for other genotype 2a strains (Tanaka, T. et al. 1996 J. Virol. 70:3307-3312) but not for HC-J6 or HC-J6.sub.CH.

[0123] The ORF of HC-J6.sub.CH was amplified in 3 fragments by RT-PCR (FIG. 1). Eight clones of the J6S fragment (nts. 86-2761), 6 clones of the J6B fragment (nts. 2573.5488) and 6 clones of the J6A fragment (nts. 5515-9298) were sequenced. PCR fragments containing nts. 5489-5514 were sequenced directly. A quasispecies was found at 243 nucleotide (2.7%) and 69 amino acid (2.3%) positions, scattered throughout the 9099 nts (3033 aa) of the ORF. However, the majority, 231 nucleotide substitutions, were detected only once and 71.6% of these represented silent mutations. The 12 remaining nucleotide substitutions were each restricted to 2 clones and only 4 of these resulted in amino acid changes. The nucleotide difference among the J6S clones ranged from 0.1-1.3%, among the J6B clones it ranged from 0.1-0.3%, and it ranged from 0.2-4.0% among the J6A clones (FIG. 2). Three of 8 J6S clones, 4 of 6 J6B clones, and all 6 J6A clones had defective polyproteins due to nucleotide deletions, insertions or substitutions.

[0124] The sequences of clones of strain HC-J6.sub.CH were relatively homogeneous. This was highlighted by the high degree of conservation among clones of the HVR1 (FIG. 3), a region frequently used to study the quasispecies of HCV (Bukh, J. et al. 1995 Semin. Liver Dis. 15:41-63). An exception was the sequence of clone J6A1, which differed by about 4% from the other clones of this region (FIG. 2).

[0125] Importantly, the consensus sequence of strain HC-J6.sub.CH (nts. 17-9629) could be determined with no ambiguity at the nucleotide or deduced amino acid level. The difference between the consensus ORF sequence of HC-J6.sub.CH from the experimentally infected chimpanzee and that of HC-J6 of the inoculum (Okamoto, H. et al. 1991 J. Gen. Virol. 72:2697-2704) was 4.1% and 2.2% at the nucleotide and deduced amino acid levels, respectively (FIG. 2, Table 2). Moreover, we found that 12 (44.4%) of the 27 amino acids constituting HVR1 differed between HC-J6.sub.CH and HC-J6 (FIG. 3). Such diversities are greater than the <2% generally considered to comprise a quasispecies. In fact, these differences are equivalent to those found between the two prototype strains of HCV genotype 1a [strains HCV-1 (Choo, Q.-L et al. 1991 PNAS USA 88:2451-2455) and H77 (Yanagi, M. et al. 1997 PNAS USA 94:8738-8743)].

[0126] These results indicated that HC-J6CH, which represented the major species in the experimentally infected chimpanzee, was a minor species in the original inoculum. TABLE-US-00002 TABLE 2 Percent difference of nucleotide and predicted amino acid sequences between strain HC-J6 (Okamoto, H. et al. 1991 J. Gen. Virol. 72: 2697-2704) and strain HC-J6.sub.CH from acute phase plasma pool of a chimpanzee inoculated with HC-J6 Genome nt. % nt. % a.a. Region position.sup.a difference difference ORF 341-9439 4.1 (373/9099).sup.b 2.2 (66/3033).sup.b 5' UTR 17-340 0.6 (2/324) Core 341-913 0.5 (3/573) 0 (0/191) E1 914-1489 4.3 (25/576) 2.1 (4/192) HVR1 1490-1570 24.7 (20/81) 44.4 (12/27) E2_HVR1 1571-2590 3.9 (40/1020) 3.2 (11/340) p7 2591-2779 3.7 (7/189) 3.2 (2/63) NS2 2780-3430 4.0 (26/651) 2.8 (6/217) NS3 3431-5323 4.0 (76/1893) 0.8 (5/631) NS4A 5324-5485 4.3 (7/162) 1.9 (1/54) NS4B 5486-6268 3.7 (29/783) 0.4 (1/261) NS5A 6269-7666 5.4 (75/1398) 3.4 (16/466) NS5B 7667-9439 3.7 (65/1773) 1.4 (8/591) 3' UTR 9440-9481 0 (0/42) .sup.aThe nucleotide positions correspond to those of the infectious full-length genotype 2a clone (pJ6CF). .sup.bThe numbers in parenthesis indicate the nucleotide or amino acid differences for each region.

Chimeric Molecular Clones

[0127] As chimeric flaviviruses with substituted structural genes have been useful in defining the biological function of viral sequences or proteins, in analyzing immune responses and in generating attenuated vaccine candidates (Bray, M. and Lai, C.-J. 1991 PNAS USA 88:10342-10346; Chambers T. J et al. 1999 J. Virol. 73:3095-3101; Pletnev, A. G. 1992 PNAS USA 89:10532-10536, Pletnev, A. G. 1993. J. Virol. 67:4956-4963, Pletnev, A. G. and Men, R. 1998 PNAS USA 95:1746-1751). The consensus sequence of the 2a structural genes and surrounding region was substituted for that of the infectious 1a cDNA clone. In the genotype 1a backbone, two silent mutations were introduced for cloning purposes [at positions 2765 (p7) and 9158 (NS5B) of pCV-H77C]; (FIG. 4). The complete sequence of each chimera was verified. Infectivity of RNA transcripts from four different intertypic chimeric clones (FIGS. 4, 5A, 5B) was evaluated by consecutive intrahepatic transfections of a chimpanzee. Clones were considered not to be viable if viral RNA was not detected in the serum within two weeks of the repeat transfection. All chimeric clones contained the C, E1 and E2 genes of genotype 2a. The two chimeric clones tested initially differed from each other in that one had the p7 gene of 2a (pH77CV-J6S) and the other [pH77(p7)CV-J6S] the p7 gene of 1a. They differed from the two other clones in that the 186 nucleotides of the 5' UTR just upstream of the initiation codon were from the 2a genotype. Since neither clone containing the chimeric 5' UTR was infectious, the chimeric 5' UTR was replaced with the consensus genotype 1a 5' UTR to generate the two p7 varieties [pH77-J6S and PH77(p7)-J6S]. After consecutive transfection of the four clones, no HCV RNA, anti-HCV or ALT elevation was detected in the chimpanzee during 28 weeks of follow-up, suggesting that RNA transcripts from these intertypic chimeric clones were not viable in vivo.

[0128] This finding that the intertypic clones between genotypes 1a and 2a were not viable was surprising since flavivirus chimeras containing the structural region of dengue virus type 1 or 2 or of tick-borne encephalitis virus and the nonstructural region of an infectious dengue type 4 virus were viable (Bray, M. and Lai, C.-J. 1991 PNAS USA 88:10342-10346; Pletnev, A. G. 1992 PNAS USA 89:10532-10536, Pletnev, A. G. 1993. J. Virol. 67:4956-4963). While considerable sequence variation exists between the infectious genotype 1a and 2a clones of HCV (Table 3), these viruses exhibit a higher degree of genetic heterogeneity than do the major genotypes of HCV. For other flaviviruses, however, it was possible to obtain infectious chimeric clones only if the capsid region was derived from the backbone cDNA clone (Chambers T. J et al. 1999 J. Virol. 73:3095-3101; Pletnev, A. G. and Men, R. 1998 PNAS USA 95:1746-1751). TABLE-US-00003 TABLE 3 Percent difference of the amino acid sequences between the infectious clone of genotype 1a (pCV-H77C; Yanagi, M. et al. 1997 PNAS USA 94: 8738-8743) and the infectious clone of genotype 2a (pJ6CF) of hepatitis C virus Genome Region.sup.a % difference Polyprotein 27.9 (839/3007).sup.b Core 8.9 (17/191) E1 37.0 (71/192) HVR1 59.3 (16/27) E2-.sub.HVR1 27.1 (91/336) p7 38.1 (24/63) NS2 41.9 (91/217) NS3 19.2 (121/631) NS4A 33.3 (18/54) NS4B 26.8 (70/261) NS5A 38.5 (171/444) NS5B 25.2 (149/591) .sup.aGenome regions defined as in Table 1. .sup.bThe numbers in parenthesis indicate the amino acid differences for each region. Positions with deletions or insertions in E2 (4 aa positions) and NS5A (26 aa positions) were not considered.

[0129] Trivial explanations may account for the lack of viability of these intertypic chimeras. First, the two silent mutations introduced in the genotype 1a backbone (one in p7 and one in NS5B) for cloning purposes could potentially eliminate infectivity. This is, however, very unlikely since mutations at these positions exist among field isolates of HCV including strain HC-J6.sub.CH (Bukh, J. et al. 1998 J. Infect. Dis. 178:1193-1197). Also, it is noteworthy that the three previously published infectious clones of strain H77 had numerous silent nucleotide differences (Hong, Z. et al. 1999 Virology 256:36-44; Kolykhalov, A. A. et al. 1997 Science 277:570-574; Yanagi, M. et al. 1997 PNAS USA 94:8738-8743). Second, signal peptidases might not cleave the chimeric E2/p7 or p7/NS2 junction. This seems unlikely, however, since eukaryotic signal peptidases typically recognize the amino acid sequences upstream of the cleavage site [the (-3, -1) rule] (Nielsen, H. et al. 1997 Protein Eng. 10:1-6) and the amino acids at these two sites are conserved between genotypes 1a and 2a (FIG. 5B). Finally, the E2/p7 and/or p7/NS2 gene junctions could differ between genotypes 1a and 2a.

[0130] The junctions determined for genotypes 1a and 1b were used (Lin, C. et al. 1994 J. Virol. 68:5063-5073; Mizushima, H. et al. 1994 J. Virol. 68:6215-6222; Selby, M. J. et al. 1994 Virology 204:114-122) because those for genotype 2a have not been identified. In the latter two cases, further analyses of genotype 2a should eventually provide sufficient data to overcome such potential problems and it would most likely be possible to construct a viable chimera.

[0131] More complicated explanations for the lack of viability of the chimeras might be required if critical genotype-specific interactions occur as regards the structural proteins, the nonstructural proteins and the genomic RNA. For instance, one cannot rule out that the chimeras were not viable because the IRES function was compromised. In in vitro studies the IRES activity depended on RNA sequences not only in the 5' UTR but also extending 3' of the translation initiation site (Hahm, B. et al. 1998 J. Virol. 72:8782-8788; Lemon, S. M and Honda, M. 1997 Semin. Virol. 8:274-288; Reynolds, J. E. et al. 1995 EMBO J. 14:6010-6020). Although the 3' border of the HCV IRES is still controversial it is believed to involve at most the first 39 nts of the core gene (Lemon, S. M and Honda, M. 1997 Semin. Virol. 8:274-288). The 5' UTR of the intertypic chimeras was either a chimera of genotype 1a and 2a sequences or the entire 5' UTR was derived from the la clone (FIGS. 4, 5A).

[0132] Importantly, the 5' end of core is conserved among genotypes 1a and 2a (FIG. 5A). Thus, the predicted IRES-like secondary structure is maintained in these chimeras, suggesting that the IRES activity most likely was maintained.

[0133] Possible interactions between the structural proteins and the nonstructural proteins and/or the genomic RNA, which involve RNA packaging, replication or translation are conceivable. In poliovirus, which is another positive-sense RNA virus, functional coupling of RNA packaging to RNA replication and of RNA replication to translation have been suggested (Novak, J. E. and Kirkegaard, K. 1994 Genes Dev. 8:1726-1737; Nugent, C. I. et al. 1999 J. Virol. 73:427-435). Similar to other viruses of the Flaviviridae family, a membrane-associated replicase complex is thought to initiate replication at the 3' end of HCV and to synthesize a complementary negative-strand RNA (Rice, C. M. 1996 Flaviviridae: The viruses and their replication, In Fields Virology (B. N. Fields, D. M. Knipe, P. M. Howley, et al., Eds.), Third ed., pp. 931-959. Lippincott-Raven Publishers, Philadelphia). The putative cis-acting elements at the 5' and 3' termini which are believed to be important for viral genome replication (Rice, C. M. 1996 Flaviviridae: The viruses and their replication, In Fields Virology (B. N. Fields, D. M. Knipe, P. M. Howley, et al., Eds.), Third ed., pp. 931-959. Lippincott-Raven Publishers, Philadelphia; Frolov, I. et al. 1998 RNA 4:1418-1435) should be maintained in the intertypic HCV chimeras at least in the two constructs with the authentic 1a 5'UTR.

[0134] However, it is conceivable that the viral packaging system was interrupted (Frolov, I. et al. 1998 RNA 4:1418-1435). Studies using a Kunjin flavivirus replicon system and providing the structural proteins in trans suggested that the essential encapsidation signals did not reside in the structural region of the genome (Khromykh, A. A. and Westaway, E. G. 1997 J. Virol. 71:1497-1505, Khromykh, A. A. et al. 1998 J. Virol. 72:5967-5977). The location of the packaging signals of HCV is not known. However, if the structural proteins encapsidate viral RNA via genotype-specific sequences outside of the structural region, the chimeras would be unable to package the RNA and it might be extremely difficult to construct viable chimeras between highly divergent strains.

Example 3

A Consensus Molecular Clone of Genotype 2a is Infectious in vivo

[0135] In order to prove that the genotype 2a portion used in the 4 intertypic chimeric cDNA clones indeed represented the infectious sequence, a consensus full-length cDNA clone of HC-J6.sub.CH (pJ6CF) was constructed. The core sequence of the T7 promoter, a 5' guanosine residue and the full-length sequence of HC-J6.sub.CH (9711 nts) were cloned into pGEM-9Zf vector using NotI/XbaI sites. Within the HCV sequence there were no deduced amino acid differences and only 4 nucleotide differences (at nucleotide positions 1822, 5494, 9247 and 9289) from the consensus sequence of HC-J6.sub.CH as determined in the present study. The silent mutation at position 1822 was within the structural region and so was al. so-present in the four intertypic chimeras. The 5' terminal 16 nts and the 3' terminal 82 nts were deduced from previously published HCV genotype 2a sequences (Okamoto, H. et al. 1991 J. Gen. Virol. 72:2697-2704, Tanaka, T. et al. 1996 J. Virol. 70:3307-3312). The full-length cDNA clone of genotype 2a contained a 5' UTR of 340 nts, an ORF of 9099 nts encoding 3033 amino acids and a 3' UTR consisting of a variable region of 39 nts followed by a 132 nucleotide-long polypyrimidine tract interrupted with 3 A residues and the 3' terminal conserved region of 98 nts.

[0136] RNA transcripts from pJ6CF were injected into the same chimpanzee used for injection of the 4 intertypic chimeras. The chimpanzee became infected at the first attempt with an HCV titer of 10.sup.2 GE/ml at week 1 post inoculation (p.i.), and 10.sup.3-10.sup.4 GE/ml during weeks 2 to 6 p.i. The consensus sequence of PCR products of the complete ORF, amplified from serum obtained during week 5 p.i., was identical to the sequence of pJ6CF and there was no evidence of a quasispecies. Since RNA transcripts of this infectious genotype 2a clone were infectious in vivo, and it shared an exact sequence with the non-infectious intertypic chimeric clones, their failure to replicate must have been the result of incompatibilities between the genotype 1a and 2a sequences.

[0137] To confirm that the chimpanzee used was susceptible also to infection by genotype 1a, which comprised most of the intertypic chimeras, the chimpanzee was subsequently inoculated with RNA transcripts from the infectious genotype 1a clone (pCV-H77C). Serum samples were tested in an H77-specific RT-PCR assay to identify super-infection with genotype 1a. At week 1 p.i. the total HCV genome titer was 10.sup.4 GE/ml and the H77-specific (1a) genome titer was 10.sup.2 GE/ml. The H77-specific genome titer increased to 10.sup.3 GE/ml at week 2 p.i., and reached 10.sup.4 GE/ml during weeks 3-6 p.i. The consensus sequence of PCR products amplified with H77-specific primers at weeks 1-6 p.i. were found to be identical to that of pCV-H77C. However, the direct sequences of PCR products amplified with the 5' UTR primers at weeks 1-2 after inoculation of pCV-H77C were identical to that of pJ6CF indicating that the 2a genotype was still present and represented the majority species. These experiments confirmed that the inability of the intertypic 1a, 2a cDNA clones to infect the chimpanzee was not the result of protective immune responses in the chimpanzee but represented deficiencies intrinsic to the chimeras.

Discussion

[0138] The published infectious cDNA clones of HCV represent the two most important subtypes of genotype 1 (Hong, Z. et al. 1999 Virology 256:36-44; Kolykhalov, A. A. et al. 1997 Science 277:570-574; Yanagi, M. et al. 1997 PNAS USA 94:8738-8743, Yanagi, M. et al. 1998 Virology 244:161-172). However, 5 more major genotypes of HCV are recognized. In the above Examples, the infectivity of a cDNA clone of a second major HCV genotype was demonstrated. As in previous studies, the infectivity of RNA transcripts was demonstrated in vivo by intrahepatic transfection of a chimpanzee. This new infectious clone (pJ6CF) encodes the consensus polyprotein of HCV strain HC-J6.sub.CH, genotype 2a. Its encoded polyprotein differs from those of the infectious clones of genotypes 1a and 1b by approximately 30% (Table 2). Genotype 2 strains, in particular subtypes 2a and 2b, have a worldwide distribution and important differences between genotypes 1 and 2 with respect to pathogenesis and treatment were indicated in previous studies. The availability of an infectious clone representing a second major genotype of HCV should permit new ways of studying the molecular biology and immunopathology of this important and genetically quite different human pathogen.

[0139] The 5' and 3' UTRs of HCV are believed to be critical for viral replication, translation and viral packaging (Rice, C. M. 1996 Flaviviridae: The viruses and their replication, In Fields Virology (B. N. Fields, D. M. Knipe, P. M. Howley, et al., Eds.), Third ed., pp. 931-959. Lippincott-Raven Publishers, Philadelphia). The 5' 203 terminal nucleotides and the 3' 101 terminal nucleotides of the published infectious clones of genotypes 1a and 1b were identical.

[0140] However, the sequences of UTRs of the genotype 2a clone differ from those of the genotype 1 clones. Overall, the 5' UTR of the genotype 2a clone has 17 nt differences and a single nucleotide deletion compared with the infectious clones of genotype 1a (FIG. 5A).

[0141] Five of these differences and the deletion are within the first 30 nucleotides, whereas the remainder are found within the predicted IRES structure. Differences also exist between the 3' UTR of the genotype 2a clone and the clones of genotype 1a (FIG. 5B). The sequences of the variable region are very different. Recent study has shown this region is not critical for infectivity in vivo (Yanagi, M. et al. 1999 PNAS USA 96:2291-2295). Within the regions which are critical for infectivity in vivo (Yanagi, M. et al. 1999 PNAS USA 96:2291-2295), the 132 nucleotide-long polypyrimidine tract of the genotype 2a clone has 3 unique A residues interspersed and the 3' terminal conserved region of 98 nts has 4 nt differences within the 3' terminal stable stem-loop structure (FIG. 5B) (Kolykhalov, A. A. et al. 1996 J. Virol. 70:3363-3371; Tanaka, T. et al. 1996 J. Virol. 70:3307-3312). Since the 2a clone was infectious these sequence differences are apparently real and are compatible with infectivity. Further studies are required to determine whether these represent critical genotype-specific sequences.

Sequence CWU 1

1

70 1 9711 DNA Hepatitis C virus 1 acccgcccct aataggggcg acactccgcc atgaatcact cccctgtgag gaactactgt 60 cttcacgcag aaagcgtcta gccatggcgt tagtatgagt gtcgtacagc ctccaggccc 120 ccccctcccg ggagagccat agtggtctgc ggaaccggtg agtacaccgg aattgccggg 180 aagactgggt cctttcttgg ataaacccac tctatgcccg gccatttggg cgtgcccccg 240 caagactgct agccgagtag cgttgggttg cgaaaggcct tgtggtactg cctgataggg 300 tgcttgcgag tgccccggga ggtctcgtag accgtgcacc atgagcacaa atcctaaacc 360 tcaaagaaaa accaaaagaa acaccaaccg tcgcccacaa gacgttaagt ttccgggcgg 420 cggccagatc gttggcggag tatacttgtt gccgcgcagg ggccccaggt tgggtgtgcg 480 cgcgacaagg aagacttcgg agcggtccca gccacgtgga aggcgccagc ccatccctaa 540 agatcggcgc tccactggca aatcctgggg aaaaccagga tacccctggc ccctatacgg 600 gaatgaggga ctcggctggg caggatggct cctgtccccc cgaggttccc gtccctcttg 660 gggccccaat gacccccggc ataggtcgcg caacgtgggt aaggtcatcg ataccctaac 720 gtgcggcttt gccgacctca tggggtacat ccctgtcgtg ggcgccccgc tcggcggcgt 780 cgccagagct ctcgcgcatg gcgtgagagt cctggaggac ggggttaatt ttgcaacagg 840 gaacttaccc ggttgctcct tttctatctt cttgctggcc ctgctgtcct gcatcaccac 900 cccggtctcc gctgccgaag tgaagaacat cagtaccggc tacatggtga ctaacgactg 960 caccaatgac agcattacct ggcagctcca ggctgctgtc ctccacgtcc ccgggtgcgt 1020 cccgtgcgag aaagtgggga atgcatctca gtgctggata ccggtctcac cgaatgtggc 1080 cgtgcagcgg cccggcgccc tcacgcaggg cttgcggacg cacatcgaca tggttgtgat 1140 gtccgccacg ctctgctctg ccctctacgt gggggacctc tgcggtgggg tgatgctcgc 1200 agcccaaatg ttcattgtct cgccgcagca ccactggttt gtccaagact gcaattgctc 1260 catctaccct ggtaccatca ctggacaccg catggcatgg gacatgatga tgaactggtc 1320 gcccacggct accatgatct tggcgtacgc gatgcgtgtc cccgaggtca ttatagacat 1380 cattagcggg gctcattggg gcgtcatgtt cggcttggcc tacttctcta tgcagggagc 1440 gtgggcgaaa gtcgttgtca tccttctgtt ggccgccggg gtggacgcgc gcacccatac 1500 tgttgggggt tctgccgcgc agaccaccgg gcgcctcacc agcttatttg acatgggccc 1560 caggcagaaa atccagctcg ttaacaccaa tggcagctgg cacatcaacc gcaccgccct 1620 gaactgcaat gactccttgc acaccggctt tatcgcgtct ctgttctaca cccacagctt 1680 caactcgtca ggatgtcccg aacgcatgtc cgcctgccgc agtatcgagg ccttccgggt 1740 gggatggggc gccttgcaat atgaggataa tgtcaccaat ccagaggata tgagacccta 1800 ttgctggcac tacccaccaa ggcagtgtgg cgtggtctcc gcgaagactg tgtgtggccc 1860 agtgtactgt ttcaccccca gcccagtggt agtgggcacg accgacaggc ttggagcgcc 1920 cacttacacg tggggggaga atgagacaga tgtcttccta ttgaacagca ctcgaccacc 1980 gctggggtca tggttcggct gcacgtggat gaactcttct ggctacacca agacttgcgg 2040 cgcaccaccc tgccgtacta gagctgactt caacgccagc acggacctgt tgtgccccac 2100 ggactgtttt aggaagcatc ctgataccac ttacctcaaa tgcggctctg ggccctggct 2160 cacgccaagg tgcctgatcg actaccccta caggctctgg cattacccct gcacagttaa 2220 ctataccatc ttcaaaataa ggatgtatgt gggaggggtt gagcacaggc tcacggctgc 2280 atgcaatttc actcgtgggg atcgttgcaa cttggaggac agagacagaa gtcaactgtc 2340 tcctttgttg cactccacca cggaatgggc cattttacct tgctcttact cggacctgcc 2400 cgccttgtcg actggtcttc tccacctcca ccaaaacatc gtggacgtac aattcatgta 2460 tggcctatca cctgccctca caaaatacat cgtccgatgg gagtgggtaa tactcttatt 2520 cctgctctta gcggacgcca gggtttgcgc ctgcttatgg atgctcatct tgttgggcca 2580 ggccgaagca gcactagaga agctggtcat cttgcacgct gcgagcgcag ctagctgcaa 2640 tggcttccta tattttgtca tctttttcgt ggctgcttgg tacatcaagg gtcgggtagt 2700 ccccttagct acctattccc tcactggcct gtggtccttt agcctactgc tcctagcatt 2760 gccccaacag gcttatgctt atgacgcatc tgtgcatggc cagataggag cggctctgct 2820 ggtaatgatc actctcttta ctctcacccc cgggtataag acccttctca gccggttttt 2880 gtggtggttg tgctatcttc tgaccctggg ggaagctatg gtccaggagt gggcaccacc 2940 tatgcaggtg cgcggtggcc gtgatggcat catatgggcc gtcgccatat tctacccagg 3000 tgtggtgttt gacataacca agtggctctt ggcggtgctt gggcctgctt acctcctaaa 3060 aggtgctttg acgcgcgtgc cgtacttcgt cagggctcac gctctactga ggatgtgcac 3120 catggcaagg catctcgcgg ggggcaggta cgtccagatg gcgctactag cccttggcag 3180 gtggactggc acttacatct atgaccacct cacccctatg tcggattggg ctgctagtgg 3240 cctgcgggac ctggcggtcg ccgttgagcc tatcatcttc agtccgatgg agaagaaagt 3300 cattgtctgg ggagcggaga cagctgcttg tggggacatt ttacacggac ttcccgtgtc 3360 cgcccgactt ggtcgggagg tcctccttgg cccagctgat ggctatacct ccaaggggtg 3420 gagtcttctc gcccccatca ctgcttacgc ccagcagaca cgtggccttt tgggcaccat 3480 agtggtgagc atgacggggc gcgacaagac agaacaggct ggggaaattc aggtcctgtc 3540 cacagtcact cagtccttcc tcggaacatc catctcgggg gttttgtgga ctgtctacca 3600 tggagctggc aacaagactc tggccggctc acggggtccg gtcacgcaga tgtactccag 3660 tgctgagggg gacttagtag ggtggcccag cccccctggg actaaatctt tggagccgtg 3720 cacgtgtgga gcggtcgacc tgtacctggt cacgcggaac gctgatgtca tcccggctcg 3780 aagacgcggg gacaaacggg gagcgctact ctccccgaga cctctttcca ccttgaaggg 3840 gtcctcagga ggcccggtgc tatgccccag gggccacgct gtcggagtct tccgggcagc 3900 tgtgtgctct cggggcgtgg ctaagtccat agatttcatc cccgttgaga cactcgacat 3960 cgtcacgcgg tcccccacct ttagtgacaa cagcacacca cctgctgtgc cccagaccta 4020 tcaggtcggg tacttgcatg ccccgactgg cagtggaaag agcaccaaag ttcctgtcgc 4080 atatgctgct caggggtata aagtgctagt gcttaatccc tcagtggctg ccaccctggg 4140 gtttggggcg tacttgtcta aggcacatgg catcaatccc aacattagga ctggagtcag 4200 gactgtgacg accggggcgc ccatcacgta ctccacatat ggcaaattcc tcgccgatgg 4260 gggctgtgcg ggcggcgcct acgacatcat catatgtgat gaatgccatg ccgtggactc 4320 taccaccatc cttggcatcg gaacagtcct tgatcaagca gagacagctg gggtcagact 4380 aactgtgctg gctacagcta cgccccctgg gtcagtgaca accccccacc ccaacataga 4440 ggaggtggcc cttgggcagg agggcgagat ccccttctat gggagggcga ttcccctgtc 4500 ttacatcaag ggaggaagac atctgatctt ctgccattca aagaaaaagt gtgacgagct 4560 cgcggcggcc cttcggggta tgggcttgaa ctcagtggca tactacagag ggttggacgt 4620 ctccgtaata ccaactcagg gagacgtagt ggtcgtcgcc accgacgccc tcatgacagg 4680 gtatactggg gactttgact ccgtgatcga ctgcaacgta gcggtcactc aagttgtaga 4740 cttcagttta gaccccacat tcaccataac cacacagatt gtccctcaag acgctgtctc 4800 acgtagccag cgccggggtc gcacgggtag gggaagactg ggcatttata ggtatgtttc 4860 cactggtgag cgagcctcag gaatgtttga cagtgtagtg ctctgtgagt gctacgacgc 4920 aggggccgca tggtatgagc tcacaccatc ggagaccacc gtcaggctca gggcgtattt 4980 caacacgccc ggtttgcctg tgtgccaaga ccatcttgag ttttgggagg cagttttcac 5040 cggcctcaca cacatagatg cccacttcct ttcccaaaca aagcaatcgg gggaaaattt 5100 cgcatactta acagcctacc aggctacagt gtgcgctagg gccaaagccc cccccccgtc 5160 ctgggacgtc atgtggaagt gtttgactcg actcaagccc acactcgtgg gccccacacc 5220 tctcctgtac cgcttgggct ctgttaccaa cgaggtcacc ctcacacatc ccgtgacgaa 5280 atacatcgcc acctgcatgc aagccgacct tgaggtcatg accagcacat gggtcttggc 5340 agggggagtc ttggcggccg tcgccgcgta ttgcctggcg accgggtgtg tttgcatcat 5400 cggccgcttg cacattaacc agcgagccgt cgttgcgccg gacaaggagg tcctctatga 5460 ggcttttgat gagatggagg aatgtgcctc tagggcggct ctcattgaag aggggcagcg 5520 gatagccgag atgctgaagt ccaagatcca aggcttattg cagcaagctt ccaaacaagc 5580 tcaagacata caacccactg tgcaggcttc atggcccaag gtagaacaat tctgggccaa 5640 acacatgtgg aacttcatta gcggcatcca atacctcgca ggactatcaa cactgccagg 5700 gaaccctgca gtagcttcca tgatggcgtt cagtgccgcc ctcaccagtc cgctgtcaac 5760 aagcaccact atccttctca acattttggg gggctggcta gcatcccaaa ttgcaccacc 5820 cgcgggggcc actggcttcg ttgtcagtgg cctagtggga gctgccgtag gcagtatagg 5880 cttaggtaag gtgctagtgg acatcctggc agggtatggt gcgggcattt cgggggctct 5940 cgtcgcattc aagatcatgt ctggcgagaa gccctccatg gaggatgtcg tcaacttgct 6000 gcctggaatt ctgtctccgg gtgccttggt agtgggagtc atctgcgcgg ccattctgcg 6060 ccgacacgtg ggaccggggg aaggcgccgt ccaatggatg aatagactca ttgcctttgc 6120 ttccagagga aatcacgtcg cccccaccca ctacgtgacg gagtcggatg cgtcgcagcg 6180 tgtgacccaa ctacttggct cccttaccat aaccagcctg ctcagaagac tccacaactg 6240 gattactgag gactgcccca tcccatgcgg cggctcgtgg ctccgcgatg tgtgggactg 6300 ggtttgcacc atcctaacag actttaaaaa ttggctgacc tccaaattat tcccaaagat 6360 gcccggcctc ccctttgtct cctgtcaaaa ggggtacaag ggcgtgtggg ccggcactgg 6420 catcatgacc acacggtgtc cttgcggcgc caatatctct ggcaatgtcc gcttgggctc 6480 catgagaatc acggggccta agacctgcat gaatatctgg caggggacct ttcctatcaa 6540 ttgttacacg gagggccagt gcgtgccgaa acccgcgcca aactttaagg tcgccatctg 6600 gagggtggcg gcctcagagt acgcggaggt gacgcagcac gggtcatacc actacataac 6660 aggactcacc actgataact tgaaagtccc ctgccaacta ccctctcccg agttcttttc 6720 ctgggtggac ggagtgcaga tccataggtt tgcccccaca ccgaagccgt ttttccggga 6780 tgaggtctcg ttctgcgttg ggcttaattc atttgtcgtc gggtcccagc ttccttgcga 6840 ccctgaaccc gacacagacg tattgatgtc catgctaaca gatccatctc atatcacggc 6900 ggagactgca gcgcggcgtt tagcgcgggg gtcaccccca tccgaggcaa gctcctcggc 6960 gagccagcta tcggcaccat cgctgcgagc cacctgcacc acccacggca aagcctatga 7020 tgtggacatg gtggatgcta acctgttcat ggggggcgat gtgactcgga tagagtctgg 7080 gtccaaagtg gtcgttctgg actctctcga cccaatggtc gaagaaagga gcgaccttga 7140 gccttcgata ccatcagaat acatgctccc caagaagagg ttcccaccag ctttaccggc 7200 ctgggcacgg cctgattaca acccaccgct tgtggaatcg tggaaaaggc cagattacca 7260 accggccact gttgcgggct gtgctctccc tcctcctagg aaaaccccga cgcctccccc 7320 aaggaggcgc cggacagtgg gcctaagtga ggactccata ggagatgccc ttcaacagct 7380 ggccattaag tcctttggcc agcccccccc aagcggcgat tcaggccttt ccacgggggc 7440 gggcgctgcc gattccggca gtcagacgcc tcctgatgag ttggcccttt cggagacagg 7500 ttccatctct tccatgcccc ccctcgaggg ggagcttgga gatccagacc tggagcctga 7560 gcaggtagag ccccaacccc ccccccaggg gggggtggca gctcccggct cggactcggg 7620 gtcctggtct acttgctccg aggaggacga ctccgtcgtg tgctgctcca tgtcatactc 7680 ctggaccggg gctctaataa ctccttgtag tcccgaagag gagaagttac cgattaaccc 7740 cttgagcaac tccctgttgc gatatcacaa caaggtgtac tgtaccacaa caaagagcgc 7800 ctcactaagg gctaaaaagg taacttttga taggatgcaa gtgctcgact cctactacga 7860 ctcagtctta aaggacatta agctagcggc ctccaaggtc accgcaaggc tcctcaccat 7920 ggaggaggct tgccagttaa ccccacccca ttctgcaaga tctaaatatg ggtttggggc 7980 taaggaggtc cgcagcttgt ccgggagggc cgttaaccac atcaagtccg tgtggaagga 8040 cctcctggag gactcagaaa caccaattcc cacaaccatt atggccaaaa atgaggtgtt 8100 ctgcgtggac cccaccaagg ggggcaagaa agcagctcgc cttatcgttt accctgacct 8160 cggcgtcagg gtctgcgaga agatggccct ttatgacatt acacaaaaac ttcctcaggc 8220 ggtgatgggg gcttcttatg gattccagta ttcccccgct cagcgggtag agtttctctt 8280 gaaagcatgg gcggaaaaga aggaccctat gggtttttcg tatgataccc gatgctttga 8340 ctcaaccgtc actgagagag acatcaggac tgaggagtcc atatatcggg cctgctcctt 8400 gcccgaggag gcccacactg ccatacactc gctaactgag agactttacg tgggagggcc 8460 tatgttcaac agcaagggcc aaacctgcgg gtacaggcgt tgccgcgcca gcggggtgct 8520 caccactagc atggggaaca ccatcacatg ctacgtgaaa gccttagcgg cttgtaaagc 8580 tgcagggata atcgcgccca caatgctggt atgcggcgat gacttggttg tcatctcaga 8640 aagccagggg accgaggagg acgagcggaa cctgagagcc ttcacggagg ctatgaccag 8700 gtattctgcc cctcctggtg acccccccag accggagtat gatctggagc tgataacatc 8760 ttgctcctca aatgtgtctg tggcgctggg cccacaaggc cgccgcagat actacctgac 8820 cagagaccct accactccaa tcgcccgggc tgcctgggaa acagttagac actcccctgt 8880 caattcatgg ctgggaaaca tcatccagta cgccccgacc atatgggctc gcatggtcct 8940 gatgacacac ttcttctcca ttctcatggc tcaagacacg ctggaccaga acctcaactt 9000 tgagatgtac ggagcggtgt actccgtgag tcccttggac ctcccagcta taattgaaag 9060 gttacatggg cttgacgctt tttctctgca cacatacact ccccacgaac tgacacgggt 9120 ggcttcagcc ctcagaaaac ttggggcgcc acccctcaga gcgtggaaga gccgggcacg 9180 tgcagtcagg gcgtccctca tctcccgtgg ggggagagcg gccgtttgcg gtcgatatct 9240 cttcaattgg gcggtgaaga ccaagctcaa actcactcca ttgccggaag cgcgcctcct 9300 ggatttatcc agctggttca ccgtcggcgc cggcgggggc gacatttatc acagcgtgtc 9360 gcgtgcccga ccccgcttat tgctctttgg cctactccta ctttttgtag gggtaggcct 9420 tttcctactc cccgctcggt agagcggcac acattagcta cactccatag ctaactgtcc 9480 cttttttttt tttttttttt tttttttttt tttttttttt tttttttttt tttttttttt 9540 tttttttttt tttttttttt tttttctttt tttctctttt ccttctttct taccttattt 9600 tactttcttt cctggtggct ccatcttagc cctagtcacg gctagctgtg aaaggtccgt 9660 gagccgcatg actgcagaga gtgccgtaac tggtctctct gcagatcatg t 9711 2 3033 PRT Hepatitis C virus 2 Met Ser Thr Asn Pro Lys Pro Gln Arg Lys Thr Lys Arg Asn Thr Asn 1 5 10 15 Arg Arg Pro Gln Asp Val Lys Phe Pro Gly Gly Gly Gln Ile Val Gly 20 25 30 Gly Val Tyr Leu Leu Pro Arg Arg Gly Pro Arg Leu Gly Val Arg Ala 35 40 45 Thr Arg Lys Thr Ser Glu Arg Ser Gln Pro Arg Gly Arg Arg Gln Pro 50 55 60 Ile Pro Lys Asp Arg Arg Ser Thr Gly Lys Ser Trp Gly Lys Pro Gly 65 70 75 80 Tyr Pro Trp Pro Leu Tyr Gly Asn Glu Gly Leu Gly Trp Ala Gly Trp 85 90 95 Leu Leu Ser Pro Arg Gly Ser Arg Pro Ser Trp Gly Pro Asn Asp Pro 100 105 110 Arg His Arg Ser Arg Asn Val Gly Lys Val Ile Asp Thr Leu Thr Cys 115 120 125 Gly Phe Ala Asp Leu Met Gly Tyr Ile Pro Val Val Gly Ala Pro Leu 130 135 140 Gly Gly Val Ala Arg Ala Leu Ala His Gly Val Arg Val Leu Glu Asp 145 150 155 160 Gly Val Asn Phe Ala Thr Gly Asn Leu Pro Gly Cys Ser Phe Ser Ile 165 170 175 Phe Leu Leu Ala Leu Leu Ser Cys Ile Thr Thr Pro Val Ser Ala Ala 180 185 190 Glu Val Lys Asn Ile Ser Thr Gly Tyr Met Val Thr Asn Asp Cys Thr 195 200 205 Asn Asp Ser Ile Thr Trp Gln Leu Gln Ala Ala Val Leu His Val Pro 210 215 220 Gly Cys Val Pro Cys Glu Lys Val Gly Asn Ala Ser Gln Cys Trp Ile 225 230 235 240 Pro Val Ser Pro Asn Val Ala Val Gln Arg Pro Gly Ala Leu Thr Gln 245 250 255 Gly Leu Arg Thr His Ile Asp Met Val Val Met Ser Ala Thr Leu Cys 260 265 270 Ser Ala Leu Tyr Val Gly Asp Leu Cys Gly Gly Val Met Leu Ala Ala 275 280 285 Gln Met Phe Ile Val Ser Pro Gln His His Trp Phe Val Gln Asp Cys 290 295 300 Asn Cys Ser Ile Tyr Pro Gly Thr Ile Thr Gly His Arg Met Ala Trp 305 310 315 320 Asp Met Met Met Asn Trp Ser Pro Thr Ala Thr Met Ile Leu Ala Tyr 325 330 335 Ala Met Arg Val Pro Glu Val Ile Ile Asp Ile Ile Ser Gly Ala His 340 345 350 Trp Gly Val Met Phe Gly Leu Ala Tyr Phe Ser Met Gln Gly Ala Trp 355 360 365 Ala Lys Val Val Val Ile Leu Leu Leu Ala Ala Gly Val Asp Ala Arg 370 375 380 Thr His Thr Val Gly Gly Ser Ala Ala Gln Thr Thr Gly Arg Leu Thr 385 390 395 400 Ser Leu Phe Asp Met Gly Pro Arg Gln Lys Ile Gln Leu Val Asn Thr 405 410 415 Asn Gly Ser Trp His Ile Asn Arg Thr Ala Leu Asn Cys Asn Asp Ser 420 425 430 Leu His Thr Gly Phe Ile Ala Ser Leu Phe Tyr Thr His Ser Phe Asn 435 440 445 Ser Ser Gly Cys Pro Glu Arg Met Ser Ala Cys Arg Ser Ile Glu Ala 450 455 460 Phe Arg Val Gly Trp Gly Ala Leu Gln Tyr Glu Asp Asn Val Thr Asn 465 470 475 480 Pro Glu Asp Met Arg Pro Tyr Cys Trp His Tyr Pro Pro Arg Gln Cys 485 490 495 Gly Val Val Ser Ala Lys Thr Val Cys Gly Pro Val Tyr Cys Phe Thr 500 505 510 Pro Ser Pro Val Val Val Gly Thr Thr Asp Arg Leu Gly Ala Pro Thr 515 520 525 Tyr Thr Trp Gly Glu Asn Glu Thr Asp Val Phe Leu Leu Asn Ser Thr 530 535 540 Arg Pro Pro Leu Gly Ser Trp Phe Gly Cys Thr Trp Met Asn Ser Ser 545 550 555 560 Gly Tyr Thr Lys Thr Cys Gly Ala Pro Pro Cys Arg Thr Arg Ala Asp 565 570 575 Phe Asn Ala Ser Thr Asp Leu Leu Cys Pro Thr Asp Cys Phe Arg Lys 580 585 590 His Pro Asp Thr Thr Tyr Leu Lys Cys Gly Ser Gly Pro Trp Leu Thr 595 600 605 Pro Arg Cys Leu Ile Asp Tyr Pro Tyr Arg Leu Trp His Tyr Pro Cys 610 615 620 Thr Val Asn Tyr Thr Ile Phe Lys Ile Arg Met Tyr Val Gly Gly Val 625 630 635 640 Glu His Arg Leu Thr Ala Ala Cys Asn Phe Thr Arg Gly Asp Arg Cys 645 650 655 Asn Leu Glu Asp Arg Asp Arg Ser Gln Leu Ser Pro Leu Leu His Ser 660 665 670 Thr Thr Glu Trp Ala Ile Leu Pro Cys Ser Tyr Ser Asp Leu Pro Ala 675 680 685 Leu Ser Thr Gly Leu Leu His Leu His Gln Asn Ile Val Asp Val Gln 690 695 700 Phe Met Tyr Gly Leu Ser Pro Ala Leu Thr Lys Tyr Ile Val Arg Trp 705 710 715 720 Glu Trp Val Ile Leu Leu Phe Leu Leu Leu Ala Asp Ala Arg Val Cys 725 730 735 Ala Cys Leu Trp Met Leu Ile Leu Leu Gly Gln Ala Glu Ala Ala Leu 740 745 750 Glu Lys Leu Val Ile Leu His Ala Ala Ser Ala Ala Ser Cys Asn Gly 755 760 765 Phe Leu Tyr Phe Val Ile Phe Phe Val Ala Ala Trp Tyr Ile Lys Gly 770 775 780 Arg Val Val Pro Leu Ala Thr Tyr Ser Leu Thr Gly Leu Trp Ser Phe 785 790 795 800 Ser Leu Leu Leu Leu Ala Leu Pro Gln Gln Ala Tyr Ala Tyr Asp Ala 805 810 815 Ser Val His Gly Gln Ile Gly Ala Ala Leu Leu Val Met Ile Thr Leu 820 825 830 Phe Thr Leu Thr Pro Gly Tyr Lys Thr Leu Leu Ser Arg Phe Leu Trp 835 840 845 Trp Leu Cys Tyr Leu Leu Thr Leu Gly Glu Ala Met Val Gln Glu Trp 850

855 860 Ala Pro Pro Met Gln Val Arg Gly Gly Arg Asp Gly Ile Ile Trp Ala 865 870 875 880 Val Ala Ile Phe Tyr Pro Gly Val Val Phe Asp Ile Thr Lys Trp Leu 885 890 895 Leu Ala Val Leu Gly Pro Ala Tyr Leu Leu Lys Gly Ala Leu Thr Arg 900 905 910 Val Pro Tyr Phe Val Arg Ala His Ala Leu Leu Arg Met Cys Thr Met 915 920 925 Ala Arg His Leu Ala Gly Gly Arg Tyr Val Gln Met Ala Leu Leu Ala 930 935 940 Leu Gly Arg Trp Thr Gly Thr Tyr Ile Tyr Asp His Leu Thr Pro Met 945 950 955 960 Ser Asp Trp Ala Ala Ser Gly Leu Arg Asp Leu Ala Val Ala Val Glu 965 970 975 Pro Ile Ile Phe Ser Pro Met Glu Lys Lys Val Ile Val Trp Gly Ala 980 985 990 Glu Thr Ala Ala Cys Gly Asp Ile Leu His Gly Leu Pro Val Ser Ala 995 1000 1005 Arg Leu Gly Arg Glu Val Leu Leu Gly Pro Ala Asp Gly Tyr Thr Ser 1010 1015 1020 Lys Gly Trp Ser Leu Leu Ala Pro Ile Thr Ala Tyr Ala Gln Gln Thr 1025 1030 1035 1040 Arg Gly Leu Leu Gly Thr Ile Val Val Ser Met Thr Gly Arg Asp Lys 1045 1050 1055 Thr Glu Gln Ala Gly Glu Ile Gln Val Leu Ser Thr Val Thr Gln Ser 1060 1065 1070 Phe Leu Gly Thr Ser Ile Ser Gly Val Leu Trp Thr Val Tyr His Gly 1075 1080 1085 Ala Gly Asn Lys Thr Leu Ala Gly Ser Arg Gly Pro Val Thr Gln Met 1090 1095 1100 Tyr Ser Ser Ala Glu Gly Asp Leu Val Gly Trp Pro Ser Pro Pro Gly 1105 1110 1115 1120 Thr Lys Ser Leu Glu Pro Cys Thr Cys Gly Ala Val Asp Leu Tyr Leu 1125 1130 1135 Val Thr Arg Asn Ala Asp Val Ile Pro Ala Arg Arg Arg Gly Asp Lys 1140 1145 1150 Arg Gly Ala Leu Leu Ser Pro Arg Pro Leu Ser Thr Leu Lys Gly Ser 1155 1160 1165 Ser Gly Gly Pro Val Leu Cys Pro Arg Gly His Ala Val Gly Val Phe 1170 1175 1180 Arg Ala Ala Val Cys Ser Arg Gly Val Ala Lys Ser Ile Asp Phe Ile 1185 1190 1195 1200 Pro Val Glu Thr Leu Asp Ile Val Thr Arg Ser Pro Thr Phe Ser Asp 1205 1210 1215 Asn Ser Thr Pro Pro Ala Val Pro Gln Thr Tyr Gln Val Gly Tyr Leu 1220 1225 1230 His Ala Pro Thr Gly Ser Gly Lys Ser Thr Lys Val Pro Val Ala Tyr 1235 1240 1245 Ala Ala Gln Gly Tyr Lys Val Leu Val Leu Asn Pro Ser Val Ala Ala 1250 1255 1260 Thr Leu Gly Phe Gly Ala Tyr Leu Ser Lys Ala His Gly Ile Asn Pro 1265 1270 1275 1280 Asn Ile Arg Thr Gly Val Arg Thr Val Thr Thr Gly Ala Pro Ile Thr 1285 1290 1295 Tyr Ser Thr Tyr Gly Lys Phe Leu Ala Asp Gly Gly Cys Ala Gly Gly 1300 1305 1310 Ala Tyr Asp Ile Ile Ile Cys Asp Glu Cys His Ala Val Asp Ser Thr 1315 1320 1325 Thr Ile Leu Gly Ile Gly Thr Val Leu Asp Gln Ala Glu Thr Ala Gly 1330 1335 1340 Val Arg Leu Thr Val Leu Ala Thr Ala Thr Pro Pro Gly Ser Val Thr 1345 1350 1355 1360 Thr Pro His Pro Asn Ile Glu Glu Val Ala Leu Gly Gln Glu Gly Glu 1365 1370 1375 Ile Pro Phe Tyr Gly Arg Ala Ile Pro Leu Ser Tyr Ile Lys Gly Gly 1380 1385 1390 Arg His Leu Ile Phe Cys His Ser Lys Lys Lys Cys Asp Glu Leu Ala 1395 1400 1405 Ala Ala Leu Arg Gly Met Gly Leu Asn Ser Val Ala Tyr Tyr Arg Gly 1410 1415 1420 Leu Asp Val Ser Val Ile Pro Thr Gln Gly Asp Val Val Val Val Ala 1425 1430 1435 1440 Thr Asp Ala Leu Met Thr Gly Tyr Thr Gly Asp Phe Asp Ser Val Ile 1445 1450 1455 Asp Cys Asn Val Ala Val Thr Gln Val Val Asp Phe Ser Leu Asp Pro 1460 1465 1470 Thr Phe Thr Ile Thr Thr Gln Ile Val Pro Gln Asp Ala Val Ser Arg 1475 1480 1485 Ser Gln Arg Arg Gly Arg Thr Gly Arg Gly Arg Leu Gly Ile Tyr Arg 1490 1495 1500 Tyr Val Ser Thr Gly Glu Arg Ala Ser Gly Met Phe Asp Ser Val Val 1505 1510 1515 1520 Leu Cys Glu Cys Tyr Asp Ala Gly Ala Ala Trp Tyr Glu Leu Thr Pro 1525 1530 1535 Ser Glu Thr Thr Val Arg Leu Arg Ala Tyr Phe Asn Thr Pro Gly Leu 1540 1545 1550 Pro Val Cys Gln Asp His Leu Glu Phe Trp Glu Ala Val Phe Thr Gly 1555 1560 1565 Leu Thr His Ile Asp Ala His Phe Leu Ser Gln Thr Lys Gln Ser Gly 1570 1575 1580 Glu Asn Phe Ala Tyr Leu Thr Ala Tyr Gln Ala Thr Val Cys Ala Arg 1585 1590 1595 1600 Ala Lys Ala Pro Pro Pro Ser Trp Asp Val Met Trp Lys Cys Leu Thr 1605 1610 1615 Arg Leu Lys Pro Thr Leu Val Gly Pro Thr Pro Leu Leu Tyr Arg Leu 1620 1625 1630 Gly Ser Val Thr Asn Glu Val Thr Leu Thr His Pro Val Thr Lys Tyr 1635 1640 1645 Ile Ala Thr Cys Met Gln Ala Asp Leu Glu Val Met Thr Ser Thr Trp 1650 1655 1660 Val Leu Ala Gly Gly Val Leu Ala Ala Val Ala Ala Tyr Cys Leu Ala 1665 1670 1675 1680 Thr Gly Cys Val Cys Ile Ile Gly Arg Leu His Ile Asn Gln Arg Ala 1685 1690 1695 Val Val Ala Pro Asp Lys Glu Val Leu Tyr Glu Ala Phe Asp Glu Met 1700 1705 1710 Glu Glu Cys Ala Ser Arg Ala Ala Leu Ile Glu Glu Gly Gln Arg Ile 1715 1720 1725 Ala Glu Met Leu Lys Ser Lys Ile Gln Gly Leu Leu Gln Gln Ala Ser 1730 1735 1740 Lys Gln Ala Gln Asp Ile Gln Pro Thr Val Gln Ala Ser Trp Pro Lys 1745 1750 1755 1760 Val Glu Gln Phe Trp Ala Lys His Met Trp Asn Phe Ile Ser Gly Ile 1765 1770 1775 Gln Tyr Leu Ala Gly Leu Ser Thr Leu Pro Gly Asn Pro Ala Val Ala 1780 1785 1790 Ser Met Met Ala Phe Ser Ala Ala Leu Thr Ser Pro Leu Ser Thr Ser 1795 1800 1805 Thr Thr Ile Leu Leu Asn Ile Leu Gly Gly Trp Leu Ala Ser Gln Ile 1810 1815 1820 Ala Pro Pro Ala Gly Ala Thr Gly Phe Val Val Ser Gly Leu Val Gly 1825 1830 1835 1840 Ala Ala Val Gly Ser Ile Gly Leu Gly Lys Val Leu Val Asp Ile Leu 1845 1850 1855 Ala Gly Tyr Gly Ala Gly Ile Ser Gly Ala Leu Val Ala Phe Lys Ile 1860 1865 1870 Met Ser Gly Glu Lys Pro Ser Met Glu Asp Val Val Asn Leu Leu Pro 1875 1880 1885 Gly Ile Leu Ser Pro Gly Ala Leu Val Val Gly Val Ile Cys Ala Ala 1890 1895 1900 Ile Leu Arg Arg His Val Gly Pro Gly Glu Gly Ala Val Gln Trp Met 1905 1910 1915 1920 Asn Arg Leu Ile Ala Phe Ala Ser Arg Gly Asn His Val Ala Pro Thr 1925 1930 1935 His Tyr Val Thr Glu Ser Asp Ala Ser Gln Arg Val Thr Gln Leu Leu 1940 1945 1950 Gly Ser Leu Thr Ile Thr Ser Leu Leu Arg Arg Leu His Asn Trp Ile 1955 1960 1965 Thr Glu Asp Cys Pro Ile Pro Cys Gly Gly Ser Trp Leu Arg Asp Val 1970 1975 1980 Trp Asp Trp Val Cys Thr Ile Leu Thr Asp Phe Lys Asn Trp Leu Thr 1985 1990 1995 2000 Ser Lys Leu Phe Pro Lys Met Pro Gly Leu Pro Phe Val Ser Cys Gln 2005 2010 2015 Lys Gly Tyr Lys Gly Val Trp Ala Gly Thr Gly Ile Met Thr Thr Arg 2020 2025 2030 Cys Pro Cys Gly Ala Asn Ile Ser Gly Asn Val Arg Leu Gly Ser Met 2035 2040 2045 Arg Ile Thr Gly Pro Lys Thr Cys Met Asn Ile Trp Gln Gly Thr Phe 2050 2055 2060 Pro Ile Asn Cys Tyr Thr Glu Gly Gln Cys Val Pro Lys Pro Ala Pro 2065 2070 2075 2080 Asn Phe Lys Val Ala Ile Trp Arg Val Ala Ala Ser Glu Tyr Ala Glu 2085 2090 2095 Val Thr Gln His Gly Ser Tyr His Tyr Ile Thr Gly Leu Thr Thr Asp 2100 2105 2110 Asn Leu Lys Val Pro Cys Gln Leu Pro Ser Pro Glu Phe Phe Ser Trp 2115 2120 2125 Val Asp Gly Val Gln Ile His Arg Phe Ala Pro Thr Pro Lys Pro Phe 2130 2135 2140 Phe Arg Asp Glu Val Ser Phe Cys Val Gly Leu Asn Ser Phe Val Val 2145 2150 2155 2160 Gly Ser Gln Leu Pro Cys Asp Pro Glu Pro Asp Thr Asp Val Leu Met 2165 2170 2175 Ser Met Leu Thr Asp Pro Ser His Ile Thr Ala Glu Thr Ala Ala Arg 2180 2185 2190 Arg Leu Ala Arg Gly Ser Pro Pro Ser Glu Ala Ser Ser Ser Ala Ser 2195 2200 2205 Gln Leu Ser Ala Pro Ser Leu Arg Ala Thr Cys Thr Thr His Gly Lys 2210 2215 2220 Ala Tyr Asp Val Asp Met Val Asp Ala Asn Leu Phe Met Gly Gly Asp 2225 2230 2235 2240 Val Thr Arg Ile Glu Ser Gly Ser Lys Val Val Val Leu Asp Ser Leu 2245 2250 2255 Asp Pro Met Val Glu Glu Arg Ser Asp Leu Glu Pro Ser Ile Pro Ser 2260 2265 2270 Glu Tyr Met Leu Pro Lys Lys Arg Phe Pro Pro Ala Leu Pro Ala Trp 2275 2280 2285 Ala Arg Pro Asp Tyr Asn Pro Pro Leu Val Glu Ser Trp Lys Arg Pro 2290 2295 2300 Asp Tyr Gln Pro Ala Thr Val Ala Gly Cys Ala Leu Pro Pro Pro Arg 2305 2310 2315 2320 Lys Thr Pro Thr Pro Pro Pro Arg Arg Arg Arg Thr Val Gly Leu Ser 2325 2330 2335 Glu Asp Ser Ile Gly Asp Ala Leu Gln Gln Leu Ala Ile Lys Ser Phe 2340 2345 2350 Gly Gln Pro Pro Pro Ser Gly Asp Ser Gly Leu Ser Thr Gly Ala Gly 2355 2360 2365 Ala Ala Asp Ser Gly Ser Gln Thr Pro Pro Asp Glu Leu Ala Leu Ser 2370 2375 2380 Glu Thr Gly Ser Ile Ser Ser Met Pro Pro Leu Glu Gly Glu Leu Gly 2385 2390 2395 2400 Asp Pro Asp Leu Glu Pro Glu Gln Val Glu Pro Gln Pro Pro Pro Gln 2405 2410 2415 Gly Gly Val Ala Ala Pro Gly Ser Asp Ser Gly Ser Trp Ser Thr Cys 2420 2425 2430 Ser Glu Glu Asp Asp Ser Val Val Cys Cys Ser Met Ser Tyr Ser Trp 2435 2440 2445 Thr Gly Ala Leu Ile Thr Pro Cys Ser Pro Glu Glu Glu Lys Leu Pro 2450 2455 2460 Ile Asn Pro Leu Ser Asn Ser Leu Leu Arg Tyr His Asn Lys Val Tyr 2465 2470 2475 2480 Cys Thr Thr Thr Lys Ser Ala Ser Leu Arg Ala Lys Lys Val Thr Phe 2485 2490 2495 Asp Arg Met Gln Val Leu Asp Ser Tyr Tyr Asp Ser Val Leu Lys Asp 2500 2505 2510 Ile Lys Leu Ala Ala Ser Lys Val Thr Ala Arg Leu Leu Thr Met Glu 2515 2520 2525 Glu Ala Cys Gln Leu Thr Pro Pro His Ser Ala Arg Ser Lys Tyr Gly 2530 2535 2540 Phe Gly Ala Lys Glu Val Arg Ser Leu Ser Gly Arg Ala Val Asn His 2545 2550 2555 2560 Ile Lys Ser Val Trp Lys Asp Leu Leu Glu Asp Ser Glu Thr Pro Ile 2565 2570 2575 Pro Thr Thr Ile Met Ala Lys Asn Glu Val Phe Cys Val Asp Pro Thr 2580 2585 2590 Lys Gly Gly Lys Lys Ala Ala Arg Leu Ile Val Tyr Pro Asp Leu Gly 2595 2600 2605 Val Arg Val Cys Glu Lys Met Ala Leu Tyr Asp Ile Thr Gln Lys Leu 2610 2615 2620 Pro Gln Ala Val Met Gly Ala Ser Tyr Gly Phe Gln Tyr Ser Pro Ala 2625 2630 2635 2640 Gln Arg Val Glu Phe Leu Leu Lys Ala Trp Ala Glu Lys Lys Asp Pro 2645 2650 2655 Met Gly Phe Ser Tyr Asp Thr Arg Cys Phe Asp Ser Thr Val Thr Glu 2660 2665 2670 Arg Asp Ile Arg Thr Glu Glu Ser Ile Tyr Arg Ala Cys Ser Leu Pro 2675 2680 2685 Glu Glu Ala His Thr Ala Ile His Ser Leu Thr Glu Arg Leu Tyr Val 2690 2695 2700 Gly Gly Pro Met Phe Asn Ser Lys Gly Gln Thr Cys Gly Tyr Arg Arg 2705 2710 2715 2720 Cys Arg Ala Ser Gly Val Leu Thr Thr Ser Met Gly Asn Thr Ile Thr 2725 2730 2735 Cys Tyr Val Lys Ala Leu Ala Ala Cys Lys Ala Ala Gly Ile Ile Ala 2740 2745 2750 Pro Thr Met Leu Val Cys Gly Asp Asp Leu Val Val Ile Ser Glu Ser 2755 2760 2765 Gln Gly Thr Glu Glu Asp Glu Arg Asn Leu Arg Ala Phe Thr Glu Ala 2770 2775 2780 Met Thr Arg Tyr Ser Ala Pro Pro Gly Asp Pro Pro Arg Pro Glu Tyr 2785 2790 2795 2800 Asp Leu Glu Leu Ile Thr Ser Cys Ser Ser Asn Val Ser Val Ala Leu 2805 2810 2815 Gly Pro Gln Gly Arg Arg Arg Tyr Tyr Leu Thr Arg Asp Pro Thr Thr 2820 2825 2830 Pro Ile Ala Arg Ala Ala Trp Glu Thr Val Arg His Ser Pro Val Asn 2835 2840 2845 Ser Trp Leu Gly Asn Ile Ile Gln Tyr Ala Pro Thr Ile Trp Ala Arg 2850 2855 2860 Met Val Leu Met Thr His Phe Phe Ser Ile Leu Met Ala Gln Asp Thr 2865 2870 2875 2880 Leu Asp Gln Asn Leu Asn Phe Glu Met Tyr Gly Ala Val Tyr Ser Val 2885 2890 2895 Ser Pro Leu Asp Leu Pro Ala Ile Ile Glu Arg Leu His Gly Leu Asp 2900 2905 2910 Ala Phe Ser Leu His Thr Tyr Thr Pro His Glu Leu Thr Arg Val Ala 2915 2920 2925 Ser Ala Leu Arg Lys Leu Gly Ala Pro Pro Leu Arg Ala Trp Lys Ser 2930 2935 2940 Arg Ala Arg Ala Val Arg Ala Ser Leu Ile Ser Arg Gly Gly Arg Ala 2945 2950 2955 2960 Ala Val Cys Gly Arg Tyr Leu Phe Asn Trp Ala Val Lys Thr Lys Leu 2965 2970 2975 Lys Leu Thr Pro Leu Pro Glu Ala Arg Leu Leu Asp Leu Ser Ser Trp 2980 2985 2990 Phe Thr Val Gly Ala Gly Gly Gly Asp Ile Tyr His Ser Val Ser Arg 2995 3000 3005 Ala Arg Pro Arg Leu Leu Leu Phe Gly Leu Leu Leu Leu Phe Val Gly 3010 3015 3020 Val Gly Leu Phe Leu Leu Pro Ala Arg 3025 3030 3 9611 DNA Hepatitis C virus 3 gccagccccc tgatgggggc gacactccac catgaatcac tcccctgtga ggaactactg 60 tcttcacgca gaaagcgtct agccatggcg ttagtatgag tgtcgtgcag cctccaggac 120 cccccctccc gggagagcca tagtggtctg cggaaccggt gagtacaccg gaattgccag 180 gacgaccggg tcctttcttg gataaacccg ctcaatgcct ggagatttgg gcgtgccccc 240 gcaagactgc tagccgagta gtgttgggtc gcgaaaggcc ttgtggtact gcctgatagg 300 gtgcttgcga gtgccccggg aggtctcgta gaccgtgcac catgagcaca aatcctaaac 360 ctcaaagaaa aaccaaaaga aacaccaacc gtcgcccaca agacgttaag tttccgggcg 420 gcggccagat cgttggcgga gtatacttgt tgccgcgcag gggccccagg ttgggtgtgc 480 gcgcgacaag gaagacttcg gagcggtccc agccacgtgg aaggcgccag cccatcccta 540 aagatcggcg ctccactggc aaatcctggg gaaaaccagg atacccctgg cccctatacg 600 ggaatgaggg actcggctgg gcaggatggc tcctgtcccc ccgaggttcc cgtccctctt 660 ggggccccaa tgacccccgg cataggtcgc gcaacgtggg taaggtcatc gataccctaa 720 cgtgcggctt tgccgacctc atggggtaca tccctgtcgt gggcgccccg ctcggcggcg 780 tcgccagagc tctcgcgcat ggcgtgagag tcctggagga cggggttaat tttgcaacag 840 ggaacttacc cggttgctcc ttttctatct tcttgctggc cctgctgtcc tgcatcacca 900 ccccggtctc cgctgccgaa gtgaagaaca tcagtaccgg ctacatggtg actaacgact 960 gcaccaatga cagcattacc tggcagctcc aggctgctgt cctccacgtc cccgggtgcg 1020 tcccgtgcga gaaagtgggg aatgcatctc agtgctggat accggtctca ccgaatgtgg 1080 ccgtgcagcg gcccggcgcc ctcacgcagg gcttgcggac gcacatcgac atggttgtga 1140 tgtccgccac gctctgctct gccctctacg tgggggacct ctgcggtggg gtgatgctcg 1200 cagcccaaat gttcattgtc tcgccgcagc accactggtt tgtccaagac tgcaattgct 1260 ccatctaccc tggtaccatc actggacacc gcatggcatg ggacatgatg atgaactggt 1320 cgcccacggc taccatgatc ttggcgtacg cgatgcgtgt ccccgaggtc attatagaca 1380 tcattagcgg ggctcattgg ggcgtcatgt tcggcttggc ctacttctct atgcagggag 1440 cgtgggcgaa agtcgttgtc atccttctgt tggccgccgg

ggtggacgcg cgcacccata 1500 ctgttggggg ttctgccgcg cagaccaccg ggcgcctcac cagcttattt gacatgggcc 1560 ccaggcagaa aatccagctc gttaacacca atggcagctg gcacatcaac cgcaccgccc 1620 tgaactgcaa tgactccttg cacaccggct ttatcgcgtc tctgttctac acccacagct 1680 tcaactcgtc aggatgtccc gaacgcatgt ccgcctgccg cagtatcgag gccttccggg 1740 tgggatgggg cgccttgcaa tatgaggata atgtcaccaa tccagaggat atgagaccct 1800 attgctggca ctacccacca aggcagtgtg gcgtggtctc cgcgaagact gtgtgtggcc 1860 cagtgtactg tttcaccccc agcccagtgg tagtgggcac gaccgacagg cttggagcgc 1920 ccacttacac gtggggggag aatgagacag atgtcttcct attgaacagc actcgaccac 1980 cgctggggtc atggttcggc tgcacgtgga tgaactcttc tggctacacc aagacttgcg 2040 gcgcaccacc ctgccgtact agagctgact tcaacgccag cacggacctg ttgtgcccca 2100 cggactgttt taggaagcat cctgatacca cttacctcaa atgcggctct gggccctggc 2160 tcacgccaag gtgcctgatc gactacccct acaggctctg gcattacccc tgcacagtta 2220 actataccat cttcaaaata aggatgtatg tgggaggggt tgagcacagg ctcacggctg 2280 catgcaattt cactcgtggg gatcgttgca acttggagga cagagacaga agtcaactgt 2340 ctcctttgtt gcactccacc acggaatggg ccattttacc ttgctcttac tcggacctgc 2400 ccgccttgtc gactggtctt ctccacctcc accaaaacat cgtggacgta caattcatgt 2460 atggcctatc acctgccctc acaaaataca tcgtccgatg ggagtgggta atactcttat 2520 tcctgctctt agcggacgcc agggtttgcg cctgcttatg gatgctcatc ttgttgggcc 2580 aggccgaagc agcactagag aagctggtca tcttgcacgc tgcgagcgca gctagctgca 2640 atggcttcct atattttgtc atctttttcg tggctgcttg gtacatcaag ggtcgggtag 2700 tccccttagc tacctattcc ctcactggcc tgtggtcctt tagcctactg ctcctagcat 2760 tgccccaaca ggcatatgca ctggacacgg aggtggccgc gtcgtgtggc ggcgttgttc 2820 ttgtcgggtt aatggcgctg actctgtcgc catattacaa gcgctatatc agctggtgca 2880 tgtggtggct tcagtatttt ctgaccagag tagaagcgca actgcacgtg tgggttcccc 2940 ccctcaacgt ccgggggggg cgcgatgccg tcatcttact catgtgtgta gtacacccga 3000 ccctggtatt tgacatcacc aaactactcc tggccatctt cggacccctt tggattcttc 3060 aagccagttt gcttaaagtc ccctacttcg tgcgcgttca aggccttctc cggatctgcg 3120 cgctagcgcg gaagatagcc ggaggtcatt acgtgcaaat ggccatcatc aagttagggg 3180 cgcttactgg cacctatgtg tataaccatc tcacccctct tcgagactgg gcgcacaacg 3240 gcctgcgaga tctggccgtg gctgtggaac cagtcgtctt ctcccgaatg gagaccaagc 3300 tcatcacgtg gggggcagat accgccgcgt gcggtgacat catcaacggc ttgcccgtct 3360 ctgcccgtag gggccaggag atactgcttg ggccagccga cggaatggtc tccaaggggt 3420 ggaggttgct ggcgcccatc acggcgtacg cccagcagac gagaggcctc ctagggtgta 3480 taatcaccag cctgactggc cgggacaaaa accaagtgga gggtgaggtc cagatcgtgt 3540 caactgctac ccaaaccttc ctggcaacgt gcatcaatgg ggtatgctgg actgtctacc 3600 acggggccgg aacgaggacc atcgcatcac ccaagggtcc tgtcatccag atgtatacca 3660 atgtggacca agaccttgtg ggctggcccg ctcctcaagg ttcccgctca ttgacaccct 3720 gtacctgcgg ctcctcggac ctttacctgg tcacgaggca cgccgatgtc attcccgtgc 3780 gccggcgagg tgatagcagg ggtagcctgc tttcgccccg gcccatttcc tacttgaaag 3840 gctcctcggg gggtccgctg ttgtgccccg cgggacacgc cgtgggccta ttcagggccg 3900 cggtgtgcac ccgtggagtg gctaaagcgg tggactttat ccctgtggag aacctaggga 3960 caaccatgag atccccggtg ttcacggaca actcctctcc accagcagtg ccccagagct 4020 tccaggtggc ccacctgcat gctcccaccg gcagcggtaa gagcaccaag gtcccggctg 4080 cgtacgcagc ccagggctac aaggtgttgg tgctcaaccc ctctgttgct gcaacgctgg 4140 gctttggtgc ttacatgtcc aaggcccatg gggttgatcc taatatcagg accggggtga 4200 gaacaattac cactggcagc cccatcacgt actccaccta cggcaagttc cttgccgacg 4260 gcgggtgctc aggaggtgct tatgacataa taatttgtga cgagtgccac tccacggatg 4320 ccacatccat cttgggcatc ggcactgtcc ttgaccaagc agagactgcg ggggcgagac 4380 tggttgtgct cgccactgct acccctccgg gctccgtcac tgtgtcccat cctaacatcg 4440 aggaggttgc tctgtccacc accggagaga tcccctttta cggcaaggct atccccctcg 4500 aggtgatcaa ggggggaaga catctcatct tctgccactc aaagaagaag tgcgacgagc 4560 tcgccgcgaa gctggtcgca ttgggcatca atgccgtggc ctactaccgc ggtcttgacg 4620 tgtctgtcat cccgaccagc ggcgatgttg tcgtcgtgtc gaccgatgct ctcatgactg 4680 gctttaccgg cgacttcgac tctgtgatag actgcaacac gtgtgtcact cagacagtcg 4740 atttcagcct tgaccctacc tttaccattg agacaaccac gctcccccag gatgctgtct 4800 ccaggactca acgccggggc aggactggca gggggaagcc aggcatctat agatttgtgg 4860 caccggggga gcgcccctcc ggcatgttcg actcgtccgt cctctgtgag tgctatgacg 4920 cgggctgtgc ttggtatgag ctcacgcccg ccgagactac agttaggcta cgagcgtaca 4980 tgaacacccc ggggcttccc gtgtgccagg accatcttga attttgggag ggcgtcttta 5040 cgggcctcac tcatatagat gcccactttt tatcccagac aaagcagagt ggggagaact 5100 ttccttacct ggtagcgtac caagccaccg tgtgcgctag ggctcaagcc cctcccccat 5160 cgtgggacca gatgtggaag tgtttgatcc gccttaaacc caccctccat gggccaacac 5220 ccctgctata cagactgggc gctgttcaga atgaagtcac cctgacgcac ccaatcacca 5280 aatacatcat gacatgcatg tcggccgacc tggaggtcgt cacgagcacc tgggtgctcg 5340 ttggcggcgt cctggctgct ctggccgcgt attgcctgtc aacaggctgc gtggtcatag 5400 tgggcaggat cgtcttgtcc gggaagccgg caattatacc tgacagggag gttctctacc 5460 aggagttcga tgagatggaa gagtgctctc agcacttacc gtacatcgag caagggatga 5520 tgctcgctga gcagttcaag cagaaggccc tcggcctcct gcagaccgcg tcccgccatg 5580 cagaggttat cacccctgct gtccagacca actggcagaa actcgaggtc ttttgggcga 5640 agcacatgtg gaatttcatc agtgggatac aatacttggc gggcctgtca acgctgcctg 5700 gtaaccccgc cattgcttca ttgatggctt ttacagctgc cgtcaccagc ccactaacca 5760 ctggccaaac cctcctcttc aacatattgg gggggtgggt ggctgcccag ctcgccgccc 5820 ccggtgccgc tactgccttt gtgggtgctg gcctagctgg cgccgccatc ggcagcgttg 5880 gactggggaa ggtcctcgtg gacattcttg cagggtatgg cgcgggcgtg gcgggagctc 5940 ttgtagcatt caagatcatg agcggtgagg tcccctccac ggaggacctg gtcaatctgc 6000 tgcccgccat cctctcgcct ggagcccttg tagtcggtgt ggtctgcgca gcaatactgc 6060 gccggcacgt tggcccgggc gagggggcag tgcaatggat gaaccggcta atagccttcg 6120 cctcccgggg gaaccatgtt tcccccacgc actacgtgcc ggagagcgat gcagccgccc 6180 gcgtcactgc catactcagc agcctcactg taacccagct cctgaggcga ctgcatcagt 6240 ggataagctc ggagtgtacc actccatgct ccggttcctg gctaagggac atctgggact 6300 ggatatgcga ggtgctgagc gactttaaga cctggctgaa agccaagctc atgccacaac 6360 tgcctgggat tccctttgtg tcctgccagc gcgggtatag gggggtctgg cgaggagacg 6420 gcattatgca cactcgctgc cactgtggag ctgagatcac tggacatgtc aaaaacggga 6480 cgatgaggat cgtcggtcct aggacctgca ggaacatgtg gagtgggacg ttccccatta 6540 acgcctacac cacgggcccc tgtactcccc ttcctgcgcc gaactataag ttcgcgctgt 6600 ggagggtgtc tgcagaggaa tacgtggaga taaggcgggt gggggacttc cactacgtat 6660 cgggtatgac tactgacaat cttaaatgcc cgtgccagat cccatcgccc gaatttttca 6720 cagaattgga cggggtgcgc ctacacaggt ttgcgccccc ttgcaagccc ttgctgcggg 6780 aggaggtatc attcagagta ggactccacg agtacccggt ggggtcgcaa ttaccttgcg 6840 agcccgaacc ggacgtagcc gtgttgacgt ccatgctcac tgatccctcc catataacag 6900 cagaggcggc cgggagaagg ttggcgagag ggtcaccccc ttctatggcc agctcctcgg 6960 ctagccagct gtccgctcca tctctcaagg caacttgcac cgccaaccat gactcccctg 7020 acgccgagct catagaggct aacctcctgt ggaggcagga gatgggcggc aacatcacca 7080 gggttgagtc agagaacaaa gtggtgattc tggactcctt cgatccgctt gtggcagagg 7140 aggatgagcg ggaggtctcc gtacctgcag aaattctgcg gaagtctcgg agattcgccc 7200 gggccctgcc cgtctgggcg cggccggact acaacccccc gctagtagag acgtggaaaa 7260 agcctgacta cgaaccacct gtggtccatg gctgcccgct accacctcca cggtcccctc 7320 ctgtgcctcc gcctcggaaa aagcgtacgg tggtcctcac cgaatcaacc ctatctactg 7380 ccttggccga gcttgccacc aaaagttttg gcagctcctc aacttccggc attacgggcg 7440 acaatacgac aacatcctct gagcccgccc cttctggctg cccccccgac tccgacgttg 7500 agtcctattc ttccatgccc cccctggagg gggagcctgg ggatccggat ctcagcgacg 7560 ggtcatggtc gacggtcagt agtggggccg acacggaaga tgtcgtgtgc tgctcaatgt 7620 cttattcctg gacaggcgca ctcgtcaccc cgtgcgctgc ggaagaacaa aaactgccca 7680 tcaacgcact gagcaactcg ttgctacgcc atcacaatct ggtgtattcc accacttcac 7740 gcagtgcttg ccaaaggcag aagaaagtca catttgacag actgcaagtt ctggacagcc 7800 attaccagga cgtgctcaag gaggtcaaag cagcggcgtc aaaagtgaag gctaacttgc 7860 tatccgtaga ggaagcttgc agcctgacgc ccccacattc agccaaatcc aagtttggct 7920 atggggcaaa agacgtccgt tgccatgcca gaaaggccgt agcccacatc aactccgtgt 7980 ggaaagacct tctggaagac agtgtaacac caatagacac taccatcatg gccaagaacg 8040 aggttttctg cgttcagcct gagaaggggg gtcgtaagcc agctcgtctc atcgtgttcc 8100 ccgacctggg cgtgcgcgtg tgcgagaaga tggccctgta cgacgtggtt agcaagctcc 8160 ccctggccgt gatgggaagc tcctacggat tccaatactc accaggacag cgggttgaat 8220 tcctcgtgca agcgtggaag tccaagaaga ccccgatggg gttctcgtat gatacccgct 8280 gttttgactc cacagtcact gagagcgaca tccgtacgga ggaggcaatt taccaatgtt 8340 gtgacctgga cccccaagcc cgcgtggcca tcaagtccct cactgagagg ctttatgttg 8400 ggggccctct taccaattca aggggggaaa actgcggcta ccgcaggtgc cgcgcgagcg 8460 gcgtactgac aactagctgt ggtaacaccc tcacttgcta catcaaggcc cgggcagcct 8520 gtcgagccgc agggctccag gactgcacca tgctcgtgtg tggcgacgac ttagtcgtta 8580 tctgtgaaag tgcgggggtc caggaggacg cggcgagcct gagagccttc acggaggcta 8640 tgaccaggta ctccgccccc cccggggacc ccccacaacc agaatacgac ttggagctta 8700 taacatcatg ctcctccaac gtgtcagtcg cccacgacgg cgctggaaag agggtctact 8760 accttacccg tgaccctaca acccccctcg cgagagccgc gtgggagaca gcaagacaca 8820 ctccagtcaa ttcctggcta ggcaacataa tcatgtttgc ccccacactg tgggcgagga 8880 tgatactgat gacccatttc tttagcgtcc tcatagccag ggatcagctt gaacaggctc 8940 ttaactgtga gatctacgga gcctgctact ccatagaacc actggatcta cctccaatca 9000 ttcaaagact ccatggcctc agcgcatttt cactccacag ttactctcca ggtgaaatca 9060 atagggtggc cgcatgcctc agaaaacttg gggtcccgcc cttgcgagct tggagacacc 9120 gggcccggag cgtccgcgct aggcttctgt ccagaggagg cagggctgct atatgtggca 9180 agtacctctt caactgggca gtaagaacaa agctcaaact cactccaata gcggccgctg 9240 gccggctgga cttgtccggt tggttcacgg ctggctacag cgggggagac atttatcaca 9300 gcgtgtctca tgcccggccc cgctggttct ggttttgcct actcctgctc gctgcagggg 9360 taggcatcta cctcctcccc aaccgatgaa ggttggggta aacactccgg cctcttaagc 9420 catttcctgt tttttttttt tttttttttt tttttttctt tttttttttc tttcctttcc 9480 ttcttttttt cctttctttt tcccttcttt aatggtggct ccatcttagc cctagtcacg 9540 gctagctgtg aaaggtccgt gagccgcatg actgcagaga gtgctgatac tggcctctct 9600 gcagatcatg t 9611 4 3015 PRT Hepatitis C virus 4 Met Ser Thr Asn Pro Lys Pro Gln Arg Lys Thr Lys Arg Asn Thr Asn 1 5 10 15 Arg Arg Pro Gln Asp Val Lys Phe Pro Gly Gly Gly Gln Ile Val Gly 20 25 30 Gly Val Tyr Leu Leu Pro Arg Arg Gly Pro Arg Leu Gly Val Arg Ala 35 40 45 Thr Arg Lys Thr Ser Glu Arg Ser Gln Pro Arg Gly Arg Arg Gln Pro 50 55 60 Ile Pro Lys Asp Arg Arg Ser Thr Gly Lys Ser Trp Gly Lys Pro Gly 65 70 75 80 Tyr Pro Trp Pro Leu Tyr Gly Asn Glu Gly Leu Gly Trp Ala Gly Trp 85 90 95 Leu Leu Ser Pro Arg Gly Ser Arg Pro Ser Trp Gly Pro Asn Asp Pro 100 105 110 Arg His Arg Ser Arg Asn Val Gly Lys Val Ile Asp Thr Leu Thr Cys 115 120 125 Gly Phe Ala Asp Leu Met Gly Tyr Ile Pro Val Val Gly Ala Pro Leu 130 135 140 Gly Gly Val Ala Arg Ala Leu Ala His Gly Val Arg Val Leu Glu Asp 145 150 155 160 Gly Val Asn Phe Ala Thr Gly Asn Leu Pro Gly Cys Ser Phe Ser Ile 165 170 175 Phe Leu Leu Ala Leu Leu Ser Cys Ile Thr Thr Pro Val Ser Ala Ala 180 185 190 Glu Val Lys Asn Ile Ser Thr Gly Tyr Met Val Thr Asn Asp Cys Thr 195 200 205 Asn Asp Ser Ile Thr Trp Gln Leu Gln Ala Ala Val Leu His Val Pro 210 215 220 Gly Cys Val Pro Cys Glu Lys Val Gly Asn Ala Ser Gln Cys Trp Ile 225 230 235 240 Pro Val Ser Pro Asn Val Ala Val Gln Arg Pro Gly Ala Leu Thr Gln 245 250 255 Gly Leu Arg Thr His Ile Asp Met Val Val Met Ser Ala Thr Leu Cys 260 265 270 Ser Ala Leu Tyr Val Gly Asp Leu Cys Gly Gly Val Met Leu Ala Ala 275 280 285 Gln Met Phe Ile Val Ser Pro Gln His His Trp Phe Val Gln Asp Cys 290 295 300 Asn Cys Ser Ile Tyr Pro Gly Thr Ile Thr Gly His Arg Met Ala Trp 305 310 315 320 Asp Met Met Met Asn Trp Ser Pro Thr Ala Thr Met Ile Leu Ala Tyr 325 330 335 Ala Met Arg Val Pro Glu Val Ile Ile Asp Ile Ile Ser Gly Ala His 340 345 350 Trp Gly Val Met Phe Gly Leu Ala Tyr Phe Ser Met Gln Gly Ala Trp 355 360 365 Ala Lys Val Val Val Ile Leu Leu Leu Ala Ala Gly Val Asp Ala Arg 370 375 380 Thr His Thr Val Gly Gly Ser Ala Ala Gln Thr Thr Gly Arg Leu Thr 385 390 395 400 Ser Leu Phe Asp Met Gly Pro Arg Gln Lys Ile Gln Leu Val Asn Thr 405 410 415 Asn Gly Ser Trp His Ile Asn Arg Thr Ala Leu Asn Cys Asn Asp Ser 420 425 430 Leu His Thr Gly Phe Ile Ala Ser Leu Phe Tyr Thr His Ser Phe Asn 435 440 445 Ser Ser Gly Cys Pro Glu Arg Met Ser Ala Cys Arg Ser Ile Glu Ala 450 455 460 Phe Arg Val Gly Trp Gly Ala Leu Gln Tyr Glu Asp Asn Val Thr Asn 465 470 475 480 Pro Glu Asp Met Arg Pro Tyr Cys Trp His Tyr Pro Pro Arg Gln Cys 485 490 495 Gly Val Val Ser Ala Lys Thr Val Cys Gly Pro Val Tyr Cys Phe Thr 500 505 510 Pro Ser Pro Val Val Val Gly Thr Thr Asp Arg Leu Gly Ala Pro Thr 515 520 525 Tyr Thr Trp Gly Glu Asn Glu Thr Asp Val Phe Leu Leu Asn Ser Thr 530 535 540 Arg Pro Pro Leu Gly Ser Trp Phe Gly Cys Thr Trp Met Asn Ser Ser 545 550 555 560 Gly Tyr Thr Lys Thr Cys Gly Ala Pro Pro Cys Arg Thr Arg Ala Asp 565 570 575 Phe Asn Ala Ser Thr Asp Leu Leu Cys Pro Thr Asp Cys Phe Arg Lys 580 585 590 His Pro Asp Thr Thr Tyr Leu Lys Cys Gly Ser Gly Pro Trp Leu Thr 595 600 605 Pro Arg Cys Leu Ile Asp Tyr Pro Tyr Arg Leu Trp His Tyr Pro Cys 610 615 620 Thr Val Asn Tyr Thr Ile Phe Lys Ile Arg Met Tyr Val Gly Gly Val 625 630 635 640 Glu His Arg Leu Thr Ala Ala Cys Asn Phe Thr Arg Gly Asp Arg Cys 645 650 655 Asn Leu Glu Asp Arg Asp Arg Ser Gln Leu Ser Pro Leu Leu His Ser 660 665 670 Thr Thr Glu Trp Ala Ile Leu Pro Cys Ser Tyr Ser Asp Leu Pro Ala 675 680 685 Leu Ser Thr Gly Leu Leu His Leu His Gln Asn Ile Val Asp Val Gln 690 695 700 Phe Met Tyr Gly Leu Ser Pro Ala Leu Thr Lys Tyr Ile Val Arg Trp 705 710 715 720 Glu Trp Val Ile Leu Leu Phe Leu Leu Leu Ala Asp Ala Arg Val Cys 725 730 735 Ala Cys Leu Trp Met Leu Ile Leu Leu Gly Gln Ala Glu Ala Ala Leu 740 745 750 Glu Lys Leu Val Ile Leu His Ala Ala Ser Ala Ala Ser Cys Asn Gly 755 760 765 Phe Leu Tyr Phe Val Ile Phe Phe Val Ala Ala Trp Tyr Ile Lys Gly 770 775 780 Arg Val Val Pro Leu Ala Thr Tyr Ser Leu Thr Gly Leu Trp Ser Phe 785 790 795 800 Ser Leu Leu Leu Leu Ala Leu Pro Gln Gln Ala Tyr Ala Leu Asp Thr 805 810 815 Glu Val Ala Ala Ser Cys Gly Gly Val Val Leu Val Gly Leu Met Ala 820 825 830 Leu Thr Leu Ser Pro Tyr Tyr Lys Arg Tyr Ile Ser Trp Cys Met Trp 835 840 845 Trp Leu Gln Tyr Phe Leu Thr Arg Val Glu Ala Gln Leu His Val Trp 850 855 860 Val Pro Pro Leu Asn Val Arg Gly Gly Arg Asp Ala Val Ile Leu Leu 865 870 875 880 Met Cys Val Val His Pro Thr Leu Val Phe Asp Ile Thr Lys Leu Leu 885 890 895 Leu Ala Ile Phe Gly Pro Leu Trp Ile Leu Gln Ala Ser Leu Leu Lys 900 905 910 Val Pro Tyr Phe Val Arg Val Gln Gly Leu Leu Arg Ile Cys Ala Leu 915 920 925 Ala Arg Lys Ile Ala Gly Gly His Tyr Val Gln Met Ala Ile Ile Lys 930 935 940 Leu Gly Ala Leu Thr Gly Thr Tyr Val Tyr Asn His Leu Thr Pro Leu 945 950 955 960 Arg Asp Trp Ala His Asn Gly Leu Arg Asp Leu Ala Val Ala Val Glu 965 970 975 Pro Val Val Phe Ser Arg Met Glu Thr Lys Leu Ile Thr Trp Gly Ala 980 985 990 Asp Thr Ala Ala Cys Gly Asp Ile Ile Asn Gly Leu Pro Val Ser Ala 995 1000 1005 Arg Arg Gly Gln Glu Ile Leu Leu Gly Pro Ala Asp Gly Met Val Ser 1010 1015 1020 Lys Gly Trp Arg Leu Leu Ala Pro Ile Thr Ala Tyr Ala Gln Gln Thr 1025 1030 1035 1040 Arg Gly Leu Leu Gly Cys Ile Ile Thr Ser Leu Thr Gly Arg Asp Lys 1045 1050 1055 Asn Gln Val Glu Gly Glu Val Gln Ile Val Ser Thr Ala Thr Gln Thr 1060 1065 1070 Phe Leu Ala Thr Cys Ile Asn Gly Val Cys Trp Thr Val Tyr His Gly 1075 1080 1085 Ala Gly Thr Arg Thr Ile Ala Ser Pro Lys Gly Pro Val Ile Gln Met 1090 1095 1100 Tyr Thr Asn Val Asp Gln Asp Leu Val Gly Trp Pro Ala Pro Gln Gly 1105

1110 1115 1120 Ser Arg Ser Leu Thr Pro Cys Thr Cys Gly Ser Ser Asp Leu Tyr Leu 1125 1130 1135 Val Thr Arg His Ala Asp Val Ile Pro Val Arg Arg Arg Gly Asp Ser 1140 1145 1150 Arg Gly Ser Leu Leu Ser Pro Arg Pro Ile Ser Tyr Leu Lys Gly Ser 1155 1160 1165 Ser Gly Gly Pro Leu Leu Cys Pro Ala Gly His Ala Val Gly Leu Phe 1170 1175 1180 Arg Ala Ala Val Cys Thr Arg Gly Val Ala Lys Ala Val Asp Phe Ile 1185 1190 1195 1200 Pro Val Glu Asn Leu Gly Thr Thr Met Arg Ser Pro Val Phe Thr Asp 1205 1210 1215 Asn Ser Ser Pro Pro Ala Val Pro Gln Ser Phe Gln Val Ala His Leu 1220 1225 1230 His Ala Pro Thr Gly Ser Gly Lys Ser Thr Lys Val Pro Ala Ala Tyr 1235 1240 1245 Ala Ala Gln Gly Tyr Lys Val Leu Val Leu Asn Pro Ser Val Ala Ala 1250 1255 1260 Thr Leu Gly Phe Gly Ala Tyr Met Ser Lys Ala His Gly Val Asp Pro 1265 1270 1275 1280 Asn Ile Arg Thr Gly Val Arg Thr Ile Thr Thr Gly Ser Pro Ile Thr 1285 1290 1295 Tyr Ser Thr Tyr Gly Lys Phe Leu Ala Asp Gly Gly Cys Ser Gly Gly 1300 1305 1310 Ala Tyr Asp Ile Ile Ile Cys Asp Glu Cys His Ser Thr Asp Ala Thr 1315 1320 1325 Ser Ile Leu Gly Ile Gly Thr Val Leu Asp Gln Ala Glu Thr Ala Gly 1330 1335 1340 Ala Arg Leu Val Val Leu Ala Thr Ala Thr Pro Pro Gly Ser Val Thr 1345 1350 1355 1360 Val Ser His Pro Asn Ile Glu Glu Val Ala Leu Ser Thr Thr Gly Glu 1365 1370 1375 Ile Pro Phe Tyr Gly Lys Ala Ile Pro Leu Glu Val Ile Lys Gly Gly 1380 1385 1390 Arg His Leu Ile Phe Cys His Ser Lys Lys Lys Cys Asp Glu Leu Ala 1395 1400 1405 Ala Lys Leu Val Ala Leu Gly Ile Asn Ala Val Ala Tyr Tyr Arg Gly 1410 1415 1420 Leu Asp Val Ser Val Ile Pro Thr Ser Gly Asp Val Val Val Val Ser 1425 1430 1435 1440 Thr Asp Ala Leu Met Thr Gly Phe Thr Gly Asp Phe Asp Ser Val Ile 1445 1450 1455 Asp Cys Asn Thr Cys Val Thr Gln Thr Val Asp Phe Ser Leu Asp Pro 1460 1465 1470 Thr Phe Thr Ile Glu Thr Thr Thr Leu Pro Gln Asp Ala Val Ser Arg 1475 1480 1485 Thr Gln Arg Arg Gly Arg Thr Gly Arg Gly Lys Pro Gly Ile Tyr Arg 1490 1495 1500 Phe Val Ala Pro Gly Glu Arg Pro Ser Gly Met Phe Asp Ser Ser Val 1505 1510 1515 1520 Leu Cys Glu Cys Tyr Asp Ala Gly Cys Ala Trp Tyr Glu Leu Thr Pro 1525 1530 1535 Ala Glu Thr Thr Val Arg Leu Arg Ala Tyr Met Asn Thr Pro Gly Leu 1540 1545 1550 Pro Val Cys Gln Asp His Leu Glu Phe Trp Glu Gly Val Phe Thr Gly 1555 1560 1565 Leu Thr His Ile Asp Ala His Phe Leu Ser Gln Thr Lys Gln Ser Gly 1570 1575 1580 Glu Asn Phe Pro Tyr Leu Val Ala Tyr Gln Ala Thr Val Cys Ala Arg 1585 1590 1595 1600 Ala Gln Ala Pro Pro Pro Ser Trp Asp Gln Met Trp Lys Cys Leu Ile 1605 1610 1615 Arg Leu Lys Pro Thr Leu His Gly Pro Thr Pro Leu Leu Tyr Arg Leu 1620 1625 1630 Gly Ala Val Gln Asn Glu Val Thr Leu Thr His Pro Ile Thr Lys Tyr 1635 1640 1645 Ile Met Thr Cys Met Ser Ala Asp Leu Glu Val Val Thr Ser Thr Trp 1650 1655 1660 Val Leu Val Gly Gly Val Leu Ala Ala Leu Ala Ala Tyr Cys Leu Ser 1665 1670 1675 1680 Thr Gly Cys Val Val Ile Val Gly Arg Ile Val Leu Ser Gly Lys Pro 1685 1690 1695 Ala Ile Ile Pro Asp Arg Glu Val Leu Tyr Gln Glu Phe Asp Glu Met 1700 1705 1710 Glu Glu Cys Ser Gln His Leu Pro Tyr Ile Glu Gln Gly Met Met Leu 1715 1720 1725 Ala Glu Gln Phe Lys Gln Lys Ala Leu Gly Leu Leu Gln Thr Ala Ser 1730 1735 1740 Arg His Ala Glu Val Ile Thr Pro Ala Val Gln Thr Asn Trp Gln Lys 1745 1750 1755 1760 Leu Glu Val Phe Trp Ala Lys His Met Trp Asn Phe Ile Ser Gly Ile 1765 1770 1775 Gln Tyr Leu Ala Gly Leu Ser Thr Leu Pro Gly Asn Pro Ala Ile Ala 1780 1785 1790 Ser Leu Met Ala Phe Thr Ala Ala Val Thr Ser Pro Leu Thr Thr Gly 1795 1800 1805 Gln Thr Leu Leu Phe Asn Ile Leu Gly Gly Trp Val Ala Ala Gln Leu 1810 1815 1820 Ala Ala Pro Gly Ala Ala Thr Ala Phe Val Gly Ala Gly Leu Ala Gly 1825 1830 1835 1840 Ala Ala Ile Gly Ser Val Gly Leu Gly Lys Val Leu Val Asp Ile Leu 1845 1850 1855 Ala Gly Tyr Gly Ala Gly Val Ala Gly Ala Leu Val Ala Phe Lys Ile 1860 1865 1870 Met Ser Gly Glu Val Pro Ser Thr Glu Asp Leu Val Asn Leu Leu Pro 1875 1880 1885 Ala Ile Leu Ser Pro Gly Ala Leu Val Val Gly Val Val Cys Ala Ala 1890 1895 1900 Ile Leu Arg Arg His Val Gly Pro Gly Glu Gly Ala Val Gln Trp Met 1905 1910 1915 1920 Asn Arg Leu Ile Ala Phe Ala Ser Arg Gly Asn His Val Ser Pro Thr 1925 1930 1935 His Tyr Val Pro Glu Ser Asp Ala Ala Ala Arg Val Thr Ala Ile Leu 1940 1945 1950 Ser Ser Leu Thr Val Thr Gln Leu Leu Arg Arg Leu His Gln Trp Ile 1955 1960 1965 Ser Ser Glu Cys Thr Thr Pro Cys Ser Gly Ser Trp Leu Arg Asp Ile 1970 1975 1980 Trp Asp Trp Ile Cys Glu Val Leu Ser Asp Phe Lys Thr Trp Leu Lys 1985 1990 1995 2000 Ala Lys Leu Met Pro Gln Leu Pro Gly Ile Pro Phe Val Ser Cys Gln 2005 2010 2015 Arg Gly Tyr Arg Gly Val Trp Arg Gly Asp Gly Ile Met His Thr Arg 2020 2025 2030 Cys His Cys Gly Ala Glu Ile Thr Gly His Val Lys Asn Gly Thr Met 2035 2040 2045 Arg Ile Val Gly Pro Arg Thr Cys Arg Asn Met Trp Ser Gly Thr Phe 2050 2055 2060 Pro Ile Asn Ala Tyr Thr Thr Gly Pro Cys Thr Pro Leu Pro Ala Pro 2065 2070 2075 2080 Asn Tyr Lys Phe Ala Leu Trp Arg Val Ser Ala Glu Glu Tyr Val Glu 2085 2090 2095 Ile Arg Arg Val Gly Asp Phe His Tyr Val Ser Gly Met Thr Thr Asp 2100 2105 2110 Asn Leu Lys Cys Pro Cys Gln Ile Pro Ser Pro Glu Phe Phe Thr Glu 2115 2120 2125 Leu Asp Gly Val Arg Leu His Arg Phe Ala Pro Pro Cys Lys Pro Leu 2130 2135 2140 Leu Arg Glu Glu Val Ser Phe Arg Val Gly Leu His Glu Tyr Pro Val 2145 2150 2155 2160 Gly Ser Gln Leu Pro Cys Glu Pro Glu Pro Asp Val Ala Val Leu Thr 2165 2170 2175 Ser Met Leu Thr Asp Pro Ser His Ile Thr Ala Glu Ala Ala Gly Arg 2180 2185 2190 Arg Leu Ala Arg Gly Ser Pro Pro Ser Met Ala Ser Ser Ser Ala Ser 2195 2200 2205 Gln Leu Ser Ala Pro Ser Leu Lys Ala Thr Cys Thr Ala Asn His Asp 2210 2215 2220 Ser Pro Asp Ala Glu Leu Ile Glu Ala Asn Leu Leu Trp Arg Gln Glu 2225 2230 2235 2240 Met Gly Gly Asn Ile Thr Arg Val Glu Ser Glu Asn Lys Val Val Ile 2245 2250 2255 Leu Asp Ser Phe Asp Pro Leu Val Ala Glu Glu Asp Glu Arg Glu Val 2260 2265 2270 Ser Val Pro Ala Glu Ile Leu Arg Lys Ser Arg Arg Phe Ala Arg Ala 2275 2280 2285 Leu Pro Val Trp Ala Arg Pro Asp Tyr Asn Pro Pro Leu Val Glu Thr 2290 2295 2300 Trp Lys Lys Pro Asp Tyr Glu Pro Pro Val Val His Gly Cys Pro Leu 2305 2310 2315 2320 Pro Pro Pro Arg Ser Pro Pro Val Pro Pro Pro Arg Lys Lys Arg Thr 2325 2330 2335 Val Val Leu Thr Glu Ser Thr Leu Ser Thr Ala Leu Ala Glu Leu Ala 2340 2345 2350 Thr Lys Ser Phe Gly Ser Ser Ser Thr Ser Gly Ile Thr Gly Asp Asn 2355 2360 2365 Thr Thr Thr Ser Ser Glu Pro Ala Pro Ser Gly Cys Pro Pro Asp Ser 2370 2375 2380 Asp Val Glu Ser Tyr Ser Ser Met Pro Pro Leu Glu Gly Glu Pro Gly 2385 2390 2395 2400 Asp Pro Asp Leu Ser Asp Gly Ser Trp Ser Thr Val Ser Ser Gly Ala 2405 2410 2415 Asp Thr Glu Asp Val Val Cys Cys Ser Met Ser Tyr Ser Trp Thr Gly 2420 2425 2430 Ala Leu Val Thr Pro Cys Ala Ala Glu Glu Gln Lys Leu Pro Ile Asn 2435 2440 2445 Ala Leu Ser Asn Ser Leu Leu Arg His His Asn Leu Val Tyr Ser Thr 2450 2455 2460 Thr Ser Arg Ser Ala Cys Gln Arg Gln Lys Lys Val Thr Phe Asp Arg 2465 2470 2475 2480 Leu Gln Val Leu Asp Ser His Tyr Gln Asp Val Leu Lys Glu Val Lys 2485 2490 2495 Ala Ala Ala Ser Lys Val Lys Ala Asn Leu Leu Ser Val Glu Glu Ala 2500 2505 2510 Cys Ser Leu Thr Pro Pro His Ser Ala Lys Ser Lys Phe Gly Tyr Gly 2515 2520 2525 Ala Lys Asp Val Arg Cys His Ala Arg Lys Ala Val Ala His Ile Asn 2530 2535 2540 Ser Val Trp Lys Asp Leu Leu Glu Asp Ser Val Thr Pro Ile Asp Thr 2545 2550 2555 2560 Thr Ile Met Ala Lys Asn Glu Val Phe Cys Val Gln Pro Glu Lys Gly 2565 2570 2575 Gly Arg Lys Pro Ala Arg Leu Ile Val Phe Pro Asp Leu Gly Val Arg 2580 2585 2590 Val Cys Glu Lys Met Ala Leu Tyr Asp Val Val Ser Lys Leu Pro Leu 2595 2600 2605 Ala Val Met Gly Ser Ser Tyr Gly Phe Gln Tyr Ser Pro Gly Gln Arg 2610 2615 2620 Val Glu Phe Leu Val Gln Ala Trp Lys Ser Lys Lys Thr Pro Met Gly 2625 2630 2635 2640 Phe Ser Tyr Asp Thr Arg Cys Phe Asp Ser Thr Val Thr Glu Ser Asp 2645 2650 2655 Ile Arg Thr Glu Glu Ala Ile Tyr Gln Cys Cys Asp Leu Asp Pro Gln 2660 2665 2670 Ala Arg Val Ala Ile Lys Ser Leu Thr Glu Arg Leu Tyr Val Gly Gly 2675 2680 2685 Pro Leu Thr Asn Ser Arg Gly Glu Asn Cys Gly Tyr Arg Arg Cys Arg 2690 2695 2700 Ala Ser Gly Val Leu Thr Thr Ser Cys Gly Asn Thr Leu Thr Cys Tyr 2705 2710 2715 2720 Ile Lys Ala Arg Ala Ala Cys Arg Ala Ala Gly Leu Gln Asp Cys Thr 2725 2730 2735 Met Leu Val Cys Gly Asp Asp Leu Val Val Ile Cys Glu Ser Ala Gly 2740 2745 2750 Val Gln Glu Asp Ala Ala Ser Leu Arg Ala Phe Thr Glu Ala Met Thr 2755 2760 2765 Arg Tyr Ser Ala Pro Pro Gly Asp Pro Pro Gln Pro Glu Tyr Asp Leu 2770 2775 2780 Glu Leu Ile Thr Ser Cys Ser Ser Asn Val Ser Val Ala His Asp Gly 2785 2790 2795 2800 Ala Gly Lys Arg Val Tyr Tyr Leu Thr Arg Asp Pro Thr Thr Pro Leu 2805 2810 2815 Ala Arg Ala Ala Trp Glu Thr Ala Arg His Thr Pro Val Asn Ser Trp 2820 2825 2830 Leu Gly Asn Ile Ile Met Phe Ala Pro Thr Leu Trp Ala Arg Met Ile 2835 2840 2845 Leu Met Thr His Phe Phe Ser Val Leu Ile Ala Arg Asp Gln Leu Glu 2850 2855 2860 Gln Ala Leu Asn Cys Glu Ile Tyr Gly Ala Cys Tyr Ser Ile Glu Pro 2865 2870 2875 2880 Leu Asp Leu Pro Pro Ile Ile Gln Arg Leu His Gly Leu Ser Ala Phe 2885 2890 2895 Ser Leu His Ser Tyr Ser Pro Gly Glu Ile Asn Arg Val Ala Ala Cys 2900 2905 2910 Leu Arg Lys Leu Gly Val Pro Pro Leu Arg Ala Trp Arg His Arg Ala 2915 2920 2925 Arg Ser Val Arg Ala Arg Leu Leu Ser Arg Gly Gly Arg Ala Ala Ile 2930 2935 2940 Cys Gly Lys Tyr Leu Phe Asn Trp Ala Val Arg Thr Lys Leu Lys Leu 2945 2950 2955 2960 Thr Pro Ile Ala Ala Ala Gly Arg Leu Asp Leu Ser Gly Trp Phe Thr 2965 2970 2975 Ala Gly Tyr Ser Gly Gly Asp Ile Tyr His Ser Val Ser His Ala Arg 2980 2985 2990 Pro Arg Trp Phe Trp Phe Cys Leu Leu Leu Leu Ala Ala Gly Val Gly 2995 3000 3005 Ile Tyr Leu Leu Pro Asn Arg 3010 3015 5 9611 DNA Hepatitis C virus 5 gccagccccc tgatgggggc gacactccac catgaatcac tcccctgtga ggaactactg 60 tcttcacgca gaaagcgtct agccatggcg ttagtatgag tgtcgtgcag cctccaggac 120 cccccctccc gggagagcca tagtggtctg cggaaccggt gagtacaccg gaattgccgg 180 gaagactggg tcctttcttg gataaaccca ctctatgccc ggccatttgg gcgtgccccc 240 gcaagactgc tagccgagta gcgttgggtt gcgaaaggcc ttgtggtact gcctgatagg 300 gtgcttgcga gtgccccggg aggtctcgta gaccgtgcac catgagcaca aatcctaaac 360 ctcaaagaaa aaccaaaaga aacaccaacc gtcgcccaca agacgttaag tttccgggcg 420 gcggccagat cgttggcgga gtatacttgt tgccgcgcag gggccccagg ttgggtgtgc 480 gcgcgacaag gaagacttcg gagcggtccc agccacgtgg aaggcgccag cccatcccta 540 aagatcggcg ctccactggc aaatcctggg gaaaaccagg atacccctgg cccctatacg 600 ggaatgaggg actcggctgg gcaggatggc tcctgtcccc ccgaggttcc cgtccctctt 660 ggggccccaa tgacccccgg cataggtcgc gcaacgtggg taaggtcatc gataccctaa 720 cgtgcggctt tgccgacctc atggggtaca tccctgtcgt gggcgccccg ctcggcggcg 780 tcgccagagc tctcgcgcat ggcgtgagag tcctggagga cggggttaat tttgcaacag 840 ggaacttacc cggttgctcc ttttctatct tcttgctggc cctgctgtcc tgcatcacca 900 ccccggtctc cgctgccgaa gtgaagaaca tcagtaccgg ctacatggtg actaacgact 960 gcaccaatga cagcattacc tggcagctcc aggctgctgt cctccacgtc cccgggtgcg 1020 tcccgtgcga gaaagtgggg aatgcatctc agtgctggat accggtctca ccgaatgtgg 1080 ccgtgcagcg gcccggcgcc ctcacgcagg gcttgcggac gcacatcgac atggttgtga 1140 tgtccgccac gctctgctct gccctctacg tgggggacct ctgcggtggg gtgatgctcg 1200 cagcccaaat gttcattgtc tcgccgcagc accactggtt tgtccaagac tgcaattgct 1260 ccatctaccc tggtaccatc actggacacc gcatggcatg ggacatgatg atgaactggt 1320 cgcccacggc taccatgatc ttggcgtacg cgatgcgtgt ccccgaggtc attatagaca 1380 tcattagcgg ggctcattgg ggcgtcatgt tcggcttggc ctacttctct atgcagggag 1440 cgtgggcgaa agtcgttgtc atccttctgt tggccgccgg ggtggacgcg cgcacccata 1500 ctgttggggg ttctgccgcg cagaccaccg ggcgcctcac cagcttattt gacatgggcc 1560 ccaggcagaa aatccagctc gttaacacca atggcagctg gcacatcaac cgcaccgccc 1620 tgaactgcaa tgactccttg cacaccggct ttatcgcgtc tctgttctac acccacagct 1680 tcaactcgtc aggatgtccc gaacgcatgt ccgcctgccg cagtatcgag gccttccggg 1740 tgggatgggg cgccttgcaa tatgaggata atgtcaccaa tccagaggat atgagaccct 1800 attgctggca ctacccacca aggcagtgtg gcgtggtctc cgcgaagact gtgtgtggcc 1860 cagtgtactg tttcaccccc agcccagtgg tagtgggcac gaccgacagg cttggagcgc 1920 ccacttacac gtggggggag aatgagacag atgtcttcct attgaacagc actcgaccac 1980 cgctggggtc atggttcggc tgcacgtgga tgaactcttc tggctacacc aagacttgcg 2040 gcgcaccacc ctgccgtact agagctgact tcaacgccag cacggacctg ttgtgcccca 2100 cggactgttt taggaagcat cctgatacca cttacctcaa atgcggctct gggccctggc 2160 tcacgccaag gtgcctgatc gactacccct acaggctctg gcattacccc tgcacagtta 2220 actataccat cttcaaaata aggatgtatg tgggaggggt tgagcacagg ctcacggctg 2280 catgcaattt cactcgtggg gatcgttgca acttggagga cagagacaga agtcaactgt 2340 ctcctttgtt gcactccacc acggaatggg ccattttacc ttgctcttac tcggacctgc 2400 ccgccttgtc gactggtctt ctccacctcc accaaaacat cgtggacgta caattcatgt 2460 atggcctatc acctgccctc acaaaataca tcgtccgatg ggagtgggta atactcttat 2520 tcctgctctt agcggacgcc agggtttgcg cctgcttatg gatgctcatc ttgttgggcc 2580 aggccgaagc agctttggag aacctcgtaa tactcaatgc agcatccctg gccgggacgc 2640 acggtcttgt gtccttcctc gtgttcttct gctttgcgtg gtatctgaag ggtaggtggg 2700 tgcccggagc ggtctacgcc ctctacggga tgtggcctct cctcctgctc ctgctggcgt 2760 tgcctcagcg ggcatatgca ctggacacgg aggtggccgc gtcgtgtggc ggcgttgttc 2820 ttgtcgggtt aatggcgctg actctgtcgc catattacaa gcgctatatc agctggtgca 2880 tgtggtggct tcagtatttt ctgaccagag tagaagcgca actgcacgtg tgggttcccc 2940 ccctcaacgt ccgggggggg cgcgatgccg tcatcttact catgtgtgta gtacacccga 3000 ccctggtatt tgacatcacc aaactactcc tggccatctt cggacccctt tggattcttc 3060 aagccagttt gcttaaagtc ccctacttcg tgcgcgttca aggccttctc cggatctgcg 3120 cgctagcgcg gaagatagcc ggaggtcatt

acgtgcaaat ggccatcatc aagttagggg 3180 cgcttactgg cacctatgtg tataaccatc tcacccctct tcgagactgg gcgcacaacg 3240 gcctgcgaga tctggccgtg gctgtggaac cagtcgtctt ctcccgaatg gagaccaagc 3300 tcatcacgtg gggggcagat accgccgcgt gcggtgacat catcaacggc ttgcccgtct 3360 ctgcccgtag gggccaggag atactgcttg ggccagccga cggaatggtc tccaaggggt 3420 ggaggttgct ggcgcccatc acggcgtacg cccagcagac gagaggcctc ctagggtgta 3480 taatcaccag cctgactggc cgggacaaaa accaagtgga gggtgaggtc cagatcgtgt 3540 caactgctac ccaaaccttc ctggcaacgt gcatcaatgg ggtatgctgg actgtctacc 3600 acggggccgg aacgaggacc atcgcatcac ccaagggtcc tgtcatccag atgtatacca 3660 atgtggacca agaccttgtg ggctggcccg ctcctcaagg ttcccgctca ttgacaccct 3720 gtacctgcgg ctcctcggac ctttacctgg tcacgaggca cgccgatgtc attcccgtgc 3780 gccggcgagg tgatagcagg ggtagcctgc tttcgccccg gcccatttcc tacttgaaag 3840 gctcctcggg gggtccgctg ttgtgccccg cgggacacgc cgtgggccta ttcagggccg 3900 cggtgtgcac ccgtggagtg gctaaagcgg tggactttat ccctgtggag aacctaggga 3960 caaccatgag atccccggtg ttcacggaca actcctctcc accagcagtg ccccagagct 4020 tccaggtggc ccacctgcat gctcccaccg gcagcggtaa gagcaccaag gtcccggctg 4080 cgtacgcagc ccagggctac aaggtgttgg tgctcaaccc ctctgttgct gcaacgctgg 4140 gctttggtgc ttacatgtcc aaggcccatg gggttgatcc taatatcagg accggggtga 4200 gaacaattac cactggcagc cccatcacgt actccaccta cggcaagttc cttgccgacg 4260 gcgggtgctc aggaggtgct tatgacataa taatttgtga cgagtgccac tccacggatg 4320 ccacatccat cttgggcatc ggcactgtcc ttgaccaagc agagactgcg ggggcgagac 4380 tggttgtgct cgccactgct acccctccgg gctccgtcac tgtgtcccat cctaacatcg 4440 aggaggttgc tctgtccacc accggagaga tcccctttta cggcaaggct atccccctcg 4500 aggtgatcaa ggggggaaga catctcatct tctgccactc aaagaagaag tgcgacgagc 4560 tcgccgcgaa gctggtcgca ttgggcatca atgccgtggc ctactaccgc ggtcttgacg 4620 tgtctgtcat cccgaccagc ggcgatgttg tcgtcgtgtc gaccgatgct ctcatgactg 4680 gctttaccgg cgacttcgac tctgtgatag actgcaacac gtgtgtcact cagacagtcg 4740 atttcagcct tgaccctacc tttaccattg agacaaccac gctcccccag gatgctgtct 4800 ccaggactca acgccggggc aggactggca gggggaagcc aggcatctat agatttgtgg 4860 caccggggga gcgcccctcc ggcatgttcg actcgtccgt cctctgtgag tgctatgacg 4920 cgggctgtgc ttggtatgag ctcacgcccg ccgagactac agttaggcta cgagcgtaca 4980 tgaacacccc ggggcttccc gtgtgccagg accatcttga attttgggag ggcgtcttta 5040 cgggcctcac tcatatagat gcccactttt tatcccagac aaagcagagt ggggagaact 5100 ttccttacct ggtagcgtac caagccaccg tgtgcgctag ggctcaagcc cctcccccat 5160 cgtgggacca gatgtggaag tgtttgatcc gccttaaacc caccctccat gggccaacac 5220 ccctgctata cagactgggc gctgttcaga atgaagtcac cctgacgcac ccaatcacca 5280 aatacatcat gacatgcatg tcggccgacc tggaggtcgt cacgagcacc tgggtgctcg 5340 ttggcggcgt cctggctgct ctggccgcgt attgcctgtc aacaggctgc gtggtcatag 5400 tgggcaggat cgtcttgtcc gggaagccgg caattatacc tgacagggag gttctctacc 5460 aggagttcga tgagatggaa gagtgctctc agcacttacc gtacatcgag caagggatga 5520 tgctcgctga gcagttcaag cagaaggccc tcggcctcct gcagaccgcg tcccgccatg 5580 cagaggttat cacccctgct gtccagacca actggcagaa actcgaggtc ttttgggcga 5640 agcacatgtg gaatttcatc agtgggatac aatacttggc gggcctgtca acgctgcctg 5700 gtaaccccgc cattgcttca ttgatggctt ttacagctgc cgtcaccagc ccactaacca 5760 ctggccaaac cctcctcttc aacatattgg gggggtgggt ggctgcccag ctcgccgccc 5820 ccggtgccgc tactgccttt gtgggtgctg gcctagctgg cgccgccatc ggcagcgttg 5880 gactggggaa ggtcctcgtg gacattcttg cagggtatgg cgcgggcgtg gcgggagctc 5940 ttgtagcatt caagatcatg agcggtgagg tcccctccac ggaggacctg gtcaatctgc 6000 tgcccgccat cctctcgcct ggagcccttg tagtcggtgt ggtctgcgca gcaatactgc 6060 gccggcacgt tggcccgggc gagggggcag tgcaatggat gaaccggcta atagccttcg 6120 cctcccgggg gaaccatgtt tcccccacgc actacgtgcc ggagagcgat gcagccgccc 6180 gcgtcactgc catactcagc agcctcactg taacccagct cctgaggcga ctgcatcagt 6240 ggataagctc ggagtgtacc actccatgct ccggttcctg gctaagggac atctgggact 6300 ggatatgcga ggtgctgagc gactttaaga cctggctgaa agccaagctc atgccacaac 6360 tgcctgggat tccctttgtg tcctgccagc gcgggtatag gggggtctgg cgaggagacg 6420 gcattatgca cactcgctgc cactgtggag ctgagatcac tggacatgtc aaaaacggga 6480 cgatgaggat cgtcggtcct aggacctgca ggaacatgtg gagtgggacg ttccccatta 6540 acgcctacac cacgggcccc tgtactcccc ttcctgcgcc gaactataag ttcgcgctgt 6600 ggagggtgtc tgcagaggaa tacgtggaga taaggcgggt gggggacttc cactacgtat 6660 cgggtatgac tactgacaat cttaaatgcc cgtgccagat cccatcgccc gaatttttca 6720 cagaattgga cggggtgcgc ctacacaggt ttgcgccccc ttgcaagccc ttgctgcggg 6780 aggaggtatc attcagagta ggactccacg agtacccggt ggggtcgcaa ttaccttgcg 6840 agcccgaacc ggacgtagcc gtgttgacgt ccatgctcac tgatccctcc catataacag 6900 cagaggcggc cgggagaagg ttggcgagag ggtcaccccc ttctatggcc agctcctcgg 6960 ctagccagct gtccgctcca tctctcaagg caacttgcac cgccaaccat gactcccctg 7020 acgccgagct catagaggct aacctcctgt ggaggcagga gatgggcggc aacatcacca 7080 gggttgagtc agagaacaaa gtggtgattc tggactcctt cgatccgctt gtggcagagg 7140 aggatgagcg ggaggtctcc gtacctgcag aaattctgcg gaagtctcgg agattcgccc 7200 gggccctgcc cgtctgggcg cggccggact acaacccccc gctagtagag acgtggaaaa 7260 agcctgacta cgaaccacct gtggtccatg gctgcccgct accacctcca cggtcccctc 7320 ctgtgcctcc gcctcggaaa aagcgtacgg tggtcctcac cgaatcaacc ctatctactg 7380 ccttggccga gcttgccacc aaaagttttg gcagctcctc aacttccggc attacgggcg 7440 acaatacgac aacatcctct gagcccgccc cttctggctg cccccccgac tccgacgttg 7500 agtcctattc ttccatgccc cccctggagg gggagcctgg ggatccggat ctcagcgacg 7560 ggtcatggtc gacggtcagt agtggggccg acacggaaga tgtcgtgtgc tgctcaatgt 7620 cttattcctg gacaggcgca ctcgtcaccc cgtgcgctgc ggaagaacaa aaactgccca 7680 tcaacgcact gagcaactcg ttgctacgcc atcacaatct ggtgtattcc accacttcac 7740 gcagtgcttg ccaaaggcag aagaaagtca catttgacag actgcaagtt ctggacagcc 7800 attaccagga cgtgctcaag gaggtcaaag cagcggcgtc aaaagtgaag gctaacttgc 7860 tatccgtaga ggaagcttgc agcctgacgc ccccacattc agccaaatcc aagtttggct 7920 atggggcaaa agacgtccgt tgccatgcca gaaaggccgt agcccacatc aactccgtgt 7980 ggaaagacct tctggaagac agtgtaacac caatagacac taccatcatg gccaagaacg 8040 aggttttctg cgttcagcct gagaaggggg gtcgtaagcc agctcgtctc atcgtgttcc 8100 ccgacctggg cgtgcgcgtg tgcgagaaga tggccctgta cgacgtggtt agcaagctcc 8160 ccctggccgt gatgggaagc tcctacggat tccaatactc accaggacag cgggttgaat 8220 tcctcgtgca agcgtggaag tccaagaaga ccccgatggg gttctcgtat gatacccgct 8280 gttttgactc cacagtcact gagagcgaca tccgtacgga ggaggcaatt taccaatgtt 8340 gtgacctgga cccccaagcc cgcgtggcca tcaagtccct cactgagagg ctttatgttg 8400 ggggccctct taccaattca aggggggaaa actgcggcta ccgcaggtgc cgcgcgagcg 8460 gcgtactgac aactagctgt ggtaacaccc tcacttgcta catcaaggcc cgggcagcct 8520 gtcgagccgc agggctccag gactgcacca tgctcgtgtg tggcgacgac ttagtcgtta 8580 tctgtgaaag tgcgggggtc caggaggacg cggcgagcct gagagccttc acggaggcta 8640 tgaccaggta ctccgccccc cccggggacc ccccacaacc agaatacgac ttggagctta 8700 taacatcatg ctcctccaac gtgtcagtcg cccacgacgg cgctggaaag agggtctact 8760 accttacccg tgaccctaca acccccctcg cgagagccgc gtgggagaca gcaagacaca 8820 ctccagtcaa ttcctggcta ggcaacataa tcatgtttgc ccccacactg tgggcgagga 8880 tgatactgat gacccatttc tttagcgtcc tcatagccag ggatcagctt gaacaggctc 8940 ttaactgtga gatctacgga gcctgctact ccatagaacc actggatcta cctccaatca 9000 ttcaaagact ccatggcctc agcgcatttt cactccacag ttactctcca ggtgaaatca 9060 atagggtggc cgcatgcctc agaaaacttg gggtcccgcc cttgcgagct tggagacacc 9120 gggcccggag cgtccgcgct aggcttctgt ccagaggagg cagggctgct atatgtggca 9180 agtacctctt caactgggca gtaagaacaa agctcaaact cactccaata gcggccgctg 9240 gccggctgga cttgtccggt tggttcacgg ctggctacag cgggggagac atttatcaca 9300 gcgtgtctca tgcccggccc cgctggttct ggttttgcct actcctgctc gctgcagggg 9360 taggcatcta cctcctcccc aaccgatgaa ggttggggta aacactccgg cctcttaagc 9420 catttcctgt tttttttttt tttttttttt tttttttctt tttttttttc tttcctttcc 9480 ttcttttttt cctttctttt tcccttcttt aatggtggct ccatcttagc cctagtcacg 9540 gctagctgtg aaaggtccgt gagccgcatg actgcagaga gtgctgatac tggcctctct 9600 gcagatcatg t 9611 6 3015 PRT Hepatitis C virus 6 Met Ser Thr Asn Pro Lys Pro Gln Arg Lys Thr Lys Arg Asn Thr Asn 1 5 10 15 Arg Arg Pro Gln Asp Val Lys Phe Pro Gly Gly Gly Gln Ile Val Gly 20 25 30 Gly Val Tyr Leu Leu Pro Arg Arg Gly Pro Arg Leu Gly Val Arg Ala 35 40 45 Thr Arg Lys Thr Ser Glu Arg Ser Gln Pro Arg Gly Arg Arg Gln Pro 50 55 60 Ile Pro Lys Asp Arg Arg Ser Thr Gly Lys Ser Trp Gly Lys Pro Gly 65 70 75 80 Tyr Pro Trp Pro Leu Tyr Gly Asn Glu Gly Leu Gly Trp Ala Gly Trp 85 90 95 Leu Leu Ser Pro Arg Gly Ser Arg Pro Ser Trp Gly Pro Asn Asp Pro 100 105 110 Arg His Arg Ser Arg Asn Val Gly Lys Val Ile Asp Thr Leu Thr Cys 115 120 125 Gly Phe Ala Asp Leu Met Gly Tyr Ile Pro Val Val Gly Ala Pro Leu 130 135 140 Gly Gly Val Ala Arg Ala Leu Ala His Gly Val Arg Val Leu Glu Asp 145 150 155 160 Gly Val Asn Phe Ala Thr Gly Asn Leu Pro Gly Cys Ser Phe Ser Ile 165 170 175 Phe Leu Leu Ala Leu Leu Ser Cys Ile Thr Thr Pro Val Ser Ala Ala 180 185 190 Glu Val Lys Asn Ile Ser Thr Gly Tyr Met Val Thr Asn Asp Cys Thr 195 200 205 Asn Asp Ser Ile Thr Trp Gln Leu Gln Ala Ala Val Leu His Val Pro 210 215 220 Gly Cys Val Pro Cys Glu Lys Val Gly Asn Ala Ser Gln Cys Trp Ile 225 230 235 240 Pro Val Ser Pro Asn Val Ala Val Gln Arg Pro Gly Ala Leu Thr Gln 245 250 255 Gly Leu Arg Thr His Ile Asp Met Val Val Met Ser Ala Thr Leu Cys 260 265 270 Ser Ala Leu Tyr Val Gly Asp Leu Cys Gly Gly Val Met Leu Ala Ala 275 280 285 Gln Met Phe Ile Val Ser Pro Gln His His Trp Phe Val Gln Asp Cys 290 295 300 Asn Cys Ser Ile Tyr Pro Gly Thr Ile Thr Gly His Arg Met Ala Trp 305 310 315 320 Asp Met Met Met Asn Trp Ser Pro Thr Ala Thr Met Ile Leu Ala Tyr 325 330 335 Ala Met Arg Val Pro Glu Val Ile Ile Asp Ile Ile Ser Gly Ala His 340 345 350 Trp Gly Val Met Phe Gly Leu Ala Tyr Phe Ser Met Gln Gly Ala Trp 355 360 365 Ala Lys Val Val Val Ile Leu Leu Leu Ala Ala Gly Val Asp Ala Arg 370 375 380 Thr His Thr Val Gly Gly Ser Ala Ala Gln Thr Thr Gly Arg Leu Thr 385 390 395 400 Ser Leu Phe Asp Met Gly Pro Arg Gln Lys Ile Gln Leu Val Asn Thr 405 410 415 Asn Gly Ser Trp His Ile Asn Arg Thr Ala Leu Asn Cys Asn Asp Ser 420 425 430 Leu His Thr Gly Phe Ile Ala Ser Leu Phe Tyr Thr His Ser Phe Asn 435 440 445 Ser Ser Gly Cys Pro Glu Arg Met Ser Ala Cys Arg Ser Ile Glu Ala 450 455 460 Phe Arg Val Gly Trp Gly Ala Leu Gln Tyr Glu Asp Asn Val Thr Asn 465 470 475 480 Pro Glu Asp Met Arg Pro Tyr Cys Trp His Tyr Pro Pro Arg Gln Cys 485 490 495 Gly Val Val Ser Ala Lys Thr Val Cys Gly Pro Val Tyr Cys Phe Thr 500 505 510 Pro Ser Pro Val Val Val Gly Thr Thr Asp Arg Leu Gly Ala Pro Thr 515 520 525 Tyr Thr Trp Gly Glu Asn Glu Thr Asp Val Phe Leu Leu Asn Ser Thr 530 535 540 Arg Pro Pro Leu Gly Ser Trp Phe Gly Cys Thr Trp Met Asn Ser Ser 545 550 555 560 Gly Tyr Thr Lys Thr Cys Gly Ala Pro Pro Cys Arg Thr Arg Ala Asp 565 570 575 Phe Asn Ala Ser Thr Asp Leu Leu Cys Pro Thr Asp Cys Phe Arg Lys 580 585 590 His Pro Asp Thr Thr Tyr Leu Lys Cys Gly Ser Gly Pro Trp Leu Thr 595 600 605 Pro Arg Cys Leu Ile Asp Tyr Pro Tyr Arg Leu Trp His Tyr Pro Cys 610 615 620 Thr Val Asn Tyr Thr Ile Phe Lys Ile Arg Met Tyr Val Gly Gly Val 625 630 635 640 Glu His Arg Leu Thr Ala Ala Cys Asn Phe Thr Arg Gly Asp Arg Cys 645 650 655 Asn Leu Glu Asp Arg Asp Arg Ser Gln Leu Ser Pro Leu Leu His Ser 660 665 670 Thr Thr Glu Trp Ala Ile Leu Pro Cys Ser Tyr Ser Asp Leu Pro Ala 675 680 685 Leu Ser Thr Gly Leu Leu His Leu His Gln Asn Ile Val Asp Val Gln 690 695 700 Phe Met Tyr Gly Leu Ser Pro Ala Leu Thr Lys Tyr Ile Val Arg Trp 705 710 715 720 Glu Trp Val Ile Leu Leu Phe Leu Leu Leu Ala Asp Ala Arg Val Cys 725 730 735 Ala Cys Leu Trp Met Leu Ile Leu Leu Gly Gln Ala Glu Ala Ala Leu 740 745 750 Glu Asn Leu Val Ile Leu Asn Ala Ala Ser Leu Ala Gly Thr His Gly 755 760 765 Leu Val Ser Phe Leu Val Phe Phe Cys Phe Ala Trp Tyr Leu Lys Gly 770 775 780 Arg Trp Val Pro Gly Ala Val Tyr Ala Leu Tyr Gly Met Trp Pro Leu 785 790 795 800 Leu Leu Leu Leu Leu Ala Leu Pro Gln Arg Ala Tyr Ala Leu Asp Thr 805 810 815 Glu Val Ala Ala Ser Cys Gly Gly Val Val Leu Val Gly Leu Met Ala 820 825 830 Leu Thr Leu Ser Pro Tyr Tyr Lys Arg Tyr Ile Ser Trp Cys Met Trp 835 840 845 Trp Leu Gln Tyr Phe Leu Thr Arg Val Glu Ala Gln Leu His Val Trp 850 855 860 Val Pro Pro Leu Asn Val Arg Gly Gly Arg Asp Ala Val Ile Leu Leu 865 870 875 880 Met Cys Val Val His Pro Thr Leu Val Phe Asp Ile Thr Lys Leu Leu 885 890 895 Leu Ala Ile Phe Gly Pro Leu Trp Ile Leu Gln Ala Ser Leu Leu Lys 900 905 910 Val Pro Tyr Phe Val Arg Val Gln Gly Leu Leu Arg Ile Cys Ala Leu 915 920 925 Ala Arg Lys Ile Ala Gly Gly His Tyr Val Gln Met Ala Ile Ile Lys 930 935 940 Leu Gly Ala Leu Thr Gly Thr Tyr Val Tyr Asn His Leu Thr Pro Leu 945 950 955 960 Arg Asp Trp Ala His Asn Gly Leu Arg Asp Leu Ala Val Ala Val Glu 965 970 975 Pro Val Val Phe Ser Arg Met Glu Thr Lys Leu Ile Thr Trp Gly Ala 980 985 990 Asp Thr Ala Ala Cys Gly Asp Ile Ile Asn Gly Leu Pro Val Ser Ala 995 1000 1005 Arg Arg Gly Gln Glu Ile Leu Leu Gly Pro Ala Asp Gly Met Val Ser 1010 1015 1020 Lys Gly Trp Arg Leu Leu Ala Pro Ile Thr Ala Tyr Ala Gln Gln Thr 1025 1030 1035 1040 Arg Gly Leu Leu Gly Cys Ile Ile Thr Ser Leu Thr Gly Arg Asp Lys 1045 1050 1055 Asn Gln Val Glu Gly Glu Val Gln Ile Val Ser Thr Ala Thr Gln Thr 1060 1065 1070 Phe Leu Ala Thr Cys Ile Asn Gly Val Cys Trp Thr Val Tyr His Gly 1075 1080 1085 Ala Gly Thr Arg Thr Ile Ala Ser Pro Lys Gly Pro Val Ile Gln Met 1090 1095 1100 Tyr Thr Asn Val Asp Gln Asp Leu Val Gly Trp Pro Ala Pro Gln Gly 1105 1110 1115 1120 Ser Arg Ser Leu Thr Pro Cys Thr Cys Gly Ser Ser Asp Leu Tyr Leu 1125 1130 1135 Val Thr Arg His Ala Asp Val Ile Pro Val Arg Arg Arg Gly Asp Ser 1140 1145 1150 Arg Gly Ser Leu Leu Ser Pro Arg Pro Ile Ser Tyr Leu Lys Gly Ser 1155 1160 1165 Ser Gly Gly Pro Leu Leu Cys Pro Ala Gly His Ala Val Gly Leu Phe 1170 1175 1180 Arg Ala Ala Val Cys Thr Arg Gly Val Ala Lys Ala Val Asp Phe Ile 1185 1190 1195 1200 Pro Val Glu Asn Leu Gly Thr Thr Met Arg Ser Pro Val Phe Thr Asp 1205 1210 1215 Asn Ser Ser Pro Pro Ala Val Pro Gln Ser Phe Gln Val Ala His Leu 1220 1225 1230 His Ala Pro Thr Gly Ser Gly Lys Ser Thr Lys Val Pro Ala Ala Tyr 1235 1240 1245 Ala Ala Gln Gly Tyr Lys Val Leu Val Leu Asn Pro Ser Val Ala Ala 1250 1255 1260 Thr Leu Gly Phe Gly Ala Tyr Met Ser Lys Ala His Gly Val Asp Pro 1265 1270 1275 1280 Asn Ile Arg Thr Gly Val Arg Thr Ile Thr Thr Gly Ser Pro Ile Thr 1285 1290 1295 Tyr Ser Thr Tyr Gly Lys Phe Leu Ala Asp Gly Gly Cys Ser Gly Gly 1300 1305 1310 Ala Tyr Asp Ile Ile Ile Cys Asp Glu Cys His Ser Thr Asp Ala Thr 1315 1320 1325 Ser Ile Leu Gly Ile Gly Thr Val Leu Asp Gln Ala Glu Thr Ala Gly 1330 1335 1340 Ala Arg Leu Val Val Leu Ala Thr Ala Thr Pro Pro Gly Ser Val Thr 1345 1350 1355 1360 Val Ser His Pro Asn Ile Glu Glu Val Ala Leu Ser Thr Thr Gly Glu 1365 1370 1375 Ile Pro Phe Tyr Gly Lys Ala

Ile Pro Leu Glu Val Ile Lys Gly Gly 1380 1385 1390 Arg His Leu Ile Phe Cys His Ser Lys Lys Lys Cys Asp Glu Leu Ala 1395 1400 1405 Ala Lys Leu Val Ala Leu Gly Ile Asn Ala Val Ala Tyr Tyr Arg Gly 1410 1415 1420 Leu Asp Val Ser Val Ile Pro Thr Ser Gly Asp Val Val Val Val Ser 1425 1430 1435 1440 Thr Asp Ala Leu Met Thr Gly Phe Thr Gly Asp Phe Asp Ser Val Ile 1445 1450 1455 Asp Cys Asn Thr Cys Val Thr Gln Thr Val Asp Phe Ser Leu Asp Pro 1460 1465 1470 Thr Phe Thr Ile Glu Thr Thr Thr Leu Pro Gln Asp Ala Val Ser Arg 1475 1480 1485 Thr Gln Arg Arg Gly Arg Thr Gly Arg Gly Lys Pro Gly Ile Tyr Arg 1490 1495 1500 Phe Val Ala Pro Gly Glu Arg Pro Ser Gly Met Phe Asp Ser Ser Val 1505 1510 1515 1520 Leu Cys Glu Cys Tyr Asp Ala Gly Cys Ala Trp Tyr Glu Leu Thr Pro 1525 1530 1535 Ala Glu Thr Thr Val Arg Leu Arg Ala Tyr Met Asn Thr Pro Gly Leu 1540 1545 1550 Pro Val Cys Gln Asp His Leu Glu Phe Trp Glu Gly Val Phe Thr Gly 1555 1560 1565 Leu Thr His Ile Asp Ala His Phe Leu Ser Gln Thr Lys Gln Ser Gly 1570 1575 1580 Glu Asn Phe Pro Tyr Leu Val Ala Tyr Gln Ala Thr Val Cys Ala Arg 1585 1590 1595 1600 Ala Gln Ala Pro Pro Pro Ser Trp Asp Gln Met Trp Lys Cys Leu Ile 1605 1610 1615 Arg Leu Lys Pro Thr Leu His Gly Pro Thr Pro Leu Leu Tyr Arg Leu 1620 1625 1630 Gly Ala Val Gln Asn Glu Val Thr Leu Thr His Pro Ile Thr Lys Tyr 1635 1640 1645 Ile Met Thr Cys Met Ser Ala Asp Leu Glu Val Val Thr Ser Thr Trp 1650 1655 1660 Val Leu Val Gly Gly Val Leu Ala Ala Leu Ala Ala Tyr Cys Leu Ser 1665 1670 1675 1680 Thr Gly Cys Val Val Ile Val Gly Arg Ile Val Leu Ser Gly Lys Pro 1685 1690 1695 Ala Ile Ile Pro Asp Arg Glu Val Leu Tyr Gln Glu Phe Asp Glu Met 1700 1705 1710 Glu Glu Cys Ser Gln His Leu Pro Tyr Ile Glu Gln Gly Met Met Leu 1715 1720 1725 Ala Glu Gln Phe Lys Gln Lys Ala Leu Gly Leu Leu Gln Thr Ala Ser 1730 1735 1740 Arg His Ala Glu Val Ile Thr Pro Ala Val Gln Thr Asn Trp Gln Lys 1745 1750 1755 1760 Leu Glu Val Phe Trp Ala Lys His Met Trp Asn Phe Ile Ser Gly Ile 1765 1770 1775 Gln Tyr Leu Ala Gly Leu Ser Thr Leu Pro Gly Asn Pro Ala Ile Ala 1780 1785 1790 Ser Leu Met Ala Phe Thr Ala Ala Val Thr Ser Pro Leu Thr Thr Gly 1795 1800 1805 Gln Thr Leu Leu Phe Asn Ile Leu Gly Gly Trp Val Ala Ala Gln Leu 1810 1815 1820 Ala Ala Pro Gly Ala Ala Thr Ala Phe Val Gly Ala Gly Leu Ala Gly 1825 1830 1835 1840 Ala Ala Ile Gly Ser Val Gly Leu Gly Lys Val Leu Val Asp Ile Leu 1845 1850 1855 Ala Gly Tyr Gly Ala Gly Val Ala Gly Ala Leu Val Ala Phe Lys Ile 1860 1865 1870 Met Ser Gly Glu Val Pro Ser Thr Glu Asp Leu Val Asn Leu Leu Pro 1875 1880 1885 Ala Ile Leu Ser Pro Gly Ala Leu Val Val Gly Val Val Cys Ala Ala 1890 1895 1900 Ile Leu Arg Arg His Val Gly Pro Gly Glu Gly Ala Val Gln Trp Met 1905 1910 1915 1920 Asn Arg Leu Ile Ala Phe Ala Ser Arg Gly Asn His Val Ser Pro Thr 1925 1930 1935 His Tyr Val Pro Glu Ser Asp Ala Ala Ala Arg Val Thr Ala Ile Leu 1940 1945 1950 Ser Ser Leu Thr Val Thr Gln Leu Leu Arg Arg Leu His Gln Trp Ile 1955 1960 1965 Ser Ser Glu Cys Thr Thr Pro Cys Ser Gly Ser Trp Leu Arg Asp Ile 1970 1975 1980 Trp Asp Trp Ile Cys Glu Val Leu Ser Asp Phe Lys Thr Trp Leu Lys 1985 1990 1995 2000 Ala Lys Leu Met Pro Gln Leu Pro Gly Ile Pro Phe Val Ser Cys Gln 2005 2010 2015 Arg Gly Tyr Arg Gly Val Trp Arg Gly Asp Gly Ile Met His Thr Arg 2020 2025 2030 Cys His Cys Gly Ala Glu Ile Thr Gly His Val Lys Asn Gly Thr Met 2035 2040 2045 Arg Ile Val Gly Pro Arg Thr Cys Arg Asn Met Trp Ser Gly Thr Phe 2050 2055 2060 Pro Ile Asn Ala Tyr Thr Thr Gly Pro Cys Thr Pro Leu Pro Ala Pro 2065 2070 2075 2080 Asn Tyr Lys Phe Ala Leu Trp Arg Val Ser Ala Glu Glu Tyr Val Glu 2085 2090 2095 Ile Arg Arg Val Gly Asp Phe His Tyr Val Ser Gly Met Thr Thr Asp 2100 2105 2110 Asn Leu Lys Cys Pro Cys Gln Ile Pro Ser Pro Glu Phe Phe Thr Glu 2115 2120 2125 Leu Asp Gly Val Arg Leu His Arg Phe Ala Pro Pro Cys Lys Pro Leu 2130 2135 2140 Leu Arg Glu Glu Val Ser Phe Arg Val Gly Leu His Glu Tyr Pro Val 2145 2150 2155 2160 Gly Ser Gln Leu Pro Cys Glu Pro Glu Pro Asp Val Ala Val Leu Thr 2165 2170 2175 Ser Met Leu Thr Asp Pro Ser His Ile Thr Ala Glu Ala Ala Gly Arg 2180 2185 2190 Arg Leu Ala Arg Gly Ser Pro Pro Ser Met Ala Ser Ser Ser Ala Ser 2195 2200 2205 Gln Leu Ser Ala Pro Ser Leu Lys Ala Thr Cys Thr Ala Asn His Asp 2210 2215 2220 Ser Pro Asp Ala Glu Leu Ile Glu Ala Asn Leu Leu Trp Arg Gln Glu 2225 2230 2235 2240 Met Gly Gly Asn Ile Thr Arg Val Glu Ser Glu Asn Lys Val Val Ile 2245 2250 2255 Leu Asp Ser Phe Asp Pro Leu Val Ala Glu Glu Asp Glu Arg Glu Val 2260 2265 2270 Ser Val Pro Ala Glu Ile Leu Arg Lys Ser Arg Arg Phe Ala Arg Ala 2275 2280 2285 Leu Pro Val Trp Ala Arg Pro Asp Tyr Asn Pro Pro Leu Val Glu Thr 2290 2295 2300 Trp Lys Lys Pro Asp Tyr Glu Pro Pro Val Val His Gly Cys Pro Leu 2305 2310 2315 2320 Pro Pro Pro Arg Ser Pro Pro Val Pro Pro Pro Arg Lys Lys Arg Thr 2325 2330 2335 Val Val Leu Thr Glu Ser Thr Leu Ser Thr Ala Leu Ala Glu Leu Ala 2340 2345 2350 Thr Lys Ser Phe Gly Ser Ser Ser Thr Ser Gly Ile Thr Gly Asp Asn 2355 2360 2365 Thr Thr Thr Ser Ser Glu Pro Ala Pro Ser Gly Cys Pro Pro Asp Ser 2370 2375 2380 Asp Val Glu Ser Tyr Ser Ser Met Pro Pro Leu Glu Gly Glu Pro Gly 2385 2390 2395 2400 Asp Pro Asp Leu Ser Asp Gly Ser Trp Ser Thr Val Ser Ser Gly Ala 2405 2410 2415 Asp Thr Glu Asp Val Val Cys Cys Ser Met Ser Tyr Ser Trp Thr Gly 2420 2425 2430 Ala Leu Val Thr Pro Cys Ala Ala Glu Glu Gln Lys Leu Pro Ile Asn 2435 2440 2445 Ala Leu Ser Asn Ser Leu Leu Arg His His Asn Leu Val Tyr Ser Thr 2450 2455 2460 Thr Ser Arg Ser Ala Cys Gln Arg Gln Lys Lys Val Thr Phe Asp Arg 2465 2470 2475 2480 Leu Gln Val Leu Asp Ser His Tyr Gln Asp Val Leu Lys Glu Val Lys 2485 2490 2495 Ala Ala Ala Ser Lys Val Lys Ala Asn Leu Leu Ser Val Glu Glu Ala 2500 2505 2510 Cys Ser Leu Thr Pro Pro His Ser Ala Lys Ser Lys Phe Gly Tyr Gly 2515 2520 2525 Ala Lys Asp Val Arg Cys His Ala Arg Lys Ala Val Ala His Ile Asn 2530 2535 2540 Ser Val Trp Lys Asp Leu Leu Glu Asp Ser Val Thr Pro Ile Asp Thr 2545 2550 2555 2560 Thr Ile Met Ala Lys Asn Glu Val Phe Cys Val Gln Pro Glu Lys Gly 2565 2570 2575 Gly Arg Lys Pro Ala Arg Leu Ile Val Phe Pro Asp Leu Gly Val Arg 2580 2585 2590 Val Cys Glu Lys Met Ala Leu Tyr Asp Val Val Ser Lys Leu Pro Leu 2595 2600 2605 Ala Val Met Gly Ser Ser Tyr Gly Phe Gln Tyr Ser Pro Gly Gln Arg 2610 2615 2620 Val Glu Phe Leu Val Gln Ala Trp Lys Ser Lys Lys Thr Pro Met Gly 2625 2630 2635 2640 Phe Ser Tyr Asp Thr Arg Cys Phe Asp Ser Thr Val Thr Glu Ser Asp 2645 2650 2655 Ile Arg Thr Glu Glu Ala Ile Tyr Gln Cys Cys Asp Leu Asp Pro Gln 2660 2665 2670 Ala Arg Val Ala Ile Lys Ser Leu Thr Glu Arg Leu Tyr Val Gly Gly 2675 2680 2685 Pro Leu Thr Asn Ser Arg Gly Glu Asn Cys Gly Tyr Arg Arg Cys Arg 2690 2695 2700 Ala Ser Gly Val Leu Thr Thr Ser Cys Gly Asn Thr Leu Thr Cys Tyr 2705 2710 2715 2720 Ile Lys Ala Arg Ala Ala Cys Arg Ala Ala Gly Leu Gln Asp Cys Thr 2725 2730 2735 Met Leu Val Cys Gly Asp Asp Leu Val Val Ile Cys Glu Ser Ala Gly 2740 2745 2750 Val Gln Glu Asp Ala Ala Ser Leu Arg Ala Phe Thr Glu Ala Met Thr 2755 2760 2765 Arg Tyr Ser Ala Pro Pro Gly Asp Pro Pro Gln Pro Glu Tyr Asp Leu 2770 2775 2780 Glu Leu Ile Thr Ser Cys Ser Ser Asn Val Ser Val Ala His Asp Gly 2785 2790 2795 2800 Ala Gly Lys Arg Val Tyr Tyr Leu Thr Arg Asp Pro Thr Thr Pro Leu 2805 2810 2815 Ala Arg Ala Ala Trp Glu Thr Ala Arg His Thr Pro Val Asn Ser Trp 2820 2825 2830 Leu Gly Asn Ile Ile Met Phe Ala Pro Thr Leu Trp Ala Arg Met Ile 2835 2840 2845 Leu Met Thr His Phe Phe Ser Val Leu Ile Ala Arg Asp Gln Leu Glu 2850 2855 2860 Gln Ala Leu Asn Cys Glu Ile Tyr Gly Ala Cys Tyr Ser Ile Glu Pro 2865 2870 2875 2880 Leu Asp Leu Pro Pro Ile Ile Gln Arg Leu His Gly Leu Ser Ala Phe 2885 2890 2895 Ser Leu His Ser Tyr Ser Pro Gly Glu Ile Asn Arg Val Ala Ala Cys 2900 2905 2910 Leu Arg Lys Leu Gly Val Pro Pro Leu Arg Ala Trp Arg His Arg Ala 2915 2920 2925 Arg Ser Val Arg Ala Arg Leu Leu Ser Arg Gly Gly Arg Ala Ala Ile 2930 2935 2940 Cys Gly Lys Tyr Leu Phe Asn Trp Ala Val Arg Thr Lys Leu Lys Leu 2945 2950 2955 2960 Thr Pro Ile Ala Ala Ala Gly Arg Leu Asp Leu Ser Gly Trp Phe Thr 2965 2970 2975 Ala Gly Tyr Ser Gly Gly Asp Ile Tyr His Ser Val Ser His Ala Arg 2980 2985 2990 Pro Arg Trp Phe Trp Phe Cys Leu Leu Leu Leu Ala Ala Gly Val Gly 2995 3000 3005 Ile Tyr Leu Leu Pro Asn Arg 3010 3015 7 9611 DNA Hepatitis C virus 7 gccagccccc tgatgggggc gacactccac catgaatcac tcccctgtga ggaactactg 60 tcttcacgca gaaagcgtct agccatggcg ttagtatgag tgtcgtgcag cctccaggac 120 cccccctccc gggagagcca tagtggtctg cggaaccggt gagtacaccg gaattgccag 180 gacgaccggg tcctttcttg gataaacccg ctcaatgcct ggagatttgg gcgtgccccc 240 gcaagactgc tagccgagta gtgttgggtc gcgaaaggcc ttgtggtact gcctgatagg 300 gtgcttgcga gtgccccggg aggtctcgta gaccgtgcac catgagcaca aatcctaaac 360 ctcaaagaaa aaccaaaaga aacaccaacc gtcgcccaca agacgttaag tttccgggcg 420 gcggccagat cgttggcgga gtatacttgt tgccgcgcag gggccccagg ttgggtgtgc 480 gcgcgacaag gaagacttcg gagcggtccc agccacgtgg aaggcgccag cccatcccta 540 aagatcggcg ctccactggc aaatcctggg gaaaaccagg atacccctgg cccctatacg 600 ggaatgaggg actcggctgg gcaggatggc tcctgtcccc ccgaggttcc cgtccctctt 660 ggggccccaa tgacccccgg cataggtcgc gcaacgtggg taaggtcatc gataccctaa 720 cgtgcggctt tgccgacctc atggggtaca tccctgtcgt gggcgccccg ctcggcggcg 780 tcgccagagc tctcgcgcat ggcgtgagag tcctggagga cggggttaat tttgcaacag 840 ggaacttacc cggttgctcc ttttctatct tcttgctggc cctgctgtcc tgcatcacca 900 ccccggtctc cgctgccgaa gtgaagaaca tcagtaccgg ctacatggtg actaacgact 960 gcaccaatga cagcattacc tggcagctcc aggctgctgt cctccacgtc cccgggtgcg 1020 tcccgtgcga gaaagtgggg aatgcatctc agtgctggat accggtctca ccgaatgtgg 1080 ccgtgcagcg gcccggcgcc ctcacgcagg gcttgcggac gcacatcgac atggttgtga 1140 tgtccgccac gctctgctct gccctctacg tgggggacct ctgcggtggg gtgatgctcg 1200 cagcccaaat gttcattgtc tcgccgcagc accactggtt tgtccaagac tgcaattgct 1260 ccatctaccc tggtaccatc actggacacc gcatggcatg ggacatgatg atgaactggt 1320 cgcccacggc taccatgatc ttggcgtacg cgatgcgtgt ccccgaggtc attatagaca 1380 tcattagcgg ggctcattgg ggcgtcatgt tcggcttggc ctacttctct atgcagggag 1440 cgtgggcgaa agtcgttgtc atccttctgt tggccgccgg ggtggacgcg cgcacccata 1500 ctgttggggg ttctgccgcg cagaccaccg ggcgcctcac cagcttattt gacatgggcc 1560 ccaggcagaa aatccagctc gttaacacca atggcagctg gcacatcaac cgcaccgccc 1620 tgaactgcaa tgactccttg cacaccggct ttatcgcgtc tctgttctac acccacagct 1680 tcaactcgtc aggatgtccc gaacgcatgt ccgcctgccg cagtatcgag gccttccggg 1740 tgggatgggg cgccttgcaa tatgaggata atgtcaccaa tccagaggat atgagaccct 1800 attgctggca ctacccacca aggcagtgtg gcgtggtctc cgcgaagact gtgtgtggcc 1860 cagtgtactg tttcaccccc agcccagtgg tagtgggcac gaccgacagg cttggagcgc 1920 ccacttacac gtggggggag aatgagacag atgtcttcct attgaacagc actcgaccac 1980 cgctggggtc atggttcggc tgcacgtgga tgaactcttc tggctacacc aagacttgcg 2040 gcgcaccacc ctgccgtact agagctgact tcaacgccag cacggacctg ttgtgcccca 2100 cggactgttt taggaagcat cctgatacca cttacctcaa atgcggctct gggccctggc 2160 tcacgccaag gtgcctgatc gactacccct acaggctctg gcattacccc tgcacagtta 2220 actataccat cttcaaaata aggatgtatg tgggaggggt tgagcacagg ctcacggctg 2280 catgcaattt cactcgtggg gatcgttgca acttggagga cagagacaga agtcaactgt 2340 ctcctttgtt gcactccacc acggaatggg ccattttacc ttgctcttac tcggacctgc 2400 ccgccttgtc gactggtctt ctccacctcc accaaaacat cgtggacgta caattcatgt 2460 atggcctatc acctgccctc acaaaataca tcgtccgatg ggagtgggta atactcttat 2520 tcctgctctt agcggacgcc agggtttgcg cctgcttatg gatgctcatc ttgttgggcc 2580 aggccgaagc agcactagag aagctggtca tcttgcacgc tgcgagcgca gctagctgca 2640 atggcttcct atattttgtc atctttttcg tggctgcttg gtacatcaag ggtcgggtag 2700 tccccttagc tacctattcc ctcactggcc tgtggtcctt tagcctactg ctcctagcat 2760 tgccccaaca ggcatatgca ctggacacgg aggtggccgc gtcgtgtggc ggcgttgttc 2820 ttgtcgggtt aatggcgctg actctgtcgc catattacaa gcgctatatc agctggtgca 2880 tgtggtggct tcagtatttt ctgaccagag tagaagcgca actgcacgtg tgggttcccc 2940 ccctcaacgt ccgggggggg cgcgatgccg tcatcttact catgtgtgta gtacacccga 3000 ccctggtatt tgacatcacc aaactactcc tggccatctt cggacccctt tggattcttc 3060 aagccagttt gcttaaagtc ccctacttcg tgcgcgttca aggccttctc cggatctgcg 3120 cgctagcgcg gaagatagcc ggaggtcatt acgtgcaaat ggccatcatc aagttagggg 3180 cgcttactgg cacctatgtg tataaccatc tcacccctct tcgagactgg gcgcacaacg 3240 gcctgcgaga tctggccgtg gctgtggaac cagtcgtctt ctcccgaatg gagaccaagc 3300 tcatcacgtg gggggcagat accgccgcgt gcggtgacat catcaacggc ttgcccgtct 3360 ctgcccgtag gggccaggag atactgcttg ggccagccga cggaatggtc tccaaggggt 3420 ggaggttgct ggcgcccatc acggcgtacg cccagcagac gagaggcctc ctagggtgta 3480 taatcaccag cctgactggc cgggacaaaa accaagtgga gggtgaggtc cagatcgtgt 3540 caactgctac ccaaaccttc ctggcaacgt gcatcaatgg ggtatgctgg actgtctacc 3600 acggggccgg aacgaggacc atcgcatcac ccaagggtcc tgtcatccag atgtatacca 3660 atgtggacca agaccttgtg ggctggcccg ctcctcaagg ttcccgctca ttgacaccct 3720 gtacctgcgg ctcctcggac ctttacctgg tcacgaggca cgccgatgtc attcccgtgc 3780 gccggcgagg tgatagcagg ggtagcctgc tttcgccccg gcccatttcc tacttgaaag 3840 gctcctcggg gggtccgctg ttgtgccccg cgggacacgc cgtgggccta ttcagggccg 3900 cggtgtgcac ccgtggagtg gctaaagcgg tggactttat ccctgtggag aacctaggga 3960 caaccatgag atccccggtg ttcacggaca actcctctcc accagcagtg ccccagagct 4020 tccaggtggc ccacctgcat gctcccaccg gcagcggtaa gagcaccaag gtcccggctg 4080 cgtacgcagc ccagggctac aaggtgttgg tgctcaaccc ctctgttgct gcaacgctgg 4140 gctttggtgc ttacatgtcc aaggcccatg gggttgatcc taatatcagg accggggtga 4200 gaacaattac cactggcagc cccatcacgt actccaccta cggcaagttc cttgccgacg 4260 gcgggtgctc aggaggtgct tatgacataa taatttgtga cgagtgccac tccacggatg 4320 ccacatccat cttgggcatc ggcactgtcc ttgaccaagc agagactgcg ggggcgagac 4380 tggttgtgct cgccactgct acccctccgg gctccgtcac tgtgtcccat cctaacatcg 4440 aggaggttgc tctgtccacc accggagaga tcccctttta cggcaaggct atccccctcg 4500 aggtgatcaa ggggggaaga catctcatct tctgccactc aaagaagaag tgcgacgagc 4560 tcgccgcgaa gctggtcgca ttgggcatca atgccgtggc ctactaccgc ggtcttgacg 4620 tgtctgtcat cccgaccagc ggcgatgttg tcgtcgtgtc gaccgatgct ctcatgactg 4680 gctttaccgg cgacttcgac tctgtgatag actgcaacac gtgtgtcact cagacagtcg 4740 atttcagcct tgaccctacc tttaccattg agacaaccac gctcccccag gatgctgtct 4800 ccaggactca

acgccggggc aggactggca gggggaagcc aggcatctat agatttgtgg 4860 caccggggga gcgcccctcc ggcatgttcg actcgtccgt cctctgtgag tgctatgacg 4920 cgggctgtgc ttggtatgag ctcacgcccg ccgagactac agttaggcta cgagcgtaca 4980 tgaacacccc ggggcttccc gtgtgccagg accatcttga attttgggag ggcgtcttta 5040 cgggcctcac tcatatagat gcccactttt tatcccagac aaagcagagt ggggagaact 5100 ttccttacct ggtagcgtac caagccaccg tgtgcgctag ggctcaagcc cctcccccat 5160 cgtgggacca gatgtggaag tgtttgatcc gccttaaacc caccctccat gggccaacac 5220 ccctgctata cagactgggc gctgttcaga atgaagtcac cctgacgcac ccaatcacca 5280 aatacatcat gacatgcatg tcggccgacc tggaggtcgt cacgagcacc tgggtgctcg 5340 ttggcggcgt cctggctgct ctggccgcgt attgcctgtc aacaggctgc gtggtcatag 5400 tgggcaggat cgtcttgtcc gggaagccgg caattatacc tgacagggag gttctctacc 5460 aggagttcga tgagatggaa gagtgctctc agcacttacc gtacatcgag caagggatga 5520 tgctcgctga gcagttcaag cagaaggccc tcggcctcct gcagaccgcg tcccgccatg 5580 cagaggttat cacccctgct gtccagacca actggcagaa actcgaggtc ttttgggcga 5640 agcacatgtg gaatttcatc agtgggatac aatacttggc gggcctgtca acgctgcctg 5700 gtaaccccgc cattgcttca ttgatggctt ttacagctgc cgtcaccagc ccactaacca 5760 ctggccaaac cctcctcttc aacatattgg gggggtgggt ggctgcccag ctcgccgccc 5820 ccggtgccgc tactgccttt gtgggtgctg gcctagctgg cgccgccatc ggcagcgttg 5880 gactggggaa ggtcctcgtg gacattcttg cagggtatgg cgcgggcgtg gcgggagctc 5940 ttgtagcatt caagatcatg agcggtgagg tcccctccac ggaggacctg gtcaatctgc 6000 tgcccgccat cctctcgcct ggagcccttg tagtcggtgt ggtctgcgca gcaatactgc 6060 gccggcacgt tggcccgggc gagggggcag tgcaatggat gaaccggcta atagccttcg 6120 cctcccgggg gaaccatgtt tcccccacgc actacgtgcc ggagagcgat gcagccgccc 6180 gcgtcactgc catactcagc agcctcactg taacccagct cctgaggcga ctgcatcagt 6240 ggataagctc ggagtgtacc actccatgct ccggttcctg gctaagggac atctgggact 6300 ggatatgcga ggtgctgagc gactttaaga cctggctgaa agccaagctc atgccacaac 6360 tgcctgggat tccctttgtg tcctgccagc gcgggtatag gggggtctgg cgaggagacg 6420 gcattatgca cactcgctgc cactgtggag ctgagatcac tggacatgtc aaaaacggga 6480 cgatgaggat cgtcggtcct aggacctgca ggaacatgtg gagtgggacg ttccccatta 6540 acgcctacac cacgggcccc tgtactcccc ttcctgcgcc gaactataag ttcgcgctgt 6600 ggagggtgtc tgcagaggaa tacgtggaga taaggcgggt gggggacttc cactacgtat 6660 cgggtatgac tactgacaat cttaaatgcc cgtgccagat cccatcgccc gaatttttca 6720 cagaattgga cggggtgcgc ctacacaggt ttgcgccccc ttgcaagccc ttgctgcggg 6780 aggaggtatc attcagagta ggactccacg agtacccggt ggggtcgcaa ttaccttgcg 6840 agcccgaacc ggacgtagcc gtgttgacgt ccatgctcac tgatccctcc catataacag 6900 cagaggcggc cgggagaagg ttggcgagag ggtcaccccc ttctatggcc agctcctcgg 6960 ctagccagct gtccgctcca tctctcaagg caacttgcac cgccaaccat gactcccctg 7020 acgccgagct catagaggct aacctcctgt ggaggcagga gatgggcggc aacatcacca 7080 gggttgagtc agagaacaaa gtggtgattc tggactcctt cgatccgctt gtggcagagg 7140 aggatgagcg ggaggtctcc gtacctgcag aaattctgcg gaagtctcgg agattcgccc 7200 gggccctgcc cgtctgggcg cggccggact acaacccccc gctagtagag acgtggaaaa 7260 agcctgacta cgaaccacct gtggtccatg gctgcccgct accacctcca cggtcccctc 7320 ctgtgcctcc gcctcggaaa aagcgtacgg tggtcctcac cgaatcaacc ctatctactg 7380 ccttggccga gcttgccacc aaaagttttg gcagctcctc aacttccggc attacgggcg 7440 acaatacgac aacatcctct gagcccgccc cttctggctg cccccccgac tccgacgttg 7500 agtcctattc ttccatgccc cccctggagg gggagcctgg ggatccggat ctcagcgacg 7560 ggtcatggtc gacggtcagt agtggggccg acacggaaga tgtcgtgtgc tgctcaatgt 7620 cttattcctg gacaggcgca ctcgtcaccc cgtgcgctgc ggaagaacaa aaactgccca 7680 tcaacgcact gagcaactcg ttgctacgcc atcacaatct ggtgtattcc accacttcac 7740 gcagtgcttg ccaaaggcag aagaaagtca catttgacag actgcaagtt ctggacagcc 7800 attaccagga cgtgctcaag gaggtcaaag cagcggcgtc aaaagtgaag gctaacttgc 7860 tatccgtaga ggaagcttgc agcctgacgc ccccacattc agccaaatcc aagtttggct 7920 atggggcaaa agacgtccgt tgccatgcca gaaaggccgt agcccacatc aactccgtgt 7980 ggaaagacct tctggaagac agtgtaacac caatagacac taccatcatg gccaagaacg 8040 aggttttctg cgttcagcct gagaaggggg gtcgtaagcc agctcgtctc atcgtgttcc 8100 ccgacctggg cgtgcgcgtg tgcgagaaga tggccctgta cgacgtggtt agcaagctcc 8160 ccctggccgt gatgggaagc tcctacggat tccaatactc accaggacag cgggttgaat 8220 tcctcgtgca agcgtggaag tccaagaaga ccccgatggg gttctcgtat gatacccgct 8280 gttttgactc cacagtcact gagagcgaca tccgtacgga ggaggcaatt taccaatgtt 8340 gtgacctgga cccccaagcc cgcgtggcca tcaagtccct cactgagagg ctttatgttg 8400 ggggccctct taccaattca aggggggaaa actgcggcta ccgcaggtgc cgcgcgagcg 8460 gcgtactgac aactagctgt ggtaacaccc tcacttgcta catcaaggcc cgggcagcct 8520 gtcgagccgc agggctccag gactgcacca tgctcgtgtg tggcgacgac ttagtcgtta 8580 tctgtgaaag tgcgggggtc caggaggacg cggcgagcct gagagccttc acggaggcta 8640 tgaccaggta ctccgccccc cccggggacc ccccacaacc agaatacgac ttggagctta 8700 taacatcatg ctcctccaac gtgtcagtcg cccacgacgg cgctggaaag agggtctact 8760 accttacccg tgaccctaca acccccctcg cgagagccgc gtgggagaca gcaagacaca 8820 ctccagtcaa ttcctggcta ggcaacataa tcatgtttgc ccccacactg tgggcgagga 8880 tgatactgat gacccatttc tttagcgtcc tcatagccag ggatcagctt gaacaggctc 8940 ttaactgtga gatctacgga gcctgctact ccatagaacc actggatcta cctccaatca 9000 ttcaaagact ccatggcctc agcgcatttt cactccacag ttactctcca ggtgaaatca 9060 atagggtggc cgcatgcctc agaaaacttg gggtcccgcc cttgcgagct tggagacacc 9120 gggcccggag cgtccgcgct aggcttctgt ccagaggagg cagggctgct atatgtggca 9180 agtacctctt caactgggca gtaagaacaa agctcaaact cactccaata gcggccgctg 9240 gccggctgga cttgtccggt tggttcacgg ctggctacag cgggggagac atttatcaca 9300 gcgtgtctca tgcccggccc cgctggttct ggttttgcct actcctgctc gctgcagggg 9360 taggcatcta cctcctcccc aaccgatgaa ggttggggta aacactccgg cctcttaagc 9420 catttcctgt tttttttttt tttttttttt tttttttctt tttttttttc tttcctttcc 9480 ttcttttttt cctttctttt tcccttcttt aatggtggct ccatcttagc cctagtcacg 9540 gctagctgtg aaaggtccgt gagccgcatg actgcagaga gtgctgatac tggcctctct 9600 gcagatcatg t 9611 8 3015 PRT Hepatitis C virus 8 Met Ser Thr Asn Pro Lys Pro Gln Arg Lys Thr Lys Arg Asn Thr Asn 1 5 10 15 Arg Arg Pro Gln Asp Val Lys Phe Pro Gly Gly Gly Gln Ile Val Gly 20 25 30 Gly Val Tyr Leu Leu Pro Arg Arg Gly Pro Arg Leu Gly Val Arg Ala 35 40 45 Thr Arg Lys Thr Ser Glu Arg Ser Gln Pro Arg Gly Arg Arg Gln Pro 50 55 60 Ile Pro Lys Asp Arg Arg Ser Thr Gly Lys Ser Trp Gly Lys Pro Gly 65 70 75 80 Tyr Pro Trp Pro Leu Tyr Gly Asn Glu Gly Leu Gly Trp Ala Gly Trp 85 90 95 Leu Leu Ser Pro Arg Gly Ser Arg Pro Ser Trp Gly Pro Asn Asp Pro 100 105 110 Arg His Arg Ser Arg Asn Val Gly Lys Val Ile Asp Thr Leu Thr Cys 115 120 125 Gly Phe Ala Asp Leu Met Gly Tyr Ile Pro Val Val Gly Ala Pro Leu 130 135 140 Gly Gly Val Ala Arg Ala Leu Ala His Gly Val Arg Val Leu Glu Asp 145 150 155 160 Gly Val Asn Phe Ala Thr Gly Asn Leu Pro Gly Cys Ser Phe Ser Ile 165 170 175 Phe Leu Leu Ala Leu Leu Ser Cys Ile Thr Thr Pro Val Ser Ala Ala 180 185 190 Glu Val Lys Asn Ile Ser Thr Gly Tyr Met Val Thr Asn Asp Cys Thr 195 200 205 Asn Asp Ser Ile Thr Trp Gln Leu Gln Ala Ala Val Leu His Val Pro 210 215 220 Gly Cys Val Pro Cys Glu Lys Val Gly Asn Ala Ser Gln Cys Trp Ile 225 230 235 240 Pro Val Ser Pro Asn Val Ala Val Gln Arg Pro Gly Ala Leu Thr Gln 245 250 255 Gly Leu Arg Thr His Ile Asp Met Val Val Met Ser Ala Thr Leu Cys 260 265 270 Ser Ala Leu Tyr Val Gly Asp Leu Cys Gly Gly Val Met Leu Ala Ala 275 280 285 Gln Met Phe Ile Val Ser Pro Gln His His Trp Phe Val Gln Asp Cys 290 295 300 Asn Cys Ser Ile Tyr Pro Gly Thr Ile Thr Gly His Arg Met Ala Trp 305 310 315 320 Asp Met Met Met Asn Trp Ser Pro Thr Ala Thr Met Ile Leu Ala Tyr 325 330 335 Ala Met Arg Val Pro Glu Val Ile Ile Asp Ile Ile Ser Gly Ala His 340 345 350 Trp Gly Val Met Phe Gly Leu Ala Tyr Phe Ser Met Gln Gly Ala Trp 355 360 365 Ala Lys Val Val Val Ile Leu Leu Leu Ala Ala Gly Val Asp Ala Arg 370 375 380 Thr His Thr Val Gly Gly Ser Ala Ala Gln Thr Thr Gly Arg Leu Thr 385 390 395 400 Ser Leu Phe Asp Met Gly Pro Arg Gln Lys Ile Gln Leu Val Asn Thr 405 410 415 Asn Gly Ser Trp His Ile Asn Arg Thr Ala Leu Asn Cys Asn Asp Ser 420 425 430 Leu His Thr Gly Phe Ile Ala Ser Leu Phe Tyr Thr His Ser Phe Asn 435 440 445 Ser Ser Gly Cys Pro Glu Arg Met Ser Ala Cys Arg Ser Ile Glu Ala 450 455 460 Phe Arg Val Gly Trp Gly Ala Leu Gln Tyr Glu Asp Asn Val Thr Asn 465 470 475 480 Pro Glu Asp Met Arg Pro Tyr Cys Trp His Tyr Pro Pro Arg Gln Cys 485 490 495 Gly Val Val Ser Ala Lys Thr Val Cys Gly Pro Val Tyr Cys Phe Thr 500 505 510 Pro Ser Pro Val Val Val Gly Thr Thr Asp Arg Leu Gly Ala Pro Thr 515 520 525 Tyr Thr Trp Gly Glu Asn Glu Thr Asp Val Phe Leu Leu Asn Ser Thr 530 535 540 Arg Pro Pro Leu Gly Ser Trp Phe Gly Cys Thr Trp Met Asn Ser Ser 545 550 555 560 Gly Tyr Thr Lys Thr Cys Gly Ala Pro Pro Cys Arg Thr Arg Ala Asp 565 570 575 Phe Asn Ala Ser Thr Asp Leu Leu Cys Pro Thr Asp Cys Phe Arg Lys 580 585 590 His Pro Asp Thr Thr Tyr Leu Lys Cys Gly Ser Gly Pro Trp Leu Thr 595 600 605 Pro Arg Cys Leu Ile Asp Tyr Pro Tyr Arg Leu Trp His Tyr Pro Cys 610 615 620 Thr Val Asn Tyr Thr Ile Phe Lys Ile Arg Met Tyr Val Gly Gly Val 625 630 635 640 Glu His Arg Leu Thr Ala Ala Cys Asn Phe Thr Arg Gly Asp Arg Cys 645 650 655 Asn Leu Glu Asp Arg Asp Arg Ser Gln Leu Ser Pro Leu Leu His Ser 660 665 670 Thr Thr Glu Trp Ala Ile Leu Pro Cys Ser Tyr Ser Asp Leu Pro Ala 675 680 685 Leu Ser Thr Gly Leu Leu His Leu His Gln Asn Ile Val Asp Val Gln 690 695 700 Phe Met Tyr Gly Leu Ser Pro Ala Leu Thr Lys Tyr Ile Val Arg Trp 705 710 715 720 Glu Trp Val Ile Leu Leu Phe Leu Leu Leu Ala Asp Ala Arg Val Cys 725 730 735 Ala Cys Leu Trp Met Leu Ile Leu Leu Gly Gln Ala Glu Ala Ala Leu 740 745 750 Glu Lys Leu Val Ile Leu His Ala Ala Ser Ala Ala Ser Cys Asn Gly 755 760 765 Phe Leu Tyr Phe Val Ile Phe Phe Val Ala Ala Trp Tyr Ile Lys Gly 770 775 780 Arg Val Val Pro Leu Ala Thr Tyr Ser Leu Thr Gly Leu Trp Ser Phe 785 790 795 800 Ser Leu Leu Leu Leu Ala Leu Pro Gln Gln Ala Tyr Ala Leu Asp Thr 805 810 815 Glu Val Ala Ala Ser Cys Gly Gly Val Val Leu Val Gly Leu Met Ala 820 825 830 Leu Thr Leu Ser Pro Tyr Tyr Lys Arg Tyr Ile Ser Trp Cys Met Trp 835 840 845 Trp Leu Gln Tyr Phe Leu Thr Arg Val Glu Ala Gln Leu His Val Trp 850 855 860 Val Pro Pro Leu Asn Val Arg Gly Gly Arg Asp Ala Val Ile Leu Leu 865 870 875 880 Met Cys Val Val His Pro Thr Leu Val Phe Asp Ile Thr Lys Leu Leu 885 890 895 Leu Ala Ile Phe Gly Pro Leu Trp Ile Leu Gln Ala Ser Leu Leu Lys 900 905 910 Val Pro Tyr Phe Val Arg Val Gln Gly Leu Leu Arg Ile Cys Ala Leu 915 920 925 Ala Arg Lys Ile Ala Gly Gly His Tyr Val Gln Met Ala Ile Ile Lys 930 935 940 Leu Gly Ala Leu Thr Gly Thr Tyr Val Tyr Asn His Leu Thr Pro Leu 945 950 955 960 Arg Asp Trp Ala His Asn Gly Leu Arg Asp Leu Ala Val Ala Val Glu 965 970 975 Pro Val Val Phe Ser Arg Met Glu Thr Lys Leu Ile Thr Trp Gly Ala 980 985 990 Asp Thr Ala Ala Cys Gly Asp Ile Ile Asn Gly Leu Pro Val Ser Ala 995 1000 1005 Arg Arg Gly Gln Glu Ile Leu Leu Gly Pro Ala Asp Gly Met Val Ser 1010 1015 1020 Lys Gly Trp Arg Leu Leu Ala Pro Ile Thr Ala Tyr Ala Gln Gln Thr 1025 1030 1035 1040 Arg Gly Leu Leu Gly Cys Ile Ile Thr Ser Leu Thr Gly Arg Asp Lys 1045 1050 1055 Asn Gln Val Glu Gly Glu Val Gln Ile Val Ser Thr Ala Thr Gln Thr 1060 1065 1070 Phe Leu Ala Thr Cys Ile Asn Gly Val Cys Trp Thr Val Tyr His Gly 1075 1080 1085 Ala Gly Thr Arg Thr Ile Ala Ser Pro Lys Gly Pro Val Ile Gln Met 1090 1095 1100 Tyr Thr Asn Val Asp Gln Asp Leu Val Gly Trp Pro Ala Pro Gln Gly 1105 1110 1115 1120 Ser Arg Ser Leu Thr Pro Cys Thr Cys Gly Ser Ser Asp Leu Tyr Leu 1125 1130 1135 Val Thr Arg His Ala Asp Val Ile Pro Val Arg Arg Arg Gly Asp Ser 1140 1145 1150 Arg Gly Ser Leu Leu Ser Pro Arg Pro Ile Ser Tyr Leu Lys Gly Ser 1155 1160 1165 Ser Gly Gly Pro Leu Leu Cys Pro Ala Gly His Ala Val Gly Leu Phe 1170 1175 1180 Arg Ala Ala Val Cys Thr Arg Gly Val Ala Lys Ala Val Asp Phe Ile 1185 1190 1195 1200 Pro Val Glu Asn Leu Gly Thr Thr Met Arg Ser Pro Val Phe Thr Asp 1205 1210 1215 Asn Ser Ser Pro Pro Ala Val Pro Gln Ser Phe Gln Val Ala His Leu 1220 1225 1230 His Ala Pro Thr Gly Ser Gly Lys Ser Thr Lys Val Pro Ala Ala Tyr 1235 1240 1245 Ala Ala Gln Gly Tyr Lys Val Leu Val Leu Asn Pro Ser Val Ala Ala 1250 1255 1260 Thr Leu Gly Phe Gly Ala Tyr Met Ser Lys Ala His Gly Val Asp Pro 1265 1270 1275 1280 Asn Ile Arg Thr Gly Val Arg Thr Ile Thr Thr Gly Ser Pro Ile Thr 1285 1290 1295 Tyr Ser Thr Tyr Gly Lys Phe Leu Ala Asp Gly Gly Cys Ser Gly Gly 1300 1305 1310 Ala Tyr Asp Ile Ile Ile Cys Asp Glu Cys His Ser Thr Asp Ala Thr 1315 1320 1325 Ser Ile Leu Gly Ile Gly Thr Val Leu Asp Gln Ala Glu Thr Ala Gly 1330 1335 1340 Ala Arg Leu Val Val Leu Ala Thr Ala Thr Pro Pro Gly Ser Val Thr 1345 1350 1355 1360 Val Ser His Pro Asn Ile Glu Glu Val Ala Leu Ser Thr Thr Gly Glu 1365 1370 1375 Ile Pro Phe Tyr Gly Lys Ala Ile Pro Leu Glu Val Ile Lys Gly Gly 1380 1385 1390 Arg His Leu Ile Phe Cys His Ser Lys Lys Lys Cys Asp Glu Leu Ala 1395 1400 1405 Ala Lys Leu Val Ala Leu Gly Ile Asn Ala Val Ala Tyr Tyr Arg Gly 1410 1415 1420 Leu Asp Val Ser Val Ile Pro Thr Ser Gly Asp Val Val Val Val Ser 1425 1430 1435 1440 Thr Asp Ala Leu Met Thr Gly Phe Thr Gly Asp Phe Asp Ser Val Ile 1445 1450 1455 Asp Cys Asn Thr Cys Val Thr Gln Thr Val Asp Phe Ser Leu Asp Pro 1460 1465 1470 Thr Phe Thr Ile Glu Thr Thr Thr Leu Pro Gln Asp Ala Val Ser Arg 1475 1480 1485 Thr Gln Arg Arg Gly Arg Thr Gly Arg Gly Lys Pro Gly Ile Tyr Arg 1490 1495 1500 Phe Val Ala Pro Gly Glu Arg Pro Ser Gly Met Phe Asp Ser Ser Val 1505 1510 1515 1520 Leu Cys Glu Cys Tyr Asp Ala Gly Cys Ala Trp Tyr Glu Leu Thr Pro 1525 1530 1535 Ala Glu Thr Thr Val Arg Leu Arg Ala Tyr Met Asn Thr Pro Gly Leu 1540 1545 1550 Pro Val Cys Gln Asp His Leu Glu Phe Trp Glu Gly Val Phe Thr Gly 1555 1560 1565 Leu Thr His Ile Asp Ala His Phe Leu Ser Gln Thr Lys Gln Ser Gly 1570 1575 1580 Glu Asn Phe Pro Tyr Leu Val Ala Tyr Gln Ala Thr Val Cys Ala Arg 1585 1590 1595 1600 Ala Gln Ala Pro Pro Pro Ser Trp Asp Gln Met Trp Lys Cys Leu Ile 1605 1610 1615 Arg Leu Lys Pro Thr Leu His Gly Pro Thr Pro Leu Leu Tyr Arg Leu 1620 1625 1630 Gly Ala Val Gln Asn Glu Val Thr Leu Thr His Pro Ile Thr Lys Tyr 1635 1640

1645 Ile Met Thr Cys Met Ser Ala Asp Leu Glu Val Val Thr Ser Thr Trp 1650 1655 1660 Val Leu Val Gly Gly Val Leu Ala Ala Leu Ala Ala Tyr Cys Leu Ser 1665 1670 1675 1680 Thr Gly Cys Val Val Ile Val Gly Arg Ile Val Leu Ser Gly Lys Pro 1685 1690 1695 Ala Ile Ile Pro Asp Arg Glu Val Leu Tyr Gln Glu Phe Asp Glu Met 1700 1705 1710 Glu Glu Cys Ser Gln His Leu Pro Tyr Ile Glu Gln Gly Met Met Leu 1715 1720 1725 Ala Glu Gln Phe Lys Gln Lys Ala Leu Gly Leu Leu Gln Thr Ala Ser 1730 1735 1740 Arg His Ala Glu Val Ile Thr Pro Ala Val Gln Thr Asn Trp Gln Lys 1745 1750 1755 1760 Leu Glu Val Phe Trp Ala Lys His Met Trp Asn Phe Ile Ser Gly Ile 1765 1770 1775 Gln Tyr Leu Ala Gly Leu Ser Thr Leu Pro Gly Asn Pro Ala Ile Ala 1780 1785 1790 Ser Leu Met Ala Phe Thr Ala Ala Val Thr Ser Pro Leu Thr Thr Gly 1795 1800 1805 Gln Thr Leu Leu Phe Asn Ile Leu Gly Gly Trp Val Ala Ala Gln Leu 1810 1815 1820 Ala Ala Pro Gly Ala Ala Thr Ala Phe Val Gly Ala Gly Leu Ala Gly 1825 1830 1835 1840 Ala Ala Ile Gly Ser Val Gly Leu Gly Lys Val Leu Val Asp Ile Leu 1845 1850 1855 Ala Gly Tyr Gly Ala Gly Val Ala Gly Ala Leu Val Ala Phe Lys Ile 1860 1865 1870 Met Ser Gly Glu Val Pro Ser Thr Glu Asp Leu Val Asn Leu Leu Pro 1875 1880 1885 Ala Ile Leu Ser Pro Gly Ala Leu Val Val Gly Val Val Cys Ala Ala 1890 1895 1900 Ile Leu Arg Arg His Val Gly Pro Gly Glu Gly Ala Val Gln Trp Met 1905 1910 1915 1920 Asn Arg Leu Ile Ala Phe Ala Ser Arg Gly Asn His Val Ser Pro Thr 1925 1930 1935 His Tyr Val Pro Glu Ser Asp Ala Ala Ala Arg Val Thr Ala Ile Leu 1940 1945 1950 Ser Ser Leu Thr Val Thr Gln Leu Leu Arg Arg Leu His Gln Trp Ile 1955 1960 1965 Ser Ser Glu Cys Thr Thr Pro Cys Ser Gly Ser Trp Leu Arg Asp Ile 1970 1975 1980 Trp Asp Trp Ile Cys Glu Val Leu Ser Asp Phe Lys Thr Trp Leu Lys 1985 1990 1995 2000 Ala Lys Leu Met Pro Gln Leu Pro Gly Ile Pro Phe Val Ser Cys Gln 2005 2010 2015 Arg Gly Tyr Arg Gly Val Trp Arg Gly Asp Gly Ile Met His Thr Arg 2020 2025 2030 Cys His Cys Gly Ala Glu Ile Thr Gly His Val Lys Asn Gly Thr Met 2035 2040 2045 Arg Ile Val Gly Pro Arg Thr Cys Arg Asn Met Trp Ser Gly Thr Phe 2050 2055 2060 Pro Ile Asn Ala Tyr Thr Thr Gly Pro Cys Thr Pro Leu Pro Ala Pro 2065 2070 2075 2080 Asn Tyr Lys Phe Ala Leu Trp Arg Val Ser Ala Glu Glu Tyr Val Glu 2085 2090 2095 Ile Arg Arg Val Gly Asp Phe His Tyr Val Ser Gly Met Thr Thr Asp 2100 2105 2110 Asn Leu Lys Cys Pro Cys Gln Ile Pro Ser Pro Glu Phe Phe Thr Glu 2115 2120 2125 Leu Asp Gly Val Arg Leu His Arg Phe Ala Pro Pro Cys Lys Pro Leu 2130 2135 2140 Leu Arg Glu Glu Val Ser Phe Arg Val Gly Leu His Glu Tyr Pro Val 2145 2150 2155 2160 Gly Ser Gln Leu Pro Cys Glu Pro Glu Pro Asp Val Ala Val Leu Thr 2165 2170 2175 Ser Met Leu Thr Asp Pro Ser His Ile Thr Ala Glu Ala Ala Gly Arg 2180 2185 2190 Arg Leu Ala Arg Gly Ser Pro Pro Ser Met Ala Ser Ser Ser Ala Ser 2195 2200 2205 Gln Leu Ser Ala Pro Ser Leu Lys Ala Thr Cys Thr Ala Asn His Asp 2210 2215 2220 Ser Pro Asp Ala Glu Leu Ile Glu Ala Asn Leu Leu Trp Arg Gln Glu 2225 2230 2235 2240 Met Gly Gly Asn Ile Thr Arg Val Glu Ser Glu Asn Lys Val Val Ile 2245 2250 2255 Leu Asp Ser Phe Asp Pro Leu Val Ala Glu Glu Asp Glu Arg Glu Val 2260 2265 2270 Ser Val Pro Ala Glu Ile Leu Arg Lys Ser Arg Arg Phe Ala Arg Ala 2275 2280 2285 Leu Pro Val Trp Ala Arg Pro Asp Tyr Asn Pro Pro Leu Val Glu Thr 2290 2295 2300 Trp Lys Lys Pro Asp Tyr Glu Pro Pro Val Val His Gly Cys Pro Leu 2305 2310 2315 2320 Pro Pro Pro Arg Ser Pro Pro Val Pro Pro Pro Arg Lys Lys Arg Thr 2325 2330 2335 Val Val Leu Thr Glu Ser Thr Leu Ser Thr Ala Leu Ala Glu Leu Ala 2340 2345 2350 Thr Lys Ser Phe Gly Ser Ser Ser Thr Ser Gly Ile Thr Gly Asp Asn 2355 2360 2365 Thr Thr Thr Ser Ser Glu Pro Ala Pro Ser Gly Cys Pro Pro Asp Ser 2370 2375 2380 Asp Val Glu Ser Tyr Ser Ser Met Pro Pro Leu Glu Gly Glu Pro Gly 2385 2390 2395 2400 Asp Pro Asp Leu Ser Asp Gly Ser Trp Ser Thr Val Ser Ser Gly Ala 2405 2410 2415 Asp Thr Glu Asp Val Val Cys Cys Ser Met Ser Tyr Ser Trp Thr Gly 2420 2425 2430 Ala Leu Val Thr Pro Cys Ala Ala Glu Glu Gln Lys Leu Pro Ile Asn 2435 2440 2445 Ala Leu Ser Asn Ser Leu Leu Arg His His Asn Leu Val Tyr Ser Thr 2450 2455 2460 Thr Ser Arg Ser Ala Cys Gln Arg Gln Lys Lys Val Thr Phe Asp Arg 2465 2470 2475 2480 Leu Gln Val Leu Asp Ser His Tyr Gln Asp Val Leu Lys Glu Val Lys 2485 2490 2495 Ala Ala Ala Ser Lys Val Lys Ala Asn Leu Leu Ser Val Glu Glu Ala 2500 2505 2510 Cys Ser Leu Thr Pro Pro His Ser Ala Lys Ser Lys Phe Gly Tyr Gly 2515 2520 2525 Ala Lys Asp Val Arg Cys His Ala Arg Lys Ala Val Ala His Ile Asn 2530 2535 2540 Ser Val Trp Lys Asp Leu Leu Glu Asp Ser Val Thr Pro Ile Asp Thr 2545 2550 2555 2560 Thr Ile Met Ala Lys Asn Glu Val Phe Cys Val Gln Pro Glu Lys Gly 2565 2570 2575 Gly Arg Lys Pro Ala Arg Leu Ile Val Phe Pro Asp Leu Gly Val Arg 2580 2585 2590 Val Cys Glu Lys Met Ala Leu Tyr Asp Val Val Ser Lys Leu Pro Leu 2595 2600 2605 Ala Val Met Gly Ser Ser Tyr Gly Phe Gln Tyr Ser Pro Gly Gln Arg 2610 2615 2620 Val Glu Phe Leu Val Gln Ala Trp Lys Ser Lys Lys Thr Pro Met Gly 2625 2630 2635 2640 Phe Ser Tyr Asp Thr Arg Cys Phe Asp Ser Thr Val Thr Glu Ser Asp 2645 2650 2655 Ile Arg Thr Glu Glu Ala Ile Tyr Gln Cys Cys Asp Leu Asp Pro Gln 2660 2665 2670 Ala Arg Val Ala Ile Lys Ser Leu Thr Glu Arg Leu Tyr Val Gly Gly 2675 2680 2685 Pro Leu Thr Asn Ser Arg Gly Glu Asn Cys Gly Tyr Arg Arg Cys Arg 2690 2695 2700 Ala Ser Gly Val Leu Thr Thr Ser Cys Gly Asn Thr Leu Thr Cys Tyr 2705 2710 2715 2720 Ile Lys Ala Arg Ala Ala Cys Arg Ala Ala Gly Leu Gln Asp Cys Thr 2725 2730 2735 Met Leu Val Cys Gly Asp Asp Leu Val Val Ile Cys Glu Ser Ala Gly 2740 2745 2750 Val Gln Glu Asp Ala Ala Ser Leu Arg Ala Phe Thr Glu Ala Met Thr 2755 2760 2765 Arg Tyr Ser Ala Pro Pro Gly Asp Pro Pro Gln Pro Glu Tyr Asp Leu 2770 2775 2780 Glu Leu Ile Thr Ser Cys Ser Ser Asn Val Ser Val Ala His Asp Gly 2785 2790 2795 2800 Ala Gly Lys Arg Val Tyr Tyr Leu Thr Arg Asp Pro Thr Thr Pro Leu 2805 2810 2815 Ala Arg Ala Ala Trp Glu Thr Ala Arg His Thr Pro Val Asn Ser Trp 2820 2825 2830 Leu Gly Asn Ile Ile Met Phe Ala Pro Thr Leu Trp Ala Arg Met Ile 2835 2840 2845 Leu Met Thr His Phe Phe Ser Val Leu Ile Ala Arg Asp Gln Leu Glu 2850 2855 2860 Gln Ala Leu Asn Cys Glu Ile Tyr Gly Ala Cys Tyr Ser Ile Glu Pro 2865 2870 2875 2880 Leu Asp Leu Pro Pro Ile Ile Gln Arg Leu His Gly Leu Ser Ala Phe 2885 2890 2895 Ser Leu His Ser Tyr Ser Pro Gly Glu Ile Asn Arg Val Ala Ala Cys 2900 2905 2910 Leu Arg Lys Leu Gly Val Pro Pro Leu Arg Ala Trp Arg His Arg Ala 2915 2920 2925 Arg Ser Val Arg Ala Arg Leu Leu Ser Arg Gly Gly Arg Ala Ala Ile 2930 2935 2940 Cys Gly Lys Tyr Leu Phe Asn Trp Ala Val Arg Thr Lys Leu Lys Leu 2945 2950 2955 2960 Thr Pro Ile Ala Ala Ala Gly Arg Leu Asp Leu Ser Gly Trp Phe Thr 2965 2970 2975 Ala Gly Tyr Ser Gly Gly Asp Ile Tyr His Ser Val Ser His Ala Arg 2980 2985 2990 Pro Arg Trp Phe Trp Phe Cys Leu Leu Leu Leu Ala Ala Gly Val Gly 2995 3000 3005 Ile Tyr Leu Leu Pro Asn Arg 3010 3015 9 9611 DNA Hepatitis C virus 9 gccagccccc tgatgggggc gacactccac catgaatcac tcccctgtga ggaactactg 60 tcttcacgca gaaagcgtct agccatggcg ttagtatgag tgtcgtgcag cctccaggac 120 cccccctccc gggagagcca tagtggtctg cggaaccggt gagtacaccg gaattgccag 180 gacgaccggg tcctttcttg gataaacccg ctcaatgcct ggagatttgg gcgtgccccc 240 gcaagactgc tagccgagta gtgttgggtc gcgaaaggcc ttgtggtact gcctgatagg 300 gtgcttgcga gtgccccggg aggtctcgta gaccgtgcac catgagcaca aatcctaaac 360 ctcaaagaaa aaccaaaaga aacaccaacc gtcgcccaca agacgttaag tttccgggcg 420 gcggccagat cgttggcgga gtatacttgt tgccgcgcag gggccccagg ttgggtgtgc 480 gcgcgacaag gaagacttcg gagcggtccc agccacgtgg aaggcgccag cccatcccta 540 aagatcggcg ctccactggc aaatcctggg gaaaaccagg atacccctgg cccctatacg 600 ggaatgaggg actcggctgg gcaggatggc tcctgtcccc ccgaggttcc cgtccctctt 660 ggggccccaa tgacccccgg cataggtcgc gcaacgtggg taaggtcatc gataccctaa 720 cgtgcggctt tgccgacctc atggggtaca tccctgtcgt gggcgccccg ctcggcggcg 780 tcgccagagc tctcgcgcat ggcgtgagag tcctggagga cggggttaat tttgcaacag 840 ggaacttacc cggttgctcc ttttctatct tcttgctggc cctgctgtcc tgcatcacca 900 ccccggtctc cgctgccgaa gtgaagaaca tcagtaccgg ctacatggtg actaacgact 960 gcaccaatga cagcattacc tggcagctcc aggctgctgt cctccacgtc cccgggtgcg 1020 tcccgtgcga gaaagtgggg aatgcatctc agtgctggat accggtctca ccgaatgtgg 1080 ccgtgcagcg gcccggcgcc ctcacgcagg gcttgcggac gcacatcgac atggttgtga 1140 tgtccgccac gctctgctct gccctctacg tgggggacct ctgcggtggg gtgatgctcg 1200 cagcccaaat gttcattgtc tcgccgcagc accactggtt tgtccaagac tgcaattgct 1260 ccatctaccc tggtaccatc actggacacc gcatggcatg ggacatgatg atgaactggt 1320 cgcccacggc taccatgatc ttggcgtacg cgatgcgtgt ccccgaggtc attatagaca 1380 tcattagcgg ggctcattgg ggcgtcatgt tcggcttggc ctacttctct atgcagggag 1440 cgtgggcgaa agtcgttgtc atccttctgt tggccgccgg ggtggacgcg cgcacccata 1500 ctgttggggg ttctgccgcg cagaccaccg ggcgcctcac cagcttattt gacatgggcc 1560 ccaggcagaa aatccagctc gttaacacca atggcagctg gcacatcaac cgcaccgccc 1620 tgaactgcaa tgactccttg cacaccggct ttatcgcgtc tctgttctac acccacagct 1680 tcaactcgtc aggatgtccc gaacgcatgt ccgcctgccg cagtatcgag gccttccggg 1740 tgggatgggg cgccttgcaa tatgaggata atgtcaccaa tccagaggat atgagaccct 1800 attgctggca ctacccacca aggcagtgtg gcgtggtctc cgcgaagact gtgtgtggcc 1860 cagtgtactg tttcaccccc agcccagtgg tagtgggcac gaccgacagg cttggagcgc 1920 ccacttacac gtggggggag aatgagacag atgtcttcct attgaacagc actcgaccac 1980 cgctggggtc atggttcggc tgcacgtgga tgaactcttc tggctacacc aagacttgcg 2040 gcgcaccacc ctgccgtact agagctgact tcaacgccag cacggacctg ttgtgcccca 2100 cggactgttt taggaagcat cctgatacca cttacctcaa atgcggctct gggccctggc 2160 tcacgccaag gtgcctgatc gactacccct acaggctctg gcattacccc tgcacagtta 2220 actataccat cttcaaaata aggatgtatg tgggaggggt tgagcacagg ctcacggctg 2280 catgcaattt cactcgtggg gatcgttgca acttggagga cagagacaga agtcaactgt 2340 ctcctttgtt gcactccacc acggaatggg ccattttacc ttgctcttac tcggacctgc 2400 ccgccttgtc gactggtctt ctccacctcc accaaaacat cgtggacgta caattcatgt 2460 atggcctatc acctgccctc acaaaataca tcgtccgatg ggagtgggta atactcttat 2520 tcctgctctt agcggacgcc agggtttgcg cctgcttatg gatgctcatc ttgttgggcc 2580 aggccgaagc agctttggag aacctcgtaa tactcaatgc agcatccctg gccgggacgc 2640 acggtcttgt gtccttcctc gtgttcttct gctttgcgtg gtatctgaag ggtaggtggg 2700 tgcccggagc ggtctacgcc ctctacggga tgtggcctct cctcctgctc ctgctggcgt 2760 tgcctcagcg ggcatatgca ctggacacgg aggtggccgc gtcgtgtggc ggcgttgttc 2820 ttgtcgggtt aatggcgctg actctgtcgc catattacaa gcgctatatc agctggtgca 2880 tgtggtggct tcagtatttt ctgaccagag tagaagcgca actgcacgtg tgggttcccc 2940 ccctcaacgt ccgggggggg cgcgatgccg tcatcttact catgtgtgta gtacacccga 3000 ccctggtatt tgacatcacc aaactactcc tggccatctt cggacccctt tggattcttc 3060 aagccagttt gcttaaagtc ccctacttcg tgcgcgttca aggccttctc cggatctgcg 3120 cgctagcgcg gaagatagcc ggaggtcatt acgtgcaaat ggccatcatc aagttagggg 3180 cgcttactgg cacctatgtg tataaccatc tcacccctct tcgagactgg gcgcacaacg 3240 gcctgcgaga tctggccgtg gctgtggaac cagtcgtctt ctcccgaatg gagaccaagc 3300 tcatcacgtg gggggcagat accgccgcgt gcggtgacat catcaacggc ttgcccgtct 3360 ctgcccgtag gggccaggag atactgcttg ggccagccga cggaatggtc tccaaggggt 3420 ggaggttgct ggcgcccatc acggcgtacg cccagcagac gagaggcctc ctagggtgta 3480 taatcaccag cctgactggc cgggacaaaa accaagtgga gggtgaggtc cagatcgtgt 3540 caactgctac ccaaaccttc ctggcaacgt gcatcaatgg ggtatgctgg actgtctacc 3600 acggggccgg aacgaggacc atcgcatcac ccaagggtcc tgtcatccag atgtatacca 3660 atgtggacca agaccttgtg ggctggcccg ctcctcaagg ttcccgctca ttgacaccct 3720 gtacctgcgg ctcctcggac ctttacctgg tcacgaggca cgccgatgtc attcccgtgc 3780 gccggcgagg tgatagcagg ggtagcctgc tttcgccccg gcccatttcc tacttgaaag 3840 gctcctcggg gggtccgctg ttgtgccccg cgggacacgc cgtgggccta ttcagggccg 3900 cggtgtgcac ccgtggagtg gctaaagcgg tggactttat ccctgtggag aacctaggga 3960 caaccatgag atccccggtg ttcacggaca actcctctcc accagcagtg ccccagagct 4020 tccaggtggc ccacctgcat gctcccaccg gcagcggtaa gagcaccaag gtcccggctg 4080 cgtacgcagc ccagggctac aaggtgttgg tgctcaaccc ctctgttgct gcaacgctgg 4140 gctttggtgc ttacatgtcc aaggcccatg gggttgatcc taatatcagg accggggtga 4200 gaacaattac cactggcagc cccatcacgt actccaccta cggcaagttc cttgccgacg 4260 gcgggtgctc aggaggtgct tatgacataa taatttgtga cgagtgccac tccacggatg 4320 ccacatccat cttgggcatc ggcactgtcc ttgaccaagc agagactgcg ggggcgagac 4380 tggttgtgct cgccactgct acccctccgg gctccgtcac tgtgtcccat cctaacatcg 4440 aggaggttgc tctgtccacc accggagaga tcccctttta cggcaaggct atccccctcg 4500 aggtgatcaa ggggggaaga catctcatct tctgccactc aaagaagaag tgcgacgagc 4560 tcgccgcgaa gctggtcgca ttgggcatca atgccgtggc ctactaccgc ggtcttgacg 4620 tgtctgtcat cccgaccagc ggcgatgttg tcgtcgtgtc gaccgatgct ctcatgactg 4680 gctttaccgg cgacttcgac tctgtgatag actgcaacac gtgtgtcact cagacagtcg 4740 atttcagcct tgaccctacc tttaccattg agacaaccac gctcccccag gatgctgtct 4800 ccaggactca acgccggggc aggactggca gggggaagcc aggcatctat agatttgtgg 4860 caccggggga gcgcccctcc ggcatgttcg actcgtccgt cctctgtgag tgctatgacg 4920 cgggctgtgc ttggtatgag ctcacgcccg ccgagactac agttaggcta cgagcgtaca 4980 tgaacacccc ggggcttccc gtgtgccagg accatcttga attttgggag ggcgtcttta 5040 cgggcctcac tcatatagat gcccactttt tatcccagac aaagcagagt ggggagaact 5100 ttccttacct ggtagcgtac caagccaccg tgtgcgctag ggctcaagcc cctcccccat 5160 cgtgggacca gatgtggaag tgtttgatcc gccttaaacc caccctccat gggccaacac 5220 ccctgctata cagactgggc gctgttcaga atgaagtcac cctgacgcac ccaatcacca 5280 aatacatcat gacatgcatg tcggccgacc tggaggtcgt cacgagcacc tgggtgctcg 5340 ttggcggcgt cctggctgct ctggccgcgt attgcctgtc aacaggctgc gtggtcatag 5400 tgggcaggat cgtcttgtcc gggaagccgg caattatacc tgacagggag gttctctacc 5460 aggagttcga tgagatggaa gagtgctctc agcacttacc gtacatcgag caagggatga 5520 tgctcgctga gcagttcaag cagaaggccc tcggcctcct gcagaccgcg tcccgccatg 5580 cagaggttat cacccctgct gtccagacca actggcagaa actcgaggtc ttttgggcga 5640 agcacatgtg gaatttcatc agtgggatac aatacttggc gggcctgtca acgctgcctg 5700 gtaaccccgc cattgcttca ttgatggctt ttacagctgc cgtcaccagc ccactaacca 5760 ctggccaaac cctcctcttc aacatattgg gggggtgggt ggctgcccag ctcgccgccc 5820 ccggtgccgc tactgccttt gtgggtgctg gcctagctgg cgccgccatc ggcagcgttg 5880 gactggggaa ggtcctcgtg gacattcttg cagggtatgg cgcgggcgtg gcgggagctc 5940 ttgtagcatt caagatcatg agcggtgagg tcccctccac ggaggacctg gtcaatctgc 6000 tgcccgccat cctctcgcct ggagcccttg tagtcggtgt ggtctgcgca gcaatactgc 6060 gccggcacgt tggcccgggc gagggggcag tgcaatggat gaaccggcta atagccttcg 6120 cctcccgggg gaaccatgtt tcccccacgc actacgtgcc ggagagcgat gcagccgccc 6180 gcgtcactgc catactcagc agcctcactg taacccagct cctgaggcga ctgcatcagt 6240 ggataagctc ggagtgtacc actccatgct ccggttcctg gctaagggac atctgggact 6300 ggatatgcga ggtgctgagc gactttaaga cctggctgaa agccaagctc atgccacaac 6360 tgcctgggat tccctttgtg tcctgccagc gcgggtatag gggggtctgg cgaggagacg 6420 gcattatgca cactcgctgc cactgtggag ctgagatcac tggacatgtc

aaaaacggga 6480 cgatgaggat cgtcggtcct aggacctgca ggaacatgtg gagtgggacg ttccccatta 6540 acgcctacac cacgggcccc tgtactcccc ttcctgcgcc gaactataag ttcgcgctgt 6600 ggagggtgtc tgcagaggaa tacgtggaga taaggcgggt gggggacttc cactacgtat 6660 cgggtatgac tactgacaat cttaaatgcc cgtgccagat cccatcgccc gaatttttca 6720 cagaattgga cggggtgcgc ctacacaggt ttgcgccccc ttgcaagccc ttgctgcggg 6780 aggaggtatc attcagagta ggactccacg agtacccggt ggggtcgcaa ttaccttgcg 6840 agcccgaacc ggacgtagcc gtgttgacgt ccatgctcac tgatccctcc catataacag 6900 cagaggcggc cgggagaagg ttggcgagag ggtcaccccc ttctatggcc agctcctcgg 6960 ctagccagct gtccgctcca tctctcaagg caacttgcac cgccaaccat gactcccctg 7020 acgccgagct catagaggct aacctcctgt ggaggcagga gatgggcggc aacatcacca 7080 gggttgagtc agagaacaaa gtggtgattc tggactcctt cgatccgctt gtggcagagg 7140 aggatgagcg ggaggtctcc gtacctgcag aaattctgcg gaagtctcgg agattcgccc 7200 gggccctgcc cgtctgggcg cggccggact acaacccccc gctagtagag acgtggaaaa 7260 agcctgacta cgaaccacct gtggtccatg gctgcccgct accacctcca cggtcccctc 7320 ctgtgcctcc gcctcggaaa aagcgtacgg tggtcctcac cgaatcaacc ctatctactg 7380 ccttggccga gcttgccacc aaaagttttg gcagctcctc aacttccggc attacgggcg 7440 acaatacgac aacatcctct gagcccgccc cttctggctg cccccccgac tccgacgttg 7500 agtcctattc ttccatgccc cccctggagg gggagcctgg ggatccggat ctcagcgacg 7560 ggtcatggtc gacggtcagt agtggggccg acacggaaga tgtcgtgtgc tgctcaatgt 7620 cttattcctg gacaggcgca ctcgtcaccc cgtgcgctgc ggaagaacaa aaactgccca 7680 tcaacgcact gagcaactcg ttgctacgcc atcacaatct ggtgtattcc accacttcac 7740 gcagtgcttg ccaaaggcag aagaaagtca catttgacag actgcaagtt ctggacagcc 7800 attaccagga cgtgctcaag gaggtcaaag cagcggcgtc aaaagtgaag gctaacttgc 7860 tatccgtaga ggaagcttgc agcctgacgc ccccacattc agccaaatcc aagtttggct 7920 atggggcaaa agacgtccgt tgccatgcca gaaaggccgt agcccacatc aactccgtgt 7980 ggaaagacct tctggaagac agtgtaacac caatagacac taccatcatg gccaagaacg 8040 aggttttctg cgttcagcct gagaaggggg gtcgtaagcc agctcgtctc atcgtgttcc 8100 ccgacctggg cgtgcgcgtg tgcgagaaga tggccctgta cgacgtggtt agcaagctcc 8160 ccctggccgt gatgggaagc tcctacggat tccaatactc accaggacag cgggttgaat 8220 tcctcgtgca agcgtggaag tccaagaaga ccccgatggg gttctcgtat gatacccgct 8280 gttttgactc cacagtcact gagagcgaca tccgtacgga ggaggcaatt taccaatgtt 8340 gtgacctgga cccccaagcc cgcgtggcca tcaagtccct cactgagagg ctttatgttg 8400 ggggccctct taccaattca aggggggaaa actgcggcta ccgcaggtgc cgcgcgagcg 8460 gcgtactgac aactagctgt ggtaacaccc tcacttgcta catcaaggcc cgggcagcct 8520 gtcgagccgc agggctccag gactgcacca tgctcgtgtg tggcgacgac ttagtcgtta 8580 tctgtgaaag tgcgggggtc caggaggacg cggcgagcct gagagccttc acggaggcta 8640 tgaccaggta ctccgccccc cccggggacc ccccacaacc agaatacgac ttggagctta 8700 taacatcatg ctcctccaac gtgtcagtcg cccacgacgg cgctggaaag agggtctact 8760 accttacccg tgaccctaca acccccctcg cgagagccgc gtgggagaca gcaagacaca 8820 ctccagtcaa ttcctggcta ggcaacataa tcatgtttgc ccccacactg tgggcgagga 8880 tgatactgat gacccatttc tttagcgtcc tcatagccag ggatcagctt gaacaggctc 8940 ttaactgtga gatctacgga gcctgctact ccatagaacc actggatcta cctccaatca 9000 ttcaaagact ccatggcctc agcgcatttt cactccacag ttactctcca ggtgaaatca 9060 atagggtggc cgcatgcctc agaaaacttg gggtcccgcc cttgcgagct tggagacacc 9120 gggcccggag cgtccgcgct aggcttctgt ccagaggagg cagggctgct atatgtggca 9180 agtacctctt caactgggca gtaagaacaa agctcaaact cactccaata gcggccgctg 9240 gccggctgga cttgtccggt tggttcacgg ctggctacag cgggggagac atttatcaca 9300 gcgtgtctca tgcccggccc cgctggttct ggttttgcct actcctgctc gctgcagggg 9360 taggcatcta cctcctcccc aaccgatgaa ggttggggta aacactccgg cctcttaagc 9420 catttcctgt tttttttttt tttttttttt tttttttctt tttttttttc tttcctttcc 9480 ttcttttttt cctttctttt tcccttcttt aatggtggct ccatcttagc cctagtcacg 9540 gctagctgtg aaaggtccgt gagccgcatg actgcagaga gtgctgatac tggcctctct 9600 gcagatcatg t 9611 10 3015 PRT Hepatitis C virus 10 Met Ser Thr Asn Pro Lys Pro Gln Arg Lys Thr Lys Arg Asn Thr Asn 1 5 10 15 Arg Arg Pro Gln Asp Val Lys Phe Pro Gly Gly Gly Gln Ile Val Gly 20 25 30 Gly Val Tyr Leu Leu Pro Arg Arg Gly Pro Arg Leu Gly Val Arg Ala 35 40 45 Thr Arg Lys Thr Ser Glu Arg Ser Gln Pro Arg Gly Arg Arg Gln Pro 50 55 60 Ile Pro Lys Asp Arg Arg Ser Thr Gly Lys Ser Trp Gly Lys Pro Gly 65 70 75 80 Tyr Pro Trp Pro Leu Tyr Gly Asn Glu Gly Leu Gly Trp Ala Gly Trp 85 90 95 Leu Leu Ser Pro Arg Gly Ser Arg Pro Ser Trp Gly Pro Asn Asp Pro 100 105 110 Arg His Arg Ser Arg Asn Val Gly Lys Val Ile Asp Thr Leu Thr Cys 115 120 125 Gly Phe Ala Asp Leu Met Gly Tyr Ile Pro Val Val Gly Ala Pro Leu 130 135 140 Gly Gly Val Ala Arg Ala Leu Ala His Gly Val Arg Val Leu Glu Asp 145 150 155 160 Gly Val Asn Phe Ala Thr Gly Asn Leu Pro Gly Cys Ser Phe Ser Ile 165 170 175 Phe Leu Leu Ala Leu Leu Ser Cys Ile Thr Thr Pro Val Ser Ala Ala 180 185 190 Glu Val Lys Asn Ile Ser Thr Gly Tyr Met Val Thr Asn Asp Cys Thr 195 200 205 Asn Asp Ser Ile Thr Trp Gln Leu Gln Ala Ala Val Leu His Val Pro 210 215 220 Gly Cys Val Pro Cys Glu Lys Val Gly Asn Ala Ser Gln Cys Trp Ile 225 230 235 240 Pro Val Ser Pro Asn Val Ala Val Gln Arg Pro Gly Ala Leu Thr Gln 245 250 255 Gly Leu Arg Thr His Ile Asp Met Val Val Met Ser Ala Thr Leu Cys 260 265 270 Ser Ala Leu Tyr Val Gly Asp Leu Cys Gly Gly Val Met Leu Ala Ala 275 280 285 Gln Met Phe Ile Val Ser Pro Gln His His Trp Phe Val Gln Asp Cys 290 295 300 Asn Cys Ser Ile Tyr Pro Gly Thr Ile Thr Gly His Arg Met Ala Trp 305 310 315 320 Asp Met Met Met Asn Trp Ser Pro Thr Ala Thr Met Ile Leu Ala Tyr 325 330 335 Ala Met Arg Val Pro Glu Val Ile Ile Asp Ile Ile Ser Gly Ala His 340 345 350 Trp Gly Val Met Phe Gly Leu Ala Tyr Phe Ser Met Gln Gly Ala Trp 355 360 365 Ala Lys Val Val Val Ile Leu Leu Leu Ala Ala Gly Val Asp Ala Arg 370 375 380 Thr His Thr Val Gly Gly Ser Ala Ala Gln Thr Thr Gly Arg Leu Thr 385 390 395 400 Ser Leu Phe Asp Met Gly Pro Arg Gln Lys Ile Gln Leu Val Asn Thr 405 410 415 Asn Gly Ser Trp His Ile Asn Arg Thr Ala Leu Asn Cys Asn Asp Ser 420 425 430 Leu His Thr Gly Phe Ile Ala Ser Leu Phe Tyr Thr His Ser Phe Asn 435 440 445 Ser Ser Gly Cys Pro Glu Arg Met Ser Ala Cys Arg Ser Ile Glu Ala 450 455 460 Phe Arg Val Gly Trp Gly Ala Leu Gln Tyr Glu Asp Asn Val Thr Asn 465 470 475 480 Pro Glu Asp Met Arg Pro Tyr Cys Trp His Tyr Pro Pro Arg Gln Cys 485 490 495 Gly Val Val Ser Ala Lys Thr Val Cys Gly Pro Val Tyr Cys Phe Thr 500 505 510 Pro Ser Pro Val Val Val Gly Thr Thr Asp Arg Leu Gly Ala Pro Thr 515 520 525 Tyr Thr Trp Gly Glu Asn Glu Thr Asp Val Phe Leu Leu Asn Ser Thr 530 535 540 Arg Pro Pro Leu Gly Ser Trp Phe Gly Cys Thr Trp Met Asn Ser Ser 545 550 555 560 Gly Tyr Thr Lys Thr Cys Gly Ala Pro Pro Cys Arg Thr Arg Ala Asp 565 570 575 Phe Asn Ala Ser Thr Asp Leu Leu Cys Pro Thr Asp Cys Phe Arg Lys 580 585 590 His Pro Asp Thr Thr Tyr Leu Lys Cys Gly Ser Gly Pro Trp Leu Thr 595 600 605 Pro Arg Cys Leu Ile Asp Tyr Pro Tyr Arg Leu Trp His Tyr Pro Cys 610 615 620 Thr Val Asn Tyr Thr Ile Phe Lys Ile Arg Met Tyr Val Gly Gly Val 625 630 635 640 Glu His Arg Leu Thr Ala Ala Cys Asn Phe Thr Arg Gly Asp Arg Cys 645 650 655 Asn Leu Glu Asp Arg Asp Arg Ser Gln Leu Ser Pro Leu Leu His Ser 660 665 670 Thr Thr Glu Trp Ala Ile Leu Pro Cys Ser Tyr Ser Asp Leu Pro Ala 675 680 685 Leu Ser Thr Gly Leu Leu His Leu His Gln Asn Ile Val Asp Val Gln 690 695 700 Phe Met Tyr Gly Leu Ser Pro Ala Leu Thr Lys Tyr Ile Val Arg Trp 705 710 715 720 Glu Trp Val Ile Leu Leu Phe Leu Leu Leu Ala Asp Ala Arg Val Cys 725 730 735 Ala Cys Leu Trp Met Leu Ile Leu Leu Gly Gln Ala Glu Ala Ala Leu 740 745 750 Glu Asn Leu Val Ile Leu Asn Ala Ala Ser Leu Ala Gly Thr His Gly 755 760 765 Leu Val Ser Phe Leu Val Phe Phe Cys Phe Ala Trp Tyr Leu Lys Gly 770 775 780 Arg Trp Val Pro Gly Ala Val Tyr Ala Leu Tyr Gly Met Trp Pro Leu 785 790 795 800 Leu Leu Leu Leu Leu Ala Leu Pro Gln Arg Ala Tyr Ala Leu Asp Thr 805 810 815 Glu Val Ala Ala Ser Cys Gly Gly Val Val Leu Val Gly Leu Met Ala 820 825 830 Leu Thr Leu Ser Pro Tyr Tyr Lys Arg Tyr Ile Ser Trp Cys Met Trp 835 840 845 Trp Leu Gln Tyr Phe Leu Thr Arg Val Glu Ala Gln Leu His Val Trp 850 855 860 Val Pro Pro Leu Asn Val Arg Gly Gly Arg Asp Ala Val Ile Leu Leu 865 870 875 880 Met Cys Val Val His Pro Thr Leu Val Phe Asp Ile Thr Lys Leu Leu 885 890 895 Leu Ala Ile Phe Gly Pro Leu Trp Ile Leu Gln Ala Ser Leu Leu Lys 900 905 910 Val Pro Tyr Phe Val Arg Val Gln Gly Leu Leu Arg Ile Cys Ala Leu 915 920 925 Ala Arg Lys Ile Ala Gly Gly His Tyr Val Gln Met Ala Ile Ile Lys 930 935 940 Leu Gly Ala Leu Thr Gly Thr Tyr Val Tyr Asn His Leu Thr Pro Leu 945 950 955 960 Arg Asp Trp Ala His Asn Gly Leu Arg Asp Leu Ala Val Ala Val Glu 965 970 975 Pro Val Val Phe Ser Arg Met Glu Thr Lys Leu Ile Thr Trp Gly Ala 980 985 990 Asp Thr Ala Ala Cys Gly Asp Ile Ile Asn Gly Leu Pro Val Ser Ala 995 1000 1005 Arg Arg Gly Gln Glu Ile Leu Leu Gly Pro Ala Asp Gly Met Val Ser 1010 1015 1020 Lys Gly Trp Arg Leu Leu Ala Pro Ile Thr Ala Tyr Ala Gln Gln Thr 1025 1030 1035 1040 Arg Gly Leu Leu Gly Cys Ile Ile Thr Ser Leu Thr Gly Arg Asp Lys 1045 1050 1055 Asn Gln Val Glu Gly Glu Val Gln Ile Val Ser Thr Ala Thr Gln Thr 1060 1065 1070 Phe Leu Ala Thr Cys Ile Asn Gly Val Cys Trp Thr Val Tyr His Gly 1075 1080 1085 Ala Gly Thr Arg Thr Ile Ala Ser Pro Lys Gly Pro Val Ile Gln Met 1090 1095 1100 Tyr Thr Asn Val Asp Gln Asp Leu Val Gly Trp Pro Ala Pro Gln Gly 1105 1110 1115 1120 Ser Arg Ser Leu Thr Pro Cys Thr Cys Gly Ser Ser Asp Leu Tyr Leu 1125 1130 1135 Val Thr Arg His Ala Asp Val Ile Pro Val Arg Arg Arg Gly Asp Ser 1140 1145 1150 Arg Gly Ser Leu Leu Ser Pro Arg Pro Ile Ser Tyr Leu Lys Gly Ser 1155 1160 1165 Ser Gly Gly Pro Leu Leu Cys Pro Ala Gly His Ala Val Gly Leu Phe 1170 1175 1180 Arg Ala Ala Val Cys Thr Arg Gly Val Ala Lys Ala Val Asp Phe Ile 1185 1190 1195 1200 Pro Val Glu Asn Leu Gly Thr Thr Met Arg Ser Pro Val Phe Thr Asp 1205 1210 1215 Asn Ser Ser Pro Pro Ala Val Pro Gln Ser Phe Gln Val Ala His Leu 1220 1225 1230 His Ala Pro Thr Gly Ser Gly Lys Ser Thr Lys Val Pro Ala Ala Tyr 1235 1240 1245 Ala Ala Gln Gly Tyr Lys Val Leu Val Leu Asn Pro Ser Val Ala Ala 1250 1255 1260 Thr Leu Gly Phe Gly Ala Tyr Met Ser Lys Ala His Gly Val Asp Pro 1265 1270 1275 1280 Asn Ile Arg Thr Gly Val Arg Thr Ile Thr Thr Gly Ser Pro Ile Thr 1285 1290 1295 Tyr Ser Thr Tyr Gly Lys Phe Leu Ala Asp Gly Gly Cys Ser Gly Gly 1300 1305 1310 Ala Tyr Asp Ile Ile Ile Cys Asp Glu Cys His Ser Thr Asp Ala Thr 1315 1320 1325 Ser Ile Leu Gly Ile Gly Thr Val Leu Asp Gln Ala Glu Thr Ala Gly 1330 1335 1340 Ala Arg Leu Val Val Leu Ala Thr Ala Thr Pro Pro Gly Ser Val Thr 1345 1350 1355 1360 Val Ser His Pro Asn Ile Glu Glu Val Ala Leu Ser Thr Thr Gly Glu 1365 1370 1375 Ile Pro Phe Tyr Gly Lys Ala Ile Pro Leu Glu Val Ile Lys Gly Gly 1380 1385 1390 Arg His Leu Ile Phe Cys His Ser Lys Lys Lys Cys Asp Glu Leu Ala 1395 1400 1405 Ala Lys Leu Val Ala Leu Gly Ile Asn Ala Val Ala Tyr Tyr Arg Gly 1410 1415 1420 Leu Asp Val Ser Val Ile Pro Thr Ser Gly Asp Val Val Val Val Ser 1425 1430 1435 1440 Thr Asp Ala Leu Met Thr Gly Phe Thr Gly Asp Phe Asp Ser Val Ile 1445 1450 1455 Asp Cys Asn Thr Cys Val Thr Gln Thr Val Asp Phe Ser Leu Asp Pro 1460 1465 1470 Thr Phe Thr Ile Glu Thr Thr Thr Leu Pro Gln Asp Ala Val Ser Arg 1475 1480 1485 Thr Gln Arg Arg Gly Arg Thr Gly Arg Gly Lys Pro Gly Ile Tyr Arg 1490 1495 1500 Phe Val Ala Pro Gly Glu Arg Pro Ser Gly Met Phe Asp Ser Ser Val 1505 1510 1515 1520 Leu Cys Glu Cys Tyr Asp Ala Gly Cys Ala Trp Tyr Glu Leu Thr Pro 1525 1530 1535 Ala Glu Thr Thr Val Arg Leu Arg Ala Tyr Met Asn Thr Pro Gly Leu 1540 1545 1550 Pro Val Cys Gln Asp His Leu Glu Phe Trp Glu Gly Val Phe Thr Gly 1555 1560 1565 Leu Thr His Ile Asp Ala His Phe Leu Ser Gln Thr Lys Gln Ser Gly 1570 1575 1580 Glu Asn Phe Pro Tyr Leu Val Ala Tyr Gln Ala Thr Val Cys Ala Arg 1585 1590 1595 1600 Ala Gln Ala Pro Pro Pro Ser Trp Asp Gln Met Trp Lys Cys Leu Ile 1605 1610 1615 Arg Leu Lys Pro Thr Leu His Gly Pro Thr Pro Leu Leu Tyr Arg Leu 1620 1625 1630 Gly Ala Val Gln Asn Glu Val Thr Leu Thr His Pro Ile Thr Lys Tyr 1635 1640 1645 Ile Met Thr Cys Met Ser Ala Asp Leu Glu Val Val Thr Ser Thr Trp 1650 1655 1660 Val Leu Val Gly Gly Val Leu Ala Ala Leu Ala Ala Tyr Cys Leu Ser 1665 1670 1675 1680 Thr Gly Cys Val Val Ile Val Gly Arg Ile Val Leu Ser Gly Lys Pro 1685 1690 1695 Ala Ile Ile Pro Asp Arg Glu Val Leu Tyr Gln Glu Phe Asp Glu Met 1700 1705 1710 Glu Glu Cys Ser Gln His Leu Pro Tyr Ile Glu Gln Gly Met Met Leu 1715 1720 1725 Ala Glu Gln Phe Lys Gln Lys Ala Leu Gly Leu Leu Gln Thr Ala Ser 1730 1735 1740 Arg His Ala Glu Val Ile Thr Pro Ala Val Gln Thr Asn Trp Gln Lys 1745 1750 1755 1760 Leu Glu Val Phe Trp Ala Lys His Met Trp Asn Phe Ile Ser Gly Ile 1765 1770 1775 Gln Tyr Leu Ala Gly Leu Ser Thr Leu Pro Gly Asn Pro Ala Ile Ala 1780 1785 1790 Ser Leu Met Ala Phe Thr Ala Ala Val Thr Ser Pro Leu Thr Thr Gly 1795 1800 1805 Gln Thr Leu Leu Phe Asn Ile Leu Gly Gly Trp Val Ala Ala Gln Leu 1810 1815 1820 Ala Ala Pro Gly Ala Ala Thr Ala Phe Val Gly Ala Gly Leu Ala Gly 1825 1830 1835 1840 Ala Ala Ile Gly Ser Val Gly Leu Gly Lys Val Leu Val Asp Ile Leu 1845 1850 1855 Ala Gly Tyr Gly Ala Gly Val Ala Gly Ala Leu Val Ala Phe Lys Ile 1860 1865 1870 Met Ser Gly Glu Val Pro Ser Thr Glu Asp Leu Val Asn Leu Leu Pro 1875 1880 1885 Ala Ile Leu Ser Pro Gly Ala Leu Val Val Gly Val Val Cys Ala Ala 1890 1895 1900 Ile Leu Arg Arg His Val Gly Pro Gly Glu Gly Ala Val Gln

Trp Met 1905 1910 1915 1920 Asn Arg Leu Ile Ala Phe Ala Ser Arg Gly Asn His Val Ser Pro Thr 1925 1930 1935 His Tyr Val Pro Glu Ser Asp Ala Ala Ala Arg Val Thr Ala Ile Leu 1940 1945 1950 Ser Ser Leu Thr Val Thr Gln Leu Leu Arg Arg Leu His Gln Trp Ile 1955 1960 1965 Ser Ser Glu Cys Thr Thr Pro Cys Ser Gly Ser Trp Leu Arg Asp Ile 1970 1975 1980 Trp Asp Trp Ile Cys Glu Val Leu Ser Asp Phe Lys Thr Trp Leu Lys 1985 1990 1995 2000 Ala Lys Leu Met Pro Gln Leu Pro Gly Ile Pro Phe Val Ser Cys Gln 2005 2010 2015 Arg Gly Tyr Arg Gly Val Trp Arg Gly Asp Gly Ile Met His Thr Arg 2020 2025 2030 Cys His Cys Gly Ala Glu Ile Thr Gly His Val Lys Asn Gly Thr Met 2035 2040 2045 Arg Ile Val Gly Pro Arg Thr Cys Arg Asn Met Trp Ser Gly Thr Phe 2050 2055 2060 Pro Ile Asn Ala Tyr Thr Thr Gly Pro Cys Thr Pro Leu Pro Ala Pro 2065 2070 2075 2080 Asn Tyr Lys Phe Ala Leu Trp Arg Val Ser Ala Glu Glu Tyr Val Glu 2085 2090 2095 Ile Arg Arg Val Gly Asp Phe His Tyr Val Ser Gly Met Thr Thr Asp 2100 2105 2110 Asn Leu Lys Cys Pro Cys Gln Ile Pro Ser Pro Glu Phe Phe Thr Glu 2115 2120 2125 Leu Asp Gly Val Arg Leu His Arg Phe Ala Pro Pro Cys Lys Pro Leu 2130 2135 2140 Leu Arg Glu Glu Val Ser Phe Arg Val Gly Leu His Glu Tyr Pro Val 2145 2150 2155 2160 Gly Ser Gln Leu Pro Cys Glu Pro Glu Pro Asp Val Ala Val Leu Thr 2165 2170 2175 Ser Met Leu Thr Asp Pro Ser His Ile Thr Ala Glu Ala Ala Gly Arg 2180 2185 2190 Arg Leu Ala Arg Gly Ser Pro Pro Ser Met Ala Ser Ser Ser Ala Ser 2195 2200 2205 Gln Leu Ser Ala Pro Ser Leu Lys Ala Thr Cys Thr Ala Asn His Asp 2210 2215 2220 Ser Pro Asp Ala Glu Leu Ile Glu Ala Asn Leu Leu Trp Arg Gln Glu 2225 2230 2235 2240 Met Gly Gly Asn Ile Thr Arg Val Glu Ser Glu Asn Lys Val Val Ile 2245 2250 2255 Leu Asp Ser Phe Asp Pro Leu Val Ala Glu Glu Asp Glu Arg Glu Val 2260 2265 2270 Ser Val Pro Ala Glu Ile Leu Arg Lys Ser Arg Arg Phe Ala Arg Ala 2275 2280 2285 Leu Pro Val Trp Ala Arg Pro Asp Tyr Asn Pro Pro Leu Val Glu Thr 2290 2295 2300 Trp Lys Lys Pro Asp Tyr Glu Pro Pro Val Val His Gly Cys Pro Leu 2305 2310 2315 2320 Pro Pro Pro Arg Ser Pro Pro Val Pro Pro Pro Arg Lys Lys Arg Thr 2325 2330 2335 Val Val Leu Thr Glu Ser Thr Leu Ser Thr Ala Leu Ala Glu Leu Ala 2340 2345 2350 Thr Lys Ser Phe Gly Ser Ser Ser Thr Ser Gly Ile Thr Gly Asp Asn 2355 2360 2365 Thr Thr Thr Ser Ser Glu Pro Ala Pro Ser Gly Cys Pro Pro Asp Ser 2370 2375 2380 Asp Val Glu Ser Tyr Ser Ser Met Pro Pro Leu Glu Gly Glu Pro Gly 2385 2390 2395 2400 Asp Pro Asp Leu Ser Asp Gly Ser Trp Ser Thr Val Ser Ser Gly Ala 2405 2410 2415 Asp Thr Glu Asp Val Val Cys Cys Ser Met Ser Tyr Ser Trp Thr Gly 2420 2425 2430 Ala Leu Val Thr Pro Cys Ala Ala Glu Glu Gln Lys Leu Pro Ile Asn 2435 2440 2445 Ala Leu Ser Asn Ser Leu Leu Arg His His Asn Leu Val Tyr Ser Thr 2450 2455 2460 Thr Ser Arg Ser Ala Cys Gln Arg Gln Lys Lys Val Thr Phe Asp Arg 2465 2470 2475 2480 Leu Gln Val Leu Asp Ser His Tyr Gln Asp Val Leu Lys Glu Val Lys 2485 2490 2495 Ala Ala Ala Ser Lys Val Lys Ala Asn Leu Leu Ser Val Glu Glu Ala 2500 2505 2510 Cys Ser Leu Thr Pro Pro His Ser Ala Lys Ser Lys Phe Gly Tyr Gly 2515 2520 2525 Ala Lys Asp Val Arg Cys His Ala Arg Lys Ala Val Ala His Ile Asn 2530 2535 2540 Ser Val Trp Lys Asp Leu Leu Glu Asp Ser Val Thr Pro Ile Asp Thr 2545 2550 2555 2560 Thr Ile Met Ala Lys Asn Glu Val Phe Cys Val Gln Pro Glu Lys Gly 2565 2570 2575 Gly Arg Lys Pro Ala Arg Leu Ile Val Phe Pro Asp Leu Gly Val Arg 2580 2585 2590 Val Cys Glu Lys Met Ala Leu Tyr Asp Val Val Ser Lys Leu Pro Leu 2595 2600 2605 Ala Val Met Gly Ser Ser Tyr Gly Phe Gln Tyr Ser Pro Gly Gln Arg 2610 2615 2620 Val Glu Phe Leu Val Gln Ala Trp Lys Ser Lys Lys Thr Pro Met Gly 2625 2630 2635 2640 Phe Ser Tyr Asp Thr Arg Cys Phe Asp Ser Thr Val Thr Glu Ser Asp 2645 2650 2655 Ile Arg Thr Glu Glu Ala Ile Tyr Gln Cys Cys Asp Leu Asp Pro Gln 2660 2665 2670 Ala Arg Val Ala Ile Lys Ser Leu Thr Glu Arg Leu Tyr Val Gly Gly 2675 2680 2685 Pro Leu Thr Asn Ser Arg Gly Glu Asn Cys Gly Tyr Arg Arg Cys Arg 2690 2695 2700 Ala Ser Gly Val Leu Thr Thr Ser Cys Gly Asn Thr Leu Thr Cys Tyr 2705 2710 2715 2720 Ile Lys Ala Arg Ala Ala Cys Arg Ala Ala Gly Leu Gln Asp Cys Thr 2725 2730 2735 Met Leu Val Cys Gly Asp Asp Leu Val Val Ile Cys Glu Ser Ala Gly 2740 2745 2750 Val Gln Glu Asp Ala Ala Ser Leu Arg Ala Phe Thr Glu Ala Met Thr 2755 2760 2765 Arg Tyr Ser Ala Pro Pro Gly Asp Pro Pro Gln Pro Glu Tyr Asp Leu 2770 2775 2780 Glu Leu Ile Thr Ser Cys Ser Ser Asn Val Ser Val Ala His Asp Gly 2785 2790 2795 2800 Ala Gly Lys Arg Val Tyr Tyr Leu Thr Arg Asp Pro Thr Thr Pro Leu 2805 2810 2815 Ala Arg Ala Ala Trp Glu Thr Ala Arg His Thr Pro Val Asn Ser Trp 2820 2825 2830 Leu Gly Asn Ile Ile Met Phe Ala Pro Thr Leu Trp Ala Arg Met Ile 2835 2840 2845 Leu Met Thr His Phe Phe Ser Val Leu Ile Ala Arg Asp Gln Leu Glu 2850 2855 2860 Gln Ala Leu Asn Cys Glu Ile Tyr Gly Ala Cys Tyr Ser Ile Glu Pro 2865 2870 2875 2880 Leu Asp Leu Pro Pro Ile Ile Gln Arg Leu His Gly Leu Ser Ala Phe 2885 2890 2895 Ser Leu His Ser Tyr Ser Pro Gly Glu Ile Asn Arg Val Ala Ala Cys 2900 2905 2910 Leu Arg Lys Leu Gly Val Pro Pro Leu Arg Ala Trp Arg His Arg Ala 2915 2920 2925 Arg Ser Val Arg Ala Arg Leu Leu Ser Arg Gly Gly Arg Ala Ala Ile 2930 2935 2940 Cys Gly Lys Tyr Leu Phe Asn Trp Ala Val Arg Thr Lys Leu Lys Leu 2945 2950 2955 2960 Thr Pro Ile Ala Ala Ala Gly Arg Leu Asp Leu Ser Gly Trp Phe Thr 2965 2970 2975 Ala Gly Tyr Ser Gly Gly Asp Ile Tyr His Ser Val Ser His Ala Arg 2980 2985 2990 Pro Arg Trp Phe Trp Phe Cys Leu Leu Leu Leu Ala Ala Gly Val Gly 2995 3000 3005 Ile Tyr Leu Leu Pro Asn Arg 3010 3015 11 24 DNA Artificial Sequence synthetic oligonucleotide 11 actggacacg gaggtggccg cgtc 24 12 24 DNA Artificial Sequence synthetic oligonucleotide 12 ttgttcttgt cgggttaatg gcgc 24 13 24 DNA Artificial Sequence synthetic oligonucleotide 13 gggtgtacta cacacatgag taag 24 14 22 DNA Artificial Sequence synthetic oligonucleotide 14 aagcgcccct aacttgatga tg 22 15 40 DNA Artificial Sequence synthetic oligonucleotide 15 cgtcatcgat acctcagcgg gcatatgcac tggacacgga 40 16 24 DNA Artificial Sequence synthetic oligonucleotide 16 gtccagtgca tatgcccgct gagg 24 17 32 DNA Artificial Sequence synthetic oligonucleotide 17 catgcaccag ctgatatagc gcttgtaata tg 32 18 30 DNA Artificial Sequence synthetic oligonucleotide 18 tccgtagagg aagcttgcag cctgacgccc 30 19 34 DNA Artificial Sequence synthetic oligonucleotide 19 cagaggaggc agggctgcta tatgtggcaa gtac 34 20 34 DNA Artificial Sequence synthetic oligonucleotide 20 gtacttgcca catatagcag ccctgcctcc tctg 34 21 43 DNA Artificial Sequence synthetic oligonucleotide 21 cgtctctaga caggaaatgg cttaagaggc cggagtgttt acc 43 22 65 DNA Artificial Sequence synthetic oligonucleotide 22 ttatggatgc tcatcttgtt gggccaggcc gaagcagctt tggagaacct cgtaatactc 60 aatgc 65 23 32 DNA Artificial Sequence synthetic oligonucleotide 23 aggatttgtg ctcatggtgc acggtctacg ag 32 24 50 DNA Artificial Sequence synthetic oligonucleotide 24 ttttttttgc ggccgctaat acgactcact atagacccgc ccctaatagg 50 25 31 DNA Artificial Sequence synthetic oligonucleotide 25 ccgtgcacca tgagcacaaa tcctaaacct c 31 26 26 DNA Artificial Sequence synthetic oligonucleotide 26 ggatgtaccc catgaggtcg gcaaag 26 27 30 DNA Artificial Sequence synthetic oligonucleotide 27 gtttgcgcct gcttatggat gctcatcttg 30 28 26 DNA Artificial Sequence synthetic oligonucleotide 28 gcgtcataag catatgcctg ttgggg 26 29 23 DNA Artificial Sequence synthetic oligonucleotide 29 ccctcagcac tggagtacat ctg 23 30 39 DNA Artificial Sequence synthetic oligonucleotide 30 cgtcatgcat acccctaggg cggctctcat tgaagaggg 39 31 30 DNA Artificial Sequence synthetic oligonucleotide 31 cgtcccctct tcaatgagag ccgctctaga 30 32 28 DNA Artificial Sequence synthetic oligonucleotide 32 gcggtgaaga ccaagctcaa actcactc 28 33 41 DNA Artificial Sequence synthetic oligonucleotide 33 aatctagaag gcgcgcttcc ggcaatggag tgagtttgag c 41 34 38 DNA Artificial Sequence synthetic oligonucleotide 34 cgtctctaga ggataaatcc aggaggcgcg cttccggc 38 35 27 DNA Artificial Sequence synthetic oligonucleotide 35 tactttttgt aggggtaggc cttttcc 27 36 34 DNA Artificial Sequence synthetic oligonucleotide 36 cgtctctaga gtgtagctaa tgtgtgccgc tcta 34 37 24 DNA Artificial Sequence synthetic oligonucleotide 37 ctatggagtg tagctaatgt gtgc 24 38 107 DNA Artificial Sequence synthetic oligonucleotide 38 cgtctctaga catgatctgc agagagacca gttacggcac tctctgcagt catgcggctc 60 acggaccttt cacagctagc cgtgactagg gctaagatgg agccacc 107 39 45 PRT Hepatitis C virus 39 Leu Leu Leu Ala Ala Gly Val Asp Ala Arg Thr His Thr Val Gly Gly 1 5 10 15 Ser Ala Ala Gln Thr Thr Gly Arg Leu Thr Ser Leu Phe Asp Met Gly 20 25 30 Pro Arg Gln Lys Ile Gln Leu Val Asn Thr Asn Gly Ser 35 40 45 40 45 PRT Hepatitis c virus 40 Leu Leu Leu Ala Ala Gly Val Asp Ala Arg Thr His Thr Val Gly Gly 1 5 10 15 Ser Ala Ala Gln Thr Thr Gly Arg Leu Thr Ser Leu Phe Asp Met Gly 20 25 30 Pro Arg Gln Lys Ile Gln Leu Val Asn Thr Asn Gly Ser 35 40 45 41 45 PRT Hepatitis C virus 41 Leu Leu Leu Ala Ala Gly Val Asp Ala Arg Thr His Thr Val Gly Gly 1 5 10 15 Ser Ala Ala Gln Thr Thr Gly Arg Leu Thr Ser Leu Phe Asp Met Gly 20 25 30 Pro Arg Gln Lys Ile Gln Leu Val Asn Thr Asn Gly Ser 35 40 45 42 45 PRT Hepatitis C virus 42 Leu Leu Leu Ala Ala Gly Val Asp Ala Arg Thr His Thr Val Gly Gly 1 5 10 15 Ser Ala Ala Gln Thr Thr Gly Arg Leu Thr Ser Leu Phe Asp Met Gly 20 25 30 Pro Arg Gln Lys Ile Gln Leu Val Asn Thr Asn Gly Ser 35 40 45 43 45 PRT Hepatitis C virus 43 Leu Leu Leu Ala Ala Gly Val Asp Ala Arg Thr His Thr Val Gly Gly 1 5 10 15 Ser Ala Ala Gln Thr Thr Gly Arg Leu Thr Ser Leu Phe Asp Met Gly 20 25 30 Pro Arg Gln Lys Ile Gln Leu Val Asn Thr Asn Gly Ser 35 40 45 44 45 PRT Hepatitis C virus 44 Leu Leu Leu Ala Ala Gly Val Asp Ala Arg Thr His Thr Val Gly Gly 1 5 10 15 Ser Ala Ala Gln Thr Thr Gly Arg Leu Thr Ser Leu Phe Asp Met Gly 20 25 30 Pro Arg Gln Lys Ile Gln Leu Val Asn Thr Asn Gly Ser 35 40 45 45 45 PRT Hepatitis C virus 45 Leu Leu Leu Ala Ala Gly Val Asp Ala Arg Thr His Thr Val Gly Gly 1 5 10 15 Ser Ala Ala Gln Thr Thr Gly Arg Leu Thr Ser Leu Phe Asp Met Gly 20 25 30 Pro Arg Gln Lys Ile Gln Leu Val Asn Thr Asn Gly Ser 35 40 45 46 45 PRT Hepatitis C virus 46 Leu Leu Leu Ala Ala Gly Val Asp Ala Gln Thr His Thr Val Gly Gly 1 5 10 15 Ser Ala Ala Gln Thr Thr Gly Arg Leu Thr Ser Leu Phe Asp Met Gly 20 25 30 Pro Arg Gln Lys Ile Gln Leu Ile Asn Thr Asn Gly Ser 35 40 45 47 45 PRT Artificial Sequence consensus sequence 47 Leu Leu Leu Ala Ala Gly Val Asp Ala Arg Thr His Thr Val Gly Gly 1 5 10 15 Ser Ala Ala Gln Thr Thr Gly Arg Leu Thr Ser Leu Phe Asp Met Gly 20 25 30 Pro Arg Gln Lys Ile Gln Leu Val Asn Thr Asn Gly Ser 35 40 45 48 45 PRT Hepatitis C virus 48 Leu Leu Leu Ala Ala Gly Val Asp Ala Gln Thr His Thr Val Gly Gly 1 5 10 15 Ser Thr Ala His Asn Ala Arg Thr Leu Thr Gly Met Phe Ser Leu Gly 20 25 30 Ala Arg Gln Lys Ile Gln Leu Ile Asn Thr Asn Gly Ser 35 40 45 49 360 DNA Hepatitis C virus 49 gccagccccc tgatgggggc gacactccac catgaatcac tcccctgtga ggaactactg 60 tcttcacgca gaaagcgtct agccatggcg ttagtatgag tgtcgtgcag cctccaggac 120 cccccctccc gggagagcca tagtggtctg cggaaccggt gagtacaccg gaattgccag 180 gacgaccggg tcctttcttg gataaacccg ctcaatgcct ggagatttgg gcgtgccccc 240 gcaagactgc tagccgagta gtgttgggtc gcgaaaggcc ttgtggtact gcctgatagg 300 gtgcttgcga gtgccccggg aggtctcgta gaccgtgcac catgagcacg aatcctaaac 360 50 360 DNA Hepatitis C virus 50 gccagccccc tgatgggggc gacactccac catgaatcac tcccctgtga ggaactactg 60 tcttcacgca gaaagcgtct agccatggcg ttagtatgag tgtcgtgcag cctccaggac 120 cccccctccc gggagagcca tagtggtctg cggaaccggt gagtacaccg gaattgccgg 180 gaagactggg tcctttcttg gataaacccg ctctatgccc ggccatttgg gcgtgccccc 240 gcaagactgc tagccgagta gcgttgggtt gcgaaaggcc ttgtggtact gcctgatagg 300 gtgcttgcga gtgccccggg aggtctcgta gaccgtgcac catgagcaca aatcctaaac 360 51 360 DNA Hepatitis C virus 51 gccagccccc tgatgggggc gacactccac catgaatcac tcccctgtga ggaactactg 60 tcttcacgca gaaagcgtct agccatggcg ttagtatgag tgtcgtgcag cctccaggac 120 cccccctccc gggagagcca tagtggtctg cggaaccggt gagtacaccg gaattgccgg 180 gaagactggg tcctttcttg gataaacccg ctctatgccc ggccatttgg gcgtgccccc 240 gcaagactgc tagccgagta gcgttgggtt gcgaaaggcc ttgtggtact gcctgatagg 300 gtgcttgcga gtgccccggg aggtctcgta gaccgtgcac catgagcaca aatcctaaac 360 52 360 DNA Hepatitis C virus 52 gccagccccc tgatgggggc gacactccac catgaatcac tcccctgtga ggaactactg 60 tcttcacgca gaaagcgtct agccatggcg ttagtatgag tgtcgtgcag cctccaggac 120 cccccctccc gggagagcca tagtggtctg cggaaccggt gagtacaccg gaattgccag 180 gacgaccggg tcctttcttg gataaacccg ctcaatgcct ggagatttgg gcgtgccccc 240 gcaagactgc tagccgagta gtgttgggtc gcgaaaggcc ttgtggtact gcctgatagg 300 gtgcttgcga gtgccccggg aggtctcgta gaccgtgcac catgagcaca aatcctaaac 360 53 360 DNA Hepatitis C virus 53 gccagccccc

tgatgggggc gacactccac catgaatcac tcccctgtga ggaactactg 60 tcttcacgca gaaagcgtct agccatggcg ttagtatgag tgtcgtgcag cctccaggac 120 cccccctccc gggagagcca tagtggtctg cggaaccggt gagtacaccg gaattgccag 180 gacgaccggg tcctttcttg gataaacccg ctcaatgcct ggagatttgg gcgtgccccc 240 gcaagactgc tagccgagta gtgttgggtc gcgaaaggcc ttgtggtact gcctgatagg 300 gtgcttgcga gtgccccggg aggtctcgta gaccgtgcac catgagcaca aatcctaaac 360 54 359 DNA Hepatitis C virus 54 acccgcccct aataggggcg acactccgcc atgaatcact cccctgtgag gaactactgt 60 cttcacgcag aaagcgtcta gccatggcgt tagtatgagt gtcgtacagc ctccaggccc 120 ccccctcccg ggagagccat agtggtctgc ggaaccggtg agtacaccgg aattgccggg 180 aagactgggt cctttcttgg ataaacccgc tctatgcccg gccatttggg cgtgcccccg 240 caagactgct agccgagtag cgttgggttg cgaaaggcct tgtggtactg cctgataggt 300 tgcttgcgag tgccccggga ggtctcgtag accgtgcacc atgagcacaa atcctaaac 359 55 225 DNA Hepatitis C virus 55 tgaaggttgg ggtaaacact ccggcctctt aagccatttc ctgyyyyyyy yyyyyyyyyy 60 yyyyyyyyyy yyyyyyyyyy yyyyyyyyyy yyyyyyyyyy yyyyyyyyyy yyyyyyyyyy 120 yyyyaatggt ggctccatct tagccctagt cacggctagc tgtgaaaggt ccgtgagccg 180 catgactgca gagagtgctg atactggcct ctctgcagat catgt 225 56 225 DNA Hepatitis C virus 56 tgaaggttgg ggtaaacact ccggcctctt aagccatttc ctgyyyyyyy yyyyyyyyyy 60 yyyyyyyyyy yyyyyyyyyy yyyyyyyyyy yyyyyyyyyy yyyyyyyyyy yyyyyyyyyy 120 yyyyaatggt ggctccatct tagccctagt cacggctagc tgtgaaaggt ccgtgagccg 180 catgactgca gagagtgctg atactggcct ctctgcagat catgt 225 57 225 DNA Hepatitis C virus 57 tgaaggttgg ggtaaacact ccggcctctt aagccatttc ctgyyyyyyy yyyyyyyyyy 60 yyyyyyyyyy yyyyyyyyyy yyyyyyyyyy yyyyyyyyyy yyyyyyyyyy yyyyyyyyyy 120 yyyyaatggt ggctccatct tagccctagt cacggctagc tgtgaaaggt ccgtgagccg 180 catgactgca gagagtgctg atactggcct ctctgcagat catgt 225 58 225 DNA Hepatitis C virus 58 tgaaggttgg ggtaaacact ccggcctctt aagccatttc ctgyyyyyyy yyyyyyyyyy 60 yyyyyyyyyy yyyyyyyyyy yyyyyyyyyy yyyyyyyyyy yyyyyyyyyy yyyyyyyyyy 120 yyyyaatggt ggctccatct tagccctagt cacggctagc tgtgaaaggt ccgtgagccg 180 catgactgca gagagtgctg atactggcct ctctgcagat catgt 225 59 225 DNA Hepatitis C virus 59 tgaaggttgg ggtaaacact ccggcctctt aagccatttc ctgyyyyyyy yyyyyyyyyy 60 yyyyyyyyyy yyyyyyyyyy yyyyyyyyyy yyyyyyyyyy yyyyyyyyyy yyyyyyyyyy 120 yyyyaatggt ggctccatct tagccctagt cacggctagc tgtgaaaggt ccgtgagccg 180 catgactgca gagagtgctg atactggcct ctctgcagat catgt 225 60 272 DNA hepatitis C virus 60 tagagcggca cacattagct acactccata gctaactgtc ccyyyyyyyy yyyyyyyyyy 60 yyyyyyyyyy yyyyyyyyyy yyyyyyyyyy yyyyyyyyyy yyyyyyyyyy yyyyyyyyyy 120 yyyyyyyyyy yyyyyyyyyy yyyyyyyyyy yyyyyyyyyy yyyyyyyyyy yyyyggtggc 180 tccatcttag ccctagtcac ggctagctgt gaaaggtccg tgagccgcat gactgcagag 240 agtgccgtaa ctggtctctc tgcagatcat gt 272 61 96 PRT Hepatitis C virus 61 Arg Val Cys Ser Cys Leu Trp Met Met Leu Leu Ile Ser Gln Ala Glu 1 5 10 15 Ala Ala Leu Glu Asn Leu Val Ile Leu Asn Ala Ala Ser Leu Ala Gly 20 25 30 Thr His Gly Leu Val Ser Phe Leu Val Phe Phe Cys Phe Ala Trp Tyr 35 40 45 Leu Lys Gly Arg Trp Val Pro Gly Ala Val Tyr Ala Leu Tyr Gly Met 50 55 60 Trp Pro Leu Leu Leu Leu Leu Leu Ala Leu Pro Gln Arg Ala Tyr Ala 65 70 75 80 Leu Asp Thr Glu Val Ala Ala Ser Cys Gly Gly Val Val Leu Val Gly 85 90 95 62 96 PRT Hepatitis C virus 62 Arg Val Cys Ala Cys Leu Trp Met Leu Ile Leu Leu Gly Gln Ala Glu 1 5 10 15 Ala Ala Leu Glu Lys Leu Val Ile Leu His Ala Ala Ser Ala Ala Ser 20 25 30 Cys Asn Gly Phe Leu Tyr Phe Val Ile Phe Phe Val Ala Ala Trp Tyr 35 40 45 Ile Lys Gly Arg Val Val Pro Leu Ala Thr Tyr Ser Leu Thr Gly Leu 50 55 60 Trp Ser Phe Ser Leu Leu Leu Leu Ala Leu Pro Gln Gln Ala Tyr Ala 65 70 75 80 Leu Asp Thr Glu Val Ala Ala Ser Cys Gly Gly Val Val Leu Val Gly 85 90 95 63 96 PRT Hepatitis C virus 63 Arg Val Cys Ala Cys Leu Trp Met Leu Ile Leu Leu Gly Gln Ala Glu 1 5 10 15 Ala Ala Leu Glu Asn Leu Val Ile Leu Asn Ala Ala Ser Leu Ala Gly 20 25 30 Thr His Gly Leu Val Ser Phe Leu Val Phe Phe Cys Phe Ala Trp Tyr 35 40 45 Leu Lys Gly Arg Trp Val Pro Gly Ala Val Tyr Ala Leu Tyr Gly Met 50 55 60 Trp Pro Leu Leu Leu Leu Leu Leu Ala Leu Pro Gln Arg Ala Tyr Ala 65 70 75 80 Leu Asp Thr Glu Val Ala Ala Ser Cys Gly Gly Val Val Leu Val Gly 85 90 95 64 96 PRT Hepatitis C virus 64 Arg Val Cys Ala Cys Leu Trp Met Leu Ile Leu Leu Gly Gln Ala Glu 1 5 10 15 Ala Ala Leu Glu Lys Leu Val Ile Leu His Ala Ala Ser Ala Ala Ser 20 25 30 Cys Asn Gly Phe Leu Tyr Phe Val Ile Phe Phe Val Ala Ala Trp Tyr 35 40 45 Ile Lys Gly Arg Val Val Pro Leu Ala Thr Tyr Ser Leu Thr Gly Leu 50 55 60 Trp Ser Phe Ser Leu Leu Leu Leu Ala Leu Pro Gln Gln Ala Tyr Ala 65 70 75 80 Leu Asp Thr Glu Val Ala Ala Ser Cys Gly Gly Val Val Leu Val Gly 85 90 95 65 96 PRT Hepatitis C virus 65 Arg Val Cys Ala Cys Leu Trp Met Leu Ile Leu Leu Gly Gln Ala Glu 1 5 10 15 Ala Ala Leu Glu Asn Leu Val Ile Leu Asn Ala Ala Ser Leu Ala Gly 20 25 30 Thr His Gly Leu Val Ser Phe Leu Val Phe Phe Cys Phe Ala Trp Tyr 35 40 45 Leu Lys Gly Arg Trp Val Pro Gly Ala Val Tyr Ala Leu Tyr Gly Met 50 55 60 Trp Pro Leu Leu Leu Leu Leu Leu Ala Leu Pro Gln Arg Ala Tyr Ala 65 70 75 80 Leu Asp Thr Glu Val Ala Ala Ser Cys Gly Gly Val Val Leu Val Gly 85 90 95 66 96 PRT Hepatitis C virus 66 Arg Val Cys Ala Cys Leu Trp Met Leu Ile Leu Leu Gly Gln Ala Glu 1 5 10 15 Ala Ala Leu Glu Lys Leu Val Ile Leu His Ala Ala Ser Ala Ala Ser 20 25 30 Cys Asn Gly Phe Leu Tyr Phe Val Ile Phe Phe Val Ala Ala Trp Tyr 35 40 45 Ile Lys Gly Arg Val Val Pro Leu Ala Thr Tyr Ser Leu Thr Gly Leu 50 55 60 Trp Ser Phe Ser Leu Leu Leu Leu Ala Leu Pro Gln Gln Ala Tyr Ala 65 70 75 80 Tyr Asp Ala Ser Val His Gly Gln Ile Gly Ala Ala Leu Leu Val Met 85 90 95 67 9599 DNA Hepatitis C virus 67 gccagccccc tgatgggggc gacactccac catgaatcac tcccctgtga ggaactactg 60 tcttcacgca gaaagcgtct agccatggcg ttagtatgag tgtcgtgcag cctccaggac 120 cccccctccc gggagagcca tagtggtctg cggaaccggt gagtacaccg gaattgccag 180 gacgaccggg tcctttcttg gataaacccg ctcaatgcct ggagatttgg gcgtgccccc 240 gcaagactgc tagccgagta gtgttgggtc gcgaaaggcc ttgtggtact gcctgatagg 300 gtgcttgcga gtgccccggg aggtctcgta gaccgtgcac catgagcacg aatcctaaac 360 ctcaaagaaa aaccaaacgt aacaccaacc gtcgcccaca ggacgtcaag ttcccgggtg 420 gcggtcagat cgttggtgga gtttacttgt tgccgcgcag gggccctaga ttgggtgtgc 480 gcgcgacgag gaagacttcc gagcggtcgc aacctcgagg tagacgtcag cctatcccca 540 aggcacgtcg gcccgagggc aggacctggg ctcagcccgg gtacccttgg cccctctatg 600 gcaatgaggg ttgcgggtgg gcgggatggc tcctgtctcc ccgtggctct cggcctagct 660 ggggccccac agacccccgg cgtaggtcgc gcaatttggg taaggtcatc gataccctta 720 cgtgcggctt cgccgacctc atggggtaca taccgctcgt cggcgcccct cttggaggcg 780 ctgccagggc cctggcgcat ggcgtccggg ttctggaaga cggcgtgaac tatgcaacag 840 ggaaccttcc tggttgctct ttctctatct tccttctggc cctgctctct tgcctgactg 900 tgcccgcttc agcctaccaa gtgcgcaatt cctcggggct ttaccatgtc accaatgatt 960 gccctaactc gagtattgtg tacgaggcgg ccgatgccat cctgcacact ccggggtgtg 1020 tcccttgcgt tcgcgagggt aacgcctcga ggtgttgggt ggcggtgacc cccacggtgg 1080 ccaccaggga cggcaaactc cccacaacgc agcttcgacg tcatatcgat ctgcttgtcg 1140 ggagcgccac cctctgctcg gccctctacg tgggggacct gtgcgggtct gtctttcttg 1200 ttggtcaact gtttaccttc tctcccaggc gccactggac gacgcaagac tgcaattgtt 1260 ctatctatcc cggccatata acgggtcatc gcatggcatg ggatatgatg atgaactggt 1320 cccctacggc agcgttggtg gtagctcagc tgctccggat cccacaagcc atcatggaca 1380 tgatcgctgg tgctcactgg ggagtcctgg cgggcatagc gtatttctcc atggtgggga 1440 actgggcgaa ggtcctggta gtgctgctgc tatttgccgg cgtcgacgcg gaaacccacg 1500 tcaccggggg aaatgccggc cgcaccacgg ctgggcttgt tggtctcctt acaccaggcg 1560 ccaagcagaa catccaactg atcaacacca acggcagttg gcacatcaat agcacggcct 1620 tgaattgcaa tgaaagcctt aacaccggct ggttagcagg gctcttctat caacacaaat 1680 tcaactcttc aggctgtcct gagaggttgg ccagctgccg acgccttacc gattttgccc 1740 agggctgggg tcctatcagt tatgccaacg gaagcggcct cgacgaacgc ccctactgct 1800 ggcactaccc tccaagacct tgtggcattg tgcccgcaaa gagcgtgtgt ggcccggtat 1860 attgcttcac tcccagcccc gtggtggtgg gaacgaccga caggtcgggc gcgcctacct 1920 acagctgggg tgcaaatgat acggatgtct tcgtccttaa caacaccagg ccaccgctgg 1980 gcaattggtt cggttgtacc tggatgaact caactggatt caccaaagtg tgcggagcgc 2040 ccccttgtgt catcggaggg gtgggcaaca acaccttgct ctgccccact gattgcttcc 2100 gcaaacatcc ggaagccaca tactctcggt gcggctccgg tccctggatt acacccaggt 2160 gcatggtcga ctacccgtat aggctttggc actatccttg taccatcaat tacaccatat 2220 tcaaagtcag gatgtacgtg ggaggggtcg agcacaggct ggaagcggcc tgcaactgga 2280 cgcggggcga acgctgtgat ctggaagaca gggacaggtc cgagctcagc ccgttgctgc 2340 tgtccaccac acagtggcag gtccttccgt gttctttcac gaccctgcca gccttgtcca 2400 ccggcctcat ccacctccac cagaacattg tggacgtgca gtacttgtac ggggtagggt 2460 caagcatcgc gtcctgggcc attaagtggg agtacgtcgt tctcctgttc cttctgcttg 2520 cagacgcgcg cgtctgctcc tgcttgtgga tgatgttact catatcccaa gcggaggcgg 2580 ctttggagaa cctcgtaata ctcaatgcag catccctggc cgggacgcac ggtcttgtgt 2640 ccttcctcgt gttcttctgc tttgcgtggt atctgaaggg taggtgggtg cccggagcgg 2700 tctacgccct ctacgggatg tggcctctcc tcctgctcct gctggcgttg cctcagcggg 2760 catacgcact ggacacggag gtggccgcgt cgtgtggcgg cgttgttctt gtcgggttaa 2820 tggcgctgac tctgtcgcca tattacaagc gctatatcag ctggtgcatg tggtggcttc 2880 agtattttct gaccagagta gaagcgcaac tgcacgtgtg ggttcccccc ctcaacgtcc 2940 ggggggggcg cgatgccgtc atcttactca tgtgtgtagt acacccgacc ctggtatttg 3000 acatcaccaa actactcctg gccatcttcg gacccctttg gattcttcaa gccagtttgc 3060 ttaaagtccc ctacttcgtg cgcgttcaag gccttctccg gatctgcgcg ctagcgcgga 3120 agatagccgg aggtcattac gtgcaaatgg ccatcatcaa gttaggggcg cttactggca 3180 cctatgtgta taaccatctc acccctcttc gagactgggc gcacaacggc ctgcgagatc 3240 tggccgtggc tgtggaacca gtcgtcttct cccgaatgga gaccaagctc atcacgtggg 3300 gggcagatac cgccgcgtgc ggtgacatca tcaacggctt gcccgtctct gcccgtaggg 3360 gccaggagat actgcttggg ccagccgacg gaatggtctc caaggggtgg aggttgctgg 3420 cgcccatcac ggcgtacgcc cagcagacga gaggcctcct agggtgtata atcaccagcc 3480 tgactggccg ggacaaaaac caagtggagg gtgaggtcca gatcgtgtca actgctaccc 3540 aaaccttcct ggcaacgtgc atcaatgggg tatgctggac tgtctaccac ggggccggaa 3600 cgaggaccat cgcatcaccc aagggtcctg tcatccagat gtataccaat gtggaccaag 3660 accttgtggg ctggcccgct cctcaaggtt cccgctcatt gacaccctgt acctgcggct 3720 cctcggacct ttacctggtc acgaggcacg ccgatgtcat tcccgtgcgc cggcgaggtg 3780 atagcagggg tagcctgctt tcgccccggc ccatttccta cttgaaaggc tcctcggggg 3840 gtccgctgtt gtgccccgcg ggacacgccg tgggcctatt cagggccgcg gtgtgcaccc 3900 gtggagtggc taaagcggtg gactttatcc ctgtggagaa cctagggaca accatgagat 3960 ccccggtgtt cacggacaac tcctctccac cagcagtgcc ccagagcttc caggtggccc 4020 acctgcatgc tcccaccggc agcggtaaga gcaccaaggt cccggctgcg tacgcagccc 4080 agggctacaa ggtgttggtg ctcaacccct ctgttgctgc aacgctgggc tttggtgctt 4140 acatgtccaa ggcccatggg gttgatccta atatcaggac cggggtgaga acaattacca 4200 ctggcagccc catcacgtac tccacctacg gcaagttcct tgccgacggc gggtgctcag 4260 gaggtgctta tgacataata atttgtgacg agtgccactc cacggatgcc acatccatct 4320 tgggcatcgg cactgtcctt gaccaagcag agactgcggg ggcgagactg gttgtgctcg 4380 ccactgctac ccctccgggc tccgtcactg tgtcccatcc taacatcgag gaggttgctc 4440 tgtccaccac cggagagatc cccttttacg gcaaggctat ccccctcgag gtgatcaagg 4500 ggggaagaca tctcatcttc tgccactcaa agaagaagtg cgacgagctc gccgcgaagc 4560 tggtcgcatt gggcatcaat gccgtggcct actaccgcgg tcttgacgtg tctgtcatcc 4620 cgaccagcgg cgatgttgtc gtcgtgtcga ccgatgctct catgactggc tttaccggcg 4680 acttcgactc tgtgatagac tgcaacacgt gtgtcactca gacagtcgat ttcagccttg 4740 accctacctt taccattgag acaaccacgc tcccccagga tgctgtctcc aggactcaac 4800 gccggggcag gactggcagg gggaagccag gcatctatag atttgtggca ccgggggagc 4860 gcccctccgg catgttcgac tcgtccgtcc tctgtgagtg ctatgacgcg ggctgtgctt 4920 ggtatgagct cacgcccgcc gagactacag ttaggctacg agcgtacatg aacaccccgg 4980 ggcttcccgt gtgccaggac catcttgaat tttgggaggg cgtctttacg ggcctcactc 5040 atatagatgc ccacttttta tcccagacaa agcagagtgg ggagaacttt ccttacctgg 5100 tagcgtacca agccaccgtg tgcgctaggg ctcaagcccc tcccccatcg tgggaccaga 5160 tgtggaagtg tttgatccgc cttaaaccca ccctccatgg gccaacaccc ctgctataca 5220 gactgggcgc tgttcagaat gaagtcaccc tgacgcaccc aatcaccaaa tacatcatga 5280 catgcatgtc ggccgacctg gaggtcgtca cgagcacctg ggtgctcgtt ggcggcgtcc 5340 tggctgctct ggccgcgtat tgcctgtcaa caggctgcgt ggtcatagtg ggcaggatcg 5400 tcttgtccgg gaagccggca attatacctg acagggaggt tctctaccag gagttcgatg 5460 agatggaaga gtgctctcag cacttaccgt acatcgagca agggatgatg ctcgctgagc 5520 agttcaagca gaaggccctc ggcctcctgc agaccgcgtc ccgccatgca gaggttatca 5580 cccctgctgt ccagaccaac tggcagaaac tcgaggtctt ttgggcgaag cacatgtgga 5640 atttcatcag tgggatacaa tacttggcgg gcctgtcaac gctgcctggt aaccccgcca 5700 ttgcttcatt gatggctttt acagctgccg tcaccagccc actaaccact ggccaaaccc 5760 tcctcttcaa catattgggg gggtgggtgg ctgcccagct cgccgccccc ggtgccgcta 5820 ctgcctttgt gggtgctggc ctagctggcg ccgccatcgg cagcgttgga ctggggaagg 5880 tcctcgtgga cattcttgca gggtatggcg cgggcgtggc gggagctctt gtagcattca 5940 agatcatgag cggtgaggtc ccctccacgg aggacctggt caatctgctg cccgccatcc 6000 tctcgcctgg agcccttgta gtcggtgtgg tctgcgcagc aatactgcgc cggcacgttg 6060 gcccgggcga gggggcagtg caatggatga accggctaat agccttcgcc tcccggggga 6120 accatgtttc ccccacgcac tacgtgccgg agagcgatgc agccgcccgc gtcactgcca 6180 tactcagcag cctcactgta acccagctcc tgaggcgact gcatcagtgg ataagctcgg 6240 agtgtaccac tccatgctcc ggttcctggc taagggacat ctgggactgg atatgcgagg 6300 tgctgagcga ctttaagacc tggctgaaag ccaagctcat gccacaactg cctgggattc 6360 cctttgtgtc ctgccagcgc gggtataggg gggtctggcg aggagacggc attatgcaca 6420 ctcgctgcca ctgtggagct gagatcactg gacatgtcaa aaacgggacg atgaggatcg 6480 tcggtcctag gacctgcagg aacatgtgga gtgggacgtt ccccattaac gcctacacca 6540 cgggcccctg tactcccctt cctgcgccga actataagtt cgcgctgtgg agggtgtctg 6600 cagaggaata cgtggagata aggcgggtgg gggacttcca ctacgtatcg ggtatgacta 6660 ctgacaatct taaatgcccg tgccagatcc catcgcccga atttttcaca gaattggacg 6720 gggtgcgcct acacaggttt gcgccccctt gcaagccctt gctgcgggag gaggtatcat 6780 tcagagtagg actccacgag tacccggtgg ggtcgcaatt accttgcgag cccgaaccgg 6840 acgtagccgt gttgacgtcc atgctcactg atccctccca tataacagca gaggcggccg 6900 ggagaaggtt ggcgagaggg tcaccccctt ctatggccag ctcctcggct agccagctgt 6960 ccgctccatc tctcaaggca acttgcaccg ccaaccatga ctcccctgac gccgagctca 7020 tagaggctaa cctcctgtgg aggcaggaga tgggcggcaa catcaccagg gttgagtcag 7080 agaacaaagt ggtgattctg gactccttcg atccgcttgt ggcagaggag gatgagcggg 7140 aggtctccgt acctgcagaa attctgcgga agtctcggag attcgcccgg gccctgcccg 7200 tctgggcgcg gccggactac aaccccccgc tagtagagac gtggaaaaag cctgactacg 7260 aaccacctgt ggtccatggc tgcccgctac cacctccacg gtcccctcct gtgcctccgc 7320 ctcggaaaaa gcgtacggtg gtcctcaccg aatcaaccct atctactgcc ttggccgagc 7380 ttgccaccaa aagttttggc agctcctcaa cttccggcat tacgggcgac aatacgacaa 7440 catcctctga gcccgcccct tctggctgcc cccccgactc cgacgttgag tcctattctt 7500 ccatgccccc cctggagggg gagcctgggg atccggatct cagcgacggg tcatggtcga 7560 cggtcagtag tggggccgac acggaagatg tcgtgtgctg ctcaatgtct tattcctgga 7620 caggcgcact cgtcaccccg tgcgctgcgg aagaacaaaa actgcccatc aacgcactga 7680 gcaactcgtt gctacgccat cacaatctgg tgtattccac cacttcacgc agtgcttgcc 7740 aaaggcagaa gaaagtcaca tttgacagac tgcaagttct ggacagccat taccaggacg 7800 tgctcaagga ggtcaaagca gcggcgtcaa aagtgaaggc taacttgcta tccgtagagg 7860 aagcttgcag cctgacgccc ccacattcag ccaaatccaa gtttggctat ggggcaaaag 7920 acgtccgttg ccatgccaga aaggccgtag cccacatcaa ctccgtgtgg aaagaccttc 7980 tggaagacag tgtaacacca atagacacta ccatcatggc caagaacgag gttttctgcg 8040 ttcagcctga gaaggggggt cgtaagccag ctcgtctcat cgtgttcccc gacctgggcg 8100 tgcgcgtgtg cgagaagatg gccctgtacg acgtggttag caagctcccc ctggccgtga 8160 tgggaagctc ctacggattc caatactcac caggacagcg ggttgaattc ctcgtgcaag 8220 cgtggaagtc caagaagacc ccgatggggt tctcgtatga tacccgctgt tttgactcca 8280 cagtcactga gagcgacatc cgtacggagg aggcaattta ccaatgttgt gacctggacc 8340 cccaagcccg cgtggccatc aagtccctca ctgagaggct ttatgttggg ggccctctta 8400 ccaattcaag gggggaaaac tgcggctacc gcaggtgccg cgcgagcggc gtactgacaa 8460 ctagctgtgg taacaccctc acttgctaca tcaaggcccg ggcagcctgt cgagccgcag 8520 ggctccagga ctgcaccatg ctcgtgtgtg gcgacgactt agtcgttatc tgtgaaagtg 8580 cgggggtcca ggaggacgcg gcgagcctga gagccttcac ggaggctatg accaggtact 8640 ccgccccccc cggggacccc ccacaaccag aatacgactt ggagcttata acatcatgct 8700 cctccaacgt gtcagtcgcc cacgacggcg ctggaaagag ggtctactac cttacccgtg 8760 accctacaac ccccctcgcg agagccgcgt gggagacagc aagacacact ccagtcaatt 8820 cctggctagg caacataatc atgtttgccc ccacactgtg ggcgaggatg atactgatga 8880 cccatttctt tagcgtcctc atagccaggg atcagcttga

acaggctctt aactgtgaga 8940 tctacggagc ctgctactcc atagaaccac tggatctacc tccaatcatt caaagactcc 9000 atggcctcag cgcattttca ctccacagtt actctccagg tgaaatcaat agggtggccg 9060 catgcctcag aaaacttggg gtcccgccct tgcgagcttg gagacaccgg gcccggagcg 9120 tccgcgctag gcttctgtcc agaggaggca gggctgccat atgtggcaag tacctcttca 9180 actgggcagt aagaacaaag ctcaaactca ctccaatagc ggccgctggc cggctggact 9240 tgtccggttg gttcacggct ggctacagcg ggggagacat ttatcacagc gtgtctcatg 9300 cccggccccg ctggttctgg ttttgcctac tcctgctcgc tgcaggggta ggcatctacc 9360 tcctccccaa ccgatgaagg ttggggtaaa cactccggcc tcttaagcca tttcctgttt 9420 tttttttttt tttttttttt tttttctttt tttttttctt tcctttcctt ctttttttcc 9480 tttctttttc ccttctttaa tggtggctcc atcttagccc tagtcacggc tagctgtgaa 9540 aggtccgtga gccgcatgac tgcagagagt gctgatactg gcctctctgc agatcatgt 9599 68 3011 PRT Hepatitis C Virus 68 Met Ser Thr Asn Pro Lys Pro Gln Arg Lys Thr Lys Arg Asn Thr Asn 1 5 10 15 Arg Arg Pro Gln Asp Val Lys Phe Pro Gly Gly Gly Gln Ile Val Gly 20 25 30 Gly Val Tyr Leu Leu Pro Arg Arg Gly Pro Arg Leu Gly Val Arg Ala 35 40 45 Thr Arg Lys Thr Ser Glu Arg Ser Gln Pro Arg Gly Arg Arg Gln Pro 50 55 60 Ile Pro Lys Ala Arg Arg Pro Glu Gly Arg Thr Trp Ala Gln Pro Gly 65 70 75 80 Tyr Pro Trp Pro Leu Tyr Gly Asn Glu Gly Cys Gly Trp Ala Gly Trp 85 90 95 Leu Leu Ser Pro Arg Gly Ser Arg Pro Ser Trp Gly Pro Thr Asp Pro 100 105 110 Arg Arg Arg Ser Arg Asn Leu Gly Lys Val Ile Asp Thr Leu Thr Cys 115 120 125 Gly Phe Ala Asp Leu Met Gly Tyr Ile Pro Leu Val Gly Ala Pro Leu 130 135 140 Gly Gly Ala Ala Arg Ala Leu Ala His Gly Val Arg Val Leu Glu Asp 145 150 155 160 Gly Val Asn Tyr Ala Thr Gly Asn Leu Pro Gly Cys Ser Phe Ser Ile 165 170 175 Phe Leu Leu Ala Leu Leu Ser Cys Leu Thr Val Pro Ala Ser Ala Tyr 180 185 190 Gln Val Arg Asn Ser Ser Gly Leu Tyr His Val Thr Asn Asp Cys Pro 195 200 205 Asn Ser Ser Ile Val Tyr Glu Ala Ala Asp Ala Ile Leu His Thr Pro 210 215 220 Gly Cys Val Pro Cys Val Arg Glu Gly Asn Ala Ser Arg Cys Trp Val 225 230 235 240 Ala Val Thr Pro Thr Val Ala Thr Arg Asp Gly Lys Leu Pro Thr Thr 245 250 255 Gln Leu Arg Arg His Ile Asp Leu Leu Val Gly Ser Ala Thr Leu Cys 260 265 270 Ser Ala Leu Tyr Val Gly Asp Leu Cys Gly Ser Val Phe Leu Val Gly 275 280 285 Gln Leu Phe Thr Phe Ser Pro Arg Arg His Trp Thr Thr Gln Asp Cys 290 295 300 Asn Cys Ser Ile Tyr Pro Gly His Ile Thr Gly His Arg Met Ala Trp 305 310 315 320 Asp Met Met Met Asn Trp Ser Pro Thr Ala Ala Leu Val Val Ala Gln 325 330 335 Leu Leu Arg Ile Pro Gln Ala Ile Met Asp Met Ile Ala Gly Ala His 340 345 350 Trp Gly Val Leu Ala Gly Ile Ala Tyr Phe Ser Met Val Gly Asn Trp 355 360 365 Ala Lys Val Leu Val Val Leu Leu Leu Phe Ala Gly Val Asp Ala Glu 370 375 380 Thr His Val Thr Gly Gly Asn Ala Gly Arg Thr Thr Ala Gly Leu Val 385 390 395 400 Gly Leu Leu Thr Pro Gly Ala Lys Gln Asn Ile Gln Leu Ile Asn Thr 405 410 415 Asn Gly Ser Trp His Ile Asn Ser Thr Ala Leu Asn Cys Asn Glu Ser 420 425 430 Leu Asn Thr Gly Trp Leu Ala Gly Leu Phe Tyr Gln His Lys Phe Asn 435 440 445 Ser Ser Gly Cys Pro Glu Arg Leu Ala Ser Cys Arg Arg Leu Thr Asp 450 455 460 Phe Ala Gln Gly Trp Gly Pro Ile Ser Tyr Ala Asn Gly Ser Gly Leu 465 470 475 480 Asp Glu Arg Pro Tyr Cys Trp His Tyr Pro Pro Arg Pro Cys Gly Ile 485 490 495 Val Pro Ala Lys Ser Val Cys Gly Pro Val Tyr Cys Phe Thr Pro Ser 500 505 510 Pro Val Val Val Gly Thr Thr Asp Arg Ser Gly Ala Pro Thr Tyr Ser 515 520 525 Trp Gly Ala Asn Asp Thr Asp Val Phe Val Leu Asn Asn Thr Arg Pro 530 535 540 Pro Leu Gly Asn Trp Phe Gly Cys Thr Trp Met Asn Ser Thr Gly Phe 545 550 555 560 Thr Lys Val Cys Gly Ala Pro Pro Cys Val Ile Gly Gly Val Gly Asn 565 570 575 Asn Thr Leu Leu Cys Pro Thr Asp Cys Phe Arg Lys His Pro Glu Ala 580 585 590 Thr Tyr Ser Arg Cys Gly Ser Gly Pro Trp Ile Thr Pro Arg Cys Met 595 600 605 Val Asp Tyr Pro Tyr Arg Leu Trp His Tyr Pro Cys Thr Ile Asn Tyr 610 615 620 Thr Ile Phe Lys Val Arg Met Tyr Val Gly Gly Val Glu His Arg Leu 625 630 635 640 Glu Ala Ala Cys Asn Trp Thr Arg Gly Glu Arg Cys Asp Leu Glu Asp 645 650 655 Arg Asp Arg Ser Glu Leu Ser Pro Leu Leu Leu Ser Thr Thr Gln Trp 660 665 670 Gln Val Leu Pro Cys Ser Phe Thr Thr Leu Pro Ala Leu Ser Thr Gly 675 680 685 Leu Ile His Leu His Gln Asn Ile Val Asp Val Gln Tyr Leu Tyr Gly 690 695 700 Val Gly Ser Ser Ile Ala Ser Trp Ala Ile Lys Trp Glu Tyr Val Val 705 710 715 720 Leu Leu Phe Leu Leu Leu Ala Asp Ala Arg Val Cys Ser Cys Leu Trp 725 730 735 Met Met Leu Leu Ile Ser Gln Ala Glu Ala Ala Leu Glu Asn Leu Val 740 745 750 Ile Leu Asn Ala Ala Ser Leu Ala Gly Thr His Gly Leu Val Ser Phe 755 760 765 Leu Val Phe Phe Cys Phe Ala Trp Tyr Leu Lys Gly Arg Trp Val Pro 770 775 780 Gly Ala Val Tyr Ala Leu Tyr Gly Met Trp Pro Leu Leu Leu Leu Leu 785 790 795 800 Leu Ala Leu Pro Gln Arg Ala Tyr Ala Leu Asp Thr Glu Val Ala Ala 805 810 815 Ser Cys Gly Gly Val Val Leu Val Gly Leu Met Ala Leu Thr Leu Ser 820 825 830 Pro Tyr Tyr Lys Arg Tyr Ile Ser Trp Cys Met Trp Trp Leu Gln Tyr 835 840 845 Phe Leu Thr Arg Val Glu Ala Gln Leu His Val Trp Val Pro Pro Leu 850 855 860 Asn Val Arg Gly Gly Arg Asp Ala Val Ile Leu Leu Met Cys Val Val 865 870 875 880 His Pro Thr Leu Val Phe Asp Ile Thr Lys Leu Leu Leu Ala Ile Phe 885 890 895 Gly Pro Leu Trp Ile Leu Gln Ala Ser Leu Leu Lys Val Pro Tyr Phe 900 905 910 Val Arg Val Gln Gly Leu Leu Arg Ile Cys Ala Leu Ala Arg Lys Ile 915 920 925 Ala Gly Gly His Tyr Val Gln Met Ala Ile Ile Lys Leu Gly Ala Leu 930 935 940 Thr Gly Thr Tyr Val Tyr Asn His Leu Thr Pro Leu Arg Asp Trp Ala 945 950 955 960 His Asn Gly Leu Arg Asp Leu Ala Val Ala Val Glu Pro Val Val Phe 965 970 975 Ser Arg Met Glu Thr Lys Leu Ile Thr Trp Gly Ala Asp Thr Ala Ala 980 985 990 Cys Gly Asp Ile Ile Asn Gly Leu Pro Val Ser Ala Arg Arg Gly Gln 995 1000 1005 Glu Ile Leu Leu Gly Pro Ala Asp Gly Met Val Ser Lys Gly Trp Arg 1010 1015 1020 Leu Leu Ala Pro Ile Thr Ala Tyr Ala Gln Gln Thr Arg Gly Leu Leu 1025 1030 1035 1040 Gly Cys Ile Ile Thr Ser Leu Thr Gly Arg Asp Lys Asn Gln Val Glu 1045 1050 1055 Gly Glu Val Gln Ile Val Ser Thr Ala Thr Gln Thr Phe Leu Ala Thr 1060 1065 1070 Cys Ile Asn Gly Val Cys Trp Thr Val Tyr His Gly Ala Gly Thr Arg 1075 1080 1085 Thr Ile Ala Ser Pro Lys Gly Pro Val Ile Gln Met Tyr Thr Asn Val 1090 1095 1100 Asp Gln Asp Leu Val Gly Trp Pro Ala Pro Gln Gly Ser Arg Ser Leu 1105 1110 1115 1120 Thr Pro Cys Thr Cys Gly Ser Ser Asp Leu Tyr Leu Val Thr Arg His 1125 1130 1135 Ala Asp Val Ile Pro Val Arg Arg Arg Gly Asp Ser Arg Gly Ser Leu 1140 1145 1150 Leu Ser Pro Arg Pro Ile Ser Tyr Leu Lys Gly Ser Ser Gly Gly Pro 1155 1160 1165 Leu Leu Cys Pro Ala Gly His Ala Val Gly Leu Phe Arg Ala Ala Val 1170 1175 1180 Cys Thr Arg Gly Val Ala Lys Ala Val Asp Phe Ile Pro Val Glu Asn 1185 1190 1195 1200 Leu Gly Thr Thr Met Arg Ser Pro Val Phe Thr Asp Asn Ser Ser Pro 1205 1210 1215 Pro Ala Val Pro Gln Ser Phe Gln Val Ala His Leu His Ala Pro Thr 1220 1225 1230 Gly Ser Gly Lys Ser Thr Lys Val Pro Ala Ala Tyr Ala Ala Gln Gly 1235 1240 1245 Tyr Lys Val Leu Val Leu Asn Pro Ser Val Ala Ala Thr Leu Gly Phe 1250 1255 1260 Gly Ala Tyr Met Ser Lys Ala His Gly Val Asp Pro Asn Ile Arg Thr 1265 1270 1275 1280 Gly Val Arg Thr Ile Thr Thr Gly Ser Pro Ile Thr Tyr Ser Thr Tyr 1285 1290 1295 Gly Lys Phe Leu Ala Asp Gly Gly Cys Ser Gly Gly Ala Tyr Asp Ile 1300 1305 1310 Ile Ile Cys Asp Glu Cys His Ser Thr Asp Ala Thr Ser Ile Leu Gly 1315 1320 1325 Ile Gly Thr Val Leu Asp Gln Ala Glu Thr Ala Gly Ala Arg Leu Val 1330 1335 1340 Val Leu Ala Thr Ala Thr Pro Pro Gly Ser Val Thr Val Ser His Pro 1345 1350 1355 1360 Asn Ile Glu Glu Val Ala Leu Ser Thr Thr Gly Glu Ile Pro Phe Tyr 1365 1370 1375 Gly Lys Ala Ile Pro Leu Glu Val Ile Lys Gly Gly Arg His Leu Ile 1380 1385 1390 Phe Cys His Ser Lys Lys Lys Cys Asp Glu Leu Ala Ala Lys Leu Val 1395 1400 1405 Ala Leu Gly Ile Asn Ala Val Ala Tyr Tyr Arg Gly Leu Asp Val Ser 1410 1415 1420 Val Ile Pro Thr Ser Gly Asp Val Val Val Val Ser Thr Asp Ala Leu 1425 1430 1435 1440 Met Thr Gly Phe Thr Gly Asp Phe Asp Ser Val Ile Asp Cys Asn Thr 1445 1450 1455 Cys Val Thr Gln Thr Val Asp Phe Ser Leu Asp Pro Thr Phe Thr Ile 1460 1465 1470 Glu Thr Thr Thr Leu Pro Gln Asp Ala Val Ser Arg Thr Gln Arg Arg 1475 1480 1485 Gly Arg Thr Gly Arg Gly Lys Pro Gly Ile Tyr Arg Phe Val Ala Pro 1490 1495 1500 Gly Glu Arg Pro Ser Gly Met Phe Asp Ser Ser Val Leu Cys Glu Cys 1505 1510 1515 1520 Tyr Asp Ala Gly Cys Ala Trp Tyr Glu Leu Thr Pro Ala Glu Thr Thr 1525 1530 1535 Val Arg Leu Arg Ala Tyr Met Asn Thr Pro Gly Leu Pro Val Cys Gln 1540 1545 1550 Asp His Leu Glu Phe Trp Glu Gly Val Phe Thr Gly Leu Thr His Ile 1555 1560 1565 Asp Ala His Phe Leu Ser Gln Thr Lys Gln Ser Gly Glu Asn Phe Pro 1570 1575 1580 Tyr Leu Val Ala Tyr Gln Ala Thr Val Cys Ala Arg Ala Gln Ala Pro 1585 1590 1595 1600 Pro Pro Ser Trp Asp Gln Met Trp Lys Cys Leu Ile Arg Leu Lys Pro 1605 1610 1615 Thr Leu His Gly Pro Thr Pro Leu Leu Tyr Arg Leu Gly Ala Val Gln 1620 1625 1630 Asn Glu Val Thr Leu Thr His Pro Ile Thr Lys Tyr Ile Met Thr Cys 1635 1640 1645 Met Ser Ala Asp Leu Glu Val Val Thr Ser Thr Trp Val Leu Val Gly 1650 1655 1660 Gly Val Leu Ala Ala Leu Ala Ala Tyr Cys Leu Ser Thr Gly Cys Val 1665 1670 1675 1680 Val Ile Val Gly Arg Ile Val Leu Ser Gly Lys Pro Ala Ile Ile Pro 1685 1690 1695 Asp Arg Glu Val Leu Tyr Gln Glu Phe Asp Glu Met Glu Glu Cys Ser 1700 1705 1710 Gln His Leu Pro Tyr Ile Glu Gln Gly Met Met Leu Ala Glu Gln Phe 1715 1720 1725 Lys Gln Lys Ala Leu Gly Leu Leu Gln Thr Ala Ser Arg His Ala Glu 1730 1735 1740 Val Ile Thr Pro Ala Val Gln Thr Asn Trp Gln Lys Leu Glu Val Phe 1745 1750 1755 1760 Trp Ala Lys His Met Trp Asn Phe Ile Ser Gly Ile Gln Tyr Leu Ala 1765 1770 1775 Gly Leu Ser Thr Leu Pro Gly Asn Pro Ala Ile Ala Ser Leu Met Ala 1780 1785 1790 Phe Thr Ala Ala Val Thr Ser Pro Leu Thr Thr Gly Gln Thr Leu Leu 1795 1800 1805 Phe Asn Ile Leu Gly Gly Trp Val Ala Ala Gln Leu Ala Ala Pro Gly 1810 1815 1820 Ala Ala Thr Ala Phe Val Gly Ala Gly Leu Ala Gly Ala Ala Ile Gly 1825 1830 1835 1840 Ser Val Gly Leu Gly Lys Val Leu Val Asp Ile Leu Ala Gly Tyr Gly 1845 1850 1855 Ala Gly Val Ala Gly Ala Leu Val Ala Phe Lys Ile Met Ser Gly Glu 1860 1865 1870 Val Pro Ser Thr Glu Asp Leu Val Asn Leu Leu Pro Ala Ile Leu Ser 1875 1880 1885 Pro Gly Ala Leu Val Val Gly Val Val Cys Ala Ala Ile Leu Arg Arg 1890 1895 1900 His Val Gly Pro Gly Glu Gly Ala Val Gln Trp Met Asn Arg Leu Ile 1905 1910 1915 1920 Ala Phe Ala Ser Arg Gly Asn His Val Ser Pro Thr His Tyr Val Pro 1925 1930 1935 Glu Ser Asp Ala Ala Ala Arg Val Thr Ala Ile Leu Ser Ser Leu Thr 1940 1945 1950 Val Thr Gln Leu Leu Arg Arg Leu His Gln Trp Ile Ser Ser Glu Cys 1955 1960 1965 Thr Thr Pro Cys Ser Gly Ser Trp Leu Arg Asp Ile Trp Asp Trp Ile 1970 1975 1980 Cys Glu Val Leu Ser Asp Phe Lys Thr Trp Leu Lys Ala Lys Leu Met 1985 1990 1995 2000 Pro Gln Leu Pro Gly Ile Pro Phe Val Ser Cys Gln Arg Gly Tyr Arg 2005 2010 2015 Gly Val Trp Arg Gly Asp Gly Ile Met His Thr Arg Cys His Cys Gly 2020 2025 2030 Ala Glu Ile Thr Gly His Val Lys Asn Gly Thr Met Arg Ile Val Gly 2035 2040 2045 Pro Arg Thr Cys Arg Asn Met Trp Ser Gly Thr Phe Pro Ile Asn Ala 2050 2055 2060 Tyr Thr Thr Gly Pro Cys Thr Pro Leu Pro Ala Pro Asn Tyr Lys Phe 2065 2070 2075 2080 Ala Leu Trp Arg Val Ser Ala Glu Glu Tyr Val Glu Ile Arg Arg Val 2085 2090 2095 Gly Asp Phe His Tyr Val Ser Gly Met Thr Thr Asp Asn Leu Lys Cys 2100 2105 2110 Pro Cys Gln Ile Pro Ser Pro Glu Phe Phe Thr Glu Leu Asp Gly Val 2115 2120 2125 Arg Leu His Arg Phe Ala Pro Pro Cys Lys Pro Leu Leu Arg Glu Glu 2130 2135 2140 Val Ser Phe Arg Val Gly Leu His Glu Tyr Pro Val Gly Ser Gln Leu 2145 2150 2155 2160 Pro Cys Glu Pro Glu Pro Asp Val Ala Val Leu Thr Ser Met Leu Thr 2165 2170 2175 Asp Pro Ser His Ile Thr Ala Glu Ala Ala Gly Arg Arg Leu Ala Arg 2180 2185 2190 Gly Ser Pro Pro Ser Met Ala Ser Ser Ser Ala Ser Gln Leu Ser Ala 2195 2200 2205 Pro Ser Leu Lys Ala Thr Cys Thr Ala Asn His Asp Ser Pro Asp Ala 2210 2215 2220 Glu Leu Ile Glu Ala Asn Leu Leu Trp Arg Gln Glu Met Gly Gly Asn 2225 2230 2235 2240 Ile Thr Arg Val Glu Ser Glu Asn Lys Val Val Ile Leu Asp Ser Phe 2245 2250 2255 Asp Pro Leu Val Ala Glu Glu Asp Glu Arg Glu Val Ser Val Pro Ala 2260 2265 2270 Glu Ile Leu Arg Lys Ser Arg Arg Phe Ala Arg Ala Leu Pro Val Trp 2275 2280 2285 Ala Arg Pro Asp Tyr Asn Pro Pro Leu Val Glu Thr Trp Lys Lys Pro 2290 2295 2300 Asp Tyr Glu Pro Pro Val Val His Gly Cys Pro Leu Pro Pro Pro Arg 2305

2310 2315 2320 Ser Pro Pro Val Pro Pro Pro Arg Lys Lys Arg Thr Val Val Leu Thr 2325 2330 2335 Glu Ser Thr Leu Ser Thr Ala Leu Ala Glu Leu Ala Thr Lys Ser Phe 2340 2345 2350 Gly Ser Ser Ser Thr Ser Gly Ile Thr Gly Asp Asn Thr Thr Thr Ser 2355 2360 2365 Ser Glu Pro Ala Pro Ser Gly Cys Pro Pro Asp Ser Asp Val Glu Ser 2370 2375 2380 Tyr Ser Ser Met Pro Pro Leu Glu Gly Glu Pro Gly Asp Pro Asp Leu 2385 2390 2395 2400 Ser Asp Gly Ser Trp Ser Thr Val Ser Ser Gly Ala Asp Thr Glu Asp 2405 2410 2415 Val Val Cys Cys Ser Met Ser Tyr Ser Trp Thr Gly Ala Leu Val Thr 2420 2425 2430 Pro Cys Ala Ala Glu Glu Gln Lys Leu Pro Ile Asn Ala Leu Ser Asn 2435 2440 2445 Ser Leu Leu Arg His His Asn Leu Val Tyr Ser Thr Thr Ser Arg Ser 2450 2455 2460 Ala Cys Gln Arg Gln Lys Lys Val Thr Phe Asp Arg Leu Gln Val Leu 2465 2470 2475 2480 Asp Ser His Tyr Gln Asp Val Leu Lys Glu Val Lys Ala Ala Ala Ser 2485 2490 2495 Lys Val Lys Ala Asn Leu Leu Ser Val Glu Glu Ala Cys Ser Leu Thr 2500 2505 2510 Pro Pro His Ser Ala Lys Ser Lys Phe Gly Tyr Gly Ala Lys Asp Val 2515 2520 2525 Arg Cys His Ala Arg Lys Ala Val Ala His Ile Asn Ser Val Trp Lys 2530 2535 2540 Asp Leu Leu Glu Asp Ser Val Thr Pro Ile Asp Thr Thr Ile Met Ala 2545 2550 2555 2560 Lys Asn Glu Val Phe Cys Val Gln Pro Glu Lys Gly Gly Arg Lys Pro 2565 2570 2575 Ala Arg Leu Ile Val Phe Pro Asp Leu Gly Val Arg Val Cys Glu Lys 2580 2585 2590 Met Ala Leu Tyr Asp Val Val Ser Lys Leu Pro Leu Ala Val Met Gly 2595 2600 2605 Ser Ser Tyr Gly Phe Gln Tyr Ser Pro Gly Gln Arg Val Glu Phe Leu 2610 2615 2620 Val Gln Ala Trp Lys Ser Lys Lys Thr Pro Met Gly Phe Ser Tyr Asp 2625 2630 2635 2640 Thr Arg Cys Phe Asp Ser Thr Val Thr Glu Ser Asp Ile Arg Thr Glu 2645 2650 2655 Glu Ala Ile Tyr Gln Cys Cys Asp Leu Asp Pro Gln Ala Arg Val Ala 2660 2665 2670 Ile Lys Ser Leu Thr Glu Arg Leu Tyr Val Gly Gly Pro Leu Thr Asn 2675 2680 2685 Ser Arg Gly Glu Asn Cys Gly Tyr Arg Arg Cys Arg Ala Ser Gly Val 2690 2695 2700 Leu Thr Thr Ser Cys Gly Asn Thr Leu Thr Cys Tyr Ile Lys Ala Arg 2705 2710 2715 2720 Ala Ala Cys Arg Ala Ala Gly Leu Gln Asp Cys Thr Met Leu Val Cys 2725 2730 2735 Gly Asp Asp Leu Val Val Ile Cys Glu Ser Ala Gly Val Gln Glu Asp 2740 2745 2750 Ala Ala Ser Leu Arg Ala Phe Thr Glu Ala Met Thr Arg Tyr Ser Ala 2755 2760 2765 Pro Pro Gly Asp Pro Pro Gln Pro Glu Tyr Asp Leu Glu Leu Ile Thr 2770 2775 2780 Ser Cys Ser Ser Asn Val Ser Val Ala His Asp Gly Ala Gly Lys Arg 2785 2790 2795 2800 Val Tyr Tyr Leu Thr Arg Asp Pro Thr Thr Pro Leu Ala Arg Ala Ala 2805 2810 2815 Trp Glu Thr Ala Arg His Thr Pro Val Asn Ser Trp Leu Gly Asn Ile 2820 2825 2830 Ile Met Phe Ala Pro Thr Leu Trp Ala Arg Met Ile Leu Met Thr His 2835 2840 2845 Phe Phe Ser Val Leu Ile Ala Arg Asp Gln Leu Glu Gln Ala Leu Asn 2850 2855 2860 Cys Glu Ile Tyr Gly Ala Cys Tyr Ser Ile Glu Pro Leu Asp Leu Pro 2865 2870 2875 2880 Pro Ile Ile Gln Arg Leu His Gly Leu Ser Ala Phe Ser Leu His Ser 2885 2890 2895 Tyr Ser Pro Gly Glu Ile Asn Arg Val Ala Ala Cys Leu Arg Lys Leu 2900 2905 2910 Gly Val Pro Pro Leu Arg Ala Trp Arg His Arg Ala Arg Ser Val Arg 2915 2920 2925 Ala Arg Leu Leu Ser Arg Gly Gly Arg Ala Ala Ile Cys Gly Lys Tyr 2930 2935 2940 Leu Phe Asn Trp Ala Val Arg Thr Lys Leu Lys Leu Thr Pro Ile Ala 2945 2950 2955 2960 Ala Ala Gly Arg Leu Asp Leu Ser Gly Trp Phe Thr Ala Gly Tyr Ser 2965 2970 2975 Gly Gly Asp Ile Tyr His Ser Val Ser His Ala Arg Pro Arg Trp Phe 2980 2985 2990 Trp Phe Cys Leu Leu Leu Leu Ala Ala Gly Val Gly Ile Tyr Leu Leu 2995 3000 3005 Pro Asn Arg 3010 69 9596 DNA Hepatitis C virus 69 gccagccccc tgatgggggc gacactccac catgaatcac tcccctgtga ggaactactg 60 tcttcacgca gaaagcgtct agccatggcg ttagtatgag tgtcgtgcag cctccaggac 120 cccccctccc gggagagcca tagtggtctg cggaaccggt gagtacaccg gaattgccag 180 gacgaccggg tcctttcttg gatcaaaccc gctcaatgcc tggagatttg ggcgtgcccc 240 cgcgagactg ctagccgagt agtgttgggt cgcgaaaggc cttgtggtac tgcctgatag 300 ggtgcttgcg agtgccccgg gaggtctcgt agaccgtgca ccatgagcac gaatcctaaa 360 cctcaaagaa aaaccaaacg taacaccaac cgccgcccac aggacgtcaa gttcccgggc 420 ggtggtcaaa tcgttggtgg agtttacctg ttgccgcgca ggggccccag gttgggtgtg 480 cgcgcgacta ggaagacttc cgagcggtcg caacctcgtg gaaggcgaca acctatccca 540 aaggctcgcc gacccgaggg cagggcctgg gctcagcccg ggtacccttg gcccctctat 600 ggcaatgagg gcttggggtg ggcaggatgg ctcctgtcac cccgcggctc ccggcctagt 660 tggggcccca cggacccccg gcgtaggtcg cgtaacttgg gtaaggtcat cgataccctt 720 acatgcggct tcgccgatct catggggtac attccgctcg tcggcgcccc cctagggggc 780 gctgccaggg ccttggcaca cggtgtccgg gttctggagg acggcgtgaa ctatgcaaca 840 gggaacttgc ccggttgctc tttctctatc ttcctcttgg ctctgctgtc ctgtttgacc 900 atcccagctt ccgcttatga agtgcgcaac gtgtccggga tataccatgt cacgaacgac 960 tgctccaact caagcattgt gtatgaggca gcggacgtga tcatgcatac tcccgggtgc 1020 gtgccctgtg ttcgggaggg caacagctcc cgttgctggg tagcgctcac tcccacgctc 1080 gcggccagag atgccagcgt ccccactacg acaatacgac gccacgtcga cttgctcgtt 1140 gggacggctg ctttctgctc cgctatgtac gtgggggatc tctgcggatc tattttcctc 1200 gtctcccagc tgttcacctt ctcgcctcgc cggcatgaga cagtgcagga ctgcaactgc 1260 tcaatctatc ccggccatgt atcaggtcac cgcatggctt gggatatgat gatgaactgg 1320 tcacctacaa cagccctagt ggtgtcgcag ttgctccgga tcccacaagc tgtcgtggac 1380 atggtggcgg gggcccactg gggagtcctg gcgggccttg cctactattc catggtaggg 1440 aactgggcta aggttctgat tgtggcgcta ctctttgccg gcgttgacgg ggagacccac 1500 acgacgggga gggtggtcgg ccgcaccacc tccgggttta cgtccctttt ctcatctggg 1560 gcgtctcaga aaatccagct tgtgaatacc aacggcagct ggcacatcaa caggactgct 1620 ctaaattgca atgactccct ccagactggg ttccttgccg cgctgttcta cacacacaag 1680 ttcaactcgc ccgggtgccc ggagcgcatg gccagctgcc gccccattga ctggttcgcc 1740 caggggtggg gccccatcac ctatactgag cctaacagct cggatcagag gccttattgc 1800 tggcattacg cgcctcgacc gtgtggtatc gtacccgcgt cgcaggtgtg tggtccagtg 1860 tattgtttca ccccaagccc tgttgtggtg gggaccaccg atcgttccgg tgtccctacg 1920 tatagctggg gggagaatga gacagacgtg atgctcctga acaacacgcg tccgccacaa 1980 ggcaactggt tcggctgtac atggatgaat agtactgggt tcactaagac gtgcggaggc 2040 cccccgtgta acatcggggg ggtcggtaac cgcaccttga tctgccccac ggactgcttc 2100 cggaagcacc ccgaggctac ttacacaaaa tgtggctcgg ggccctggtt gacacctagg 2160 tgcctagtag actacccata caggctctgg cactacccct gcaccctcaa tttttccatc 2220 tttaaggtta ggatgtatgt ggggggcgtg gagcacaggc tcaatgccgc atgcaattgg 2280 actcgaggag agcgctgtaa cttggaggac agggataggt cagaactcag cccgctgctg 2340 ctgtctacaa cagagtggca gatactgccc tgtgccttca ccaccctacc ggctttatcc 2400 actggtttga tccatctcca tcagaacatc gtggacgtgc aatacctgta cggtgtaggg 2460 tcagcgtttg tctcctttgc aatcaaatgg gagtacatcc tgttgctttt ccttctcctg 2520 gcagacgcgc gagtgtgtgc ctgcttgtgg atgatgctgc tgatagccca ggctgaggcc 2580 gccttagaga acttggtggt cctcaatgcg gcgtccgtgg ccggagcgca tggtattctc 2640 tcctttcttg tgttcttctg cgccgcctgg tacattaagg gcaggctggc tcctggggcg 2700 gcgtatgctt tttatggcgt atggccgctg ctcctgctcc tactggcgtt accaccacga 2760 gcttacgcct tggaccggga gatggctgca tcgtgcgggg gtgcggttct tgtaggtctg 2820 gtattcttga ccttatcacc atactacaaa gtgtttctca ctaggctcat atggtggtta 2880 caatacttta tcaccagagc cgaggcgcac atgcaagtgt gggtcccccc cctcaacgtt 2940 cggggaggcc gcgatgccat catcctcctc acgtgtgcgg ttcatccaga gttaattttt 3000 gacatcacca aactcctgct cgccatactc ggcccgctca tggtgctcca ggctggcata 3060 acgagagtgc cgtacttcgt gcgcgctcaa gggctcattc gtgcatgcat gttagtgcga 3120 aaagtcgccg ggggtcatta tgtccaaatg gccttcatga agctgggcgc gctgacaggt 3180 acgtacgttt ataaccatct taccccactg cgggactggg cccacgcggg cctacgagac 3240 cttgcggtgg cggtagagcc cgtcgtcttc tccgccatgg agaccaaggt catcacctgg 3300 ggagcagaca ccgctgcgtg tggggacatc atcttgggtc tacccgtctc cgcccgaagg 3360 gggaaggaga tatttttggg accggctgat agtctcgaag ggcaagggtg gcgactcctt 3420 gcgcccatca cggcctactc ccaacaaacg cggggcgtac ttggttgcgt catcactagc 3480 ctcacaggcc gggacaagaa ccaggtcgaa ggggaggttc aagtggtttc taccgcaaca 3540 caatctttcc tggcgacctg catcaacggc gtgtgctgga ctgtctacca tggcgctggc 3600 tcaaagaccc tagccggtcc aaaaggtcca atcacccaaa tgtacaccaa tgtagacctg 3660 gacctcgtcg gctggcaggc gccccccggg gcgcgctcca tgacaccatg cagctgtggc 3720 agctcggacc tttacttggt cacgagacat gctgatgtca tcccggtgcg ccggcgaggc 3780 gacagcaggg ggagtctact ctcccccagg cccgtctcct acctgaaggg ctcctcgggt 3840 ggtcctttgc tttgcccttc ggggcacgtc gtgggcgtct tccgggctgc tgtgtgcacc 3900 cggggggtcg cgaaggcggt ggacttcata cccgttgagt ctatggaaac taccatgcgg 3960 tctccggtct tcacagacaa ctcatccccc ccggctgtac cgcagacatt ccaagtggca 4020 catctgcacg ctcctactgg cagcggcaag agcaccaaag tgccggctgc gtatgcagcc 4080 caagggtaca aggtgctcgt cctgaatccg tccgttgccg ccaccttagg gtttggggcg 4140 tatatgtcca aggcacacgg tatcgaccct aacatcagaa ctggggtaag gaccattacc 4200 acgggcggct ccattacgta ctccacctat ggcaagttcc ttgccgacgg tggctgctcc 4260 gggggcgcct atgacatcat aatatgtgat gagtgccact caactgactc gactaccatc 4320 ttgggcattg gcacagtcct ggaccaagcg gagacggctg gagcgcggct tgtcgtgctc 4380 gccaccgcta cacctccggg atcggttacc gtgccacacc ccaatatcga ggaaataggc 4440 ctgtccaaca atggagagat ccccttctat ggcaaagcca tccccattga ggccatcaag 4500 ggggggaggc atctcatttt ctgccattcc aagaagaaat gtgacgagct cgccgcaaag 4560 ctgacaggcc tcggactgaa cgctgtagca tattaccggg gccttgatgt gtccgtcata 4620 ccgcctatcg gagacgtcgt tgtcgtggca acagacgctc taatgacggg tttcaccggc 4680 gattttgact cagtgatcga ctgcaataca tgtgtcactc agacagtcga cttcagcttg 4740 gatcccacct tcaccattga gacgacgacc gtgccccaag acgcggtgtc gcgctcgcaa 4800 cggcgaggta gaactggcag gggtaggagt ggcatctaca ggtttgtgac tccaggagaa 4860 cggccctcgg gcatgttcga ttcttcggtc ctgtgtgagt gctatgacgc gggctgtgct 4920 tggcatgagc tcacgcccgc tgagacctcg gttaggttgc gggcttacct aaatacacca 4980 ggattgcccg tctgccagga ccatctggag ttctgggaga gcgtcttcac aggcctcacc 5040 cacatagatg cccacttcct gtcccagact aaacaggcag gagacaactt tccttacctg 5100 gtggcatatc aagctacagt gtgcgccagg gctcaagctc cacctccatc gtgggaccaa 5160 atgtggaagt gtctcatacg gctgaaacct acactgcacg ggccaacacc cctgctgtat 5220 aggctaggag ccgtccaaaa tgaggtcatc ctcacacacc ccataactaa atacatcatg 5280 gcatgcatgt cggctgacct ggaggtcgtc actagcacct gggtgctggt gggcggagtc 5340 cttgcagctt tggccgcata ctgcctgacg acaggcagtg tggtcattgt gggcaggatc 5400 atcttgtccg ggaagccagc tgtcgttccc gacagggaag tcctctacca ggagttcgat 5460 gagatggaag agtgtgcctc acaacttcct tacatcgagc agggaatgca gctcgccgag 5520 caatttaagc agaaggcgct cggattgttg caaacggcca ccaagcaagc ggaggctgct 5580 gctcccgtgg tggagtccaa gtggcgagcc ctcgagacct tctgggcgaa gcacatgtgg 5640 aatttcatca gcggaataca gtacctagca ggcttatcca ctctgcctgg aaaccccgcg 5700 atagcatcat tgatggcatt tacagcttct atcactagcc cgctcaccac ccaaaacacc 5760 ctcctgttta acatcttggg gggatgggtg gctgcccaac tcgctcctcc cagcgctgcg 5820 tcagctttcg tgggcgccgg catcgccgga gcggctgttg gcagcatagg ccttgggaag 5880 gtgctcgtgg acatcctggc gggctatggg gcgggggtag ccggcgcact cgtggccttt 5940 aaggtcatga gcggcgaggt gccctccacc gaggacctgg tcaacttact ccctgccatc 6000 ctctctcctg gtgccctggt cgtcggggtc gtgtgcgcag caatactgcg ccggcacgtg 6060 ggcccgggag agggggctgt gcagtggatg aaccggctga tagcgttcgc ttcgcggggt 6120 aaccacgtct cccccacgca ctatgtgcct gagagcgacg ctgcagcacg tgtcactcag 6180 atcctcccta gccttaccat cactcaactg ctgaagcggc ttcaccagtg gattaatgag 6240 gactgctcta cgccatgctc cggctcgtgg ctaagggatg tttgggattg gatatgcacg 6300 gtgttgactg acttcaagac ctggctccag tccaagctcc tgccgcggtt accgggagtc 6360 cctttcctgt catgccaacg cgggtacaag ggagtctggc ggggggacgg catcatgcaa 6420 accacctgcc catgtggagc acagatcgcc ggacatgtca aaaacggttc catgaggatc 6480 gtagggccta ggacctgcag caacacgtgg cacggaacgt tccccatcaa cgcatacacc 6540 acgggacctt gcacaccttc cccggcgccc aactattcca gggcgctatg gcgggtggct 6600 gctgaggagt acgtggaggt tacgcgtgtg ggggatttcc actacgtgac gggcatgacc 6660 actgacaacg taaagtgccc atgccaggtt ccggcccccg aattcttcac ggaggtggat 6720 ggagtgcggt tgcacaggta cgctccggcg tgcagacctc tcctacggga ggacgtcacg 6780 ttccaggtcg ggctcaacca atacttggtc gggtcgcagc tcccatgcga gcccgaaccg 6840 gacgtaacag tgcttacttc catgctcacc gatccctccc acattacagc agagacggct 6900 aagcgtaggc tggctagagg gtctcccccc tctttagcca gctcatcagc tagccagttg 6960 tctgcgcctt ctttgaaggc gacatgcact acccaccatg actccccgga cgctgacctc 7020 atcgaggcca acctcttgtg gcggcaggag atgggcggaa acatcactcg cgtggagtca 7080 gagaataagg tagtaattct ggactctttc gaaccgcttc acgcggaggg ggatgagagg 7140 gagatatccg tcgcggcgga gatcctgcga aaatccagga agttcccctc agcgttgccc 7200 atatgggcac gcccggacta caatcctcca ctgttagagt cctggaagga cccggactac 7260 gtccctccgg tggtacacgg atgcccattg ccacctacca aggctcctcc aataccacct 7320 ccacggagaa agaggacggt tgtcctgaca gaatccaatg tgtcttctgc cttggcggag 7380 ctcgccacta agaccttcgg tagctccgga tcgtcggccg tcgatagcgg cacggcgacc 7440 gcccttcctg acctggcctc cgacgacggt gacaaaggat ccgacgttga gtcgcactcc 7500 tccatgcccc cccttgaagg ggagccgggg gaccccgatc tcagcgacgg gtcttggtct 7560 accgtgagtg aggaggctag tgaggacgtc gtctgctgct caatgtccta tacgtggaca 7620 ggcgccctga tcacgccatg cgctgcggag gaaagtaagc tgcccatcaa cccgttgagc 7680 aactctttgc tgcgtcacca caacatggtc tacgccacaa catcccgcag cgcaagcctc 7740 cggcagaaga aggtcacctt tgacagattg caagtcctgg acgaccatta ccgggacgtg 7800 ctcaaggaga tgaaggcgaa ggcgtccaca gttaaggcta agcttctatc tatagaggag 7860 gcctgcaagc tgacgccccc acattcggcc aaatccaaat ttggctatgg ggcaaaggac 7920 gtccggaacc tatccagcag ggccgttaac cacatccgct ccgtgtggga ggacttgctg 7980 gaagacactg aaacaccaat tgacaccacc atcatggcaa aaagtgaggt tttctgcgtc 8040 caaccagaga agggaggccg caagccagct cgccttatcg tattcccaga cctgggagtt 8100 cgtgtatgcg agaagatggc cctttacgac gtggtctcca cccttcctca ggccgtgatg 8160 ggctcctcat acggatttca atactccccc aagcagcggg tcgagttcct ggtgaatacc 8220 tggaaatcaa agaaatgccc tatgggcttc tcatatgaca ctcgctgttt tgactcaacg 8280 gtcaccgaga gtgacattcg tgttgaggag tcaatttacc aatgttgtga cttggccccc 8340 gaggccagac aggccataag gtcgctcaca gagcggcttt acatcggggg tcccctgact 8400 aactcaaaag ggcagaactg cggttatcgc cggtgccgcg caagtggcgt gctgacgact 8460 agctgcggta ataccctcac atgttacttg aaggccactg cggcctgtcg agctgcaaag 8520 ctccaggact gcacgatgct cgtgaacgga gacgaccttg tcgttatctg tgaaagcgcg 8580 ggaacccagg aggatgcggc ggccctacga gccttcacgg aggctatgac taggtattcc 8640 gccccccccg gggatccgcc ccaaccagaa tacgacctgg agctgataac atcatgttcc 8700 tccaatgtgt cagtcgcgca cgatgcatcc ggcaaaaggg tatactacct cacccgtgac 8760 cccaccaccc cccttgcacg ggctgcgtgg gagacagcta gacacactcc aatcaactct 8820 tggctaggca atatcatcat gtatgcgccc accctatggg caaggatgat tctgatgact 8880 cactttttct ccatccttct agctcaagag caacttgaaa aagccctgga ttgtcagatc 8940 tacggggctt gctactccat tgagccactt gacctacctc agatcattga acgactccat 9000 ggtcttagcg catttacact ccacagttac tctccaggtg agatcaatag ggtggcttca 9060 tgcctcagga aacttggggt accacccttg cgaacctgga gacatcgggc cagaagtgtc 9120 cgcgctaagc tactgtccca gggggggagg gccgccactt gtggcagata cctctttaac 9180 tgggcagtaa ggaccaagct taaactcact ccaatcccgg ccgcgtccca gctggacttg 9240 tctggctggt tcgtcgctgg ttacagcggg ggagacatat atcacagcct gtctcgtgcc 9300 cgaccccgct ggtttccgtt gtgcctactc ctactttctg taggggtagg catttacctg 9360 ctccccaacc gatgaacggg gagctaacca ctccaggcct taagccattt cctgtttttt 9420 tttttttttt tttttttttt ttcttttttt ttttctttcc tttccttctt tttttccttt 9480 ctttttccct tctttaatgg tggctccatc ttagccctag tcacggctag ctgtgaaagg 9540 tccgtgagcc gcatgactgc agagagtgct gatactggcc tctctgcaga tcatgt 9596 70 3010 PRT Hepatitis C virus 70 Met Ser Thr Asn Pro Lys Pro Gln Arg Lys Thr Lys Arg Asn Thr Asn 1 5 10 15 Arg Arg Pro Gln Asp Val Lys Phe Pro Gly Gly Gly Gln Ile Val Gly 20 25 30 Gly Val Tyr Leu Leu Pro Arg Arg Gly Pro Arg Leu Gly Val Arg Ala 35 40 45 Thr Arg Lys Thr Ser Glu Arg Ser Gln Pro Arg Gly Arg Arg Gln Pro 50 55 60 Ile Pro Lys Ala Arg Arg Pro Glu Gly Arg Ala Trp Ala Gln Pro Gly 65 70 75 80 Tyr Pro Trp Pro Leu Tyr Gly Asn Glu Gly Leu Gly Trp Ala Gly Trp 85 90 95 Leu Leu Ser Pro Arg Gly Ser Arg Pro Ser Trp Gly Pro Thr Asp Pro 100 105 110 Arg Arg Arg Ser Arg Asn Leu Gly Lys Val Ile Asp Thr Leu Thr Cys 115 120 125 Gly Phe Ala Asp Leu Met Gly Tyr Ile Pro Leu Val Gly Ala Pro Leu 130 135 140 Gly Gly Ala Ala Arg Ala Leu Ala His Gly Val Arg Val Leu Glu Asp 145 150 155 160 Gly Val Asn Tyr Ala Thr Gly Asn Leu Pro Gly Cys Ser Phe Ser Ile

165 170 175 Phe Leu Leu Ala Leu Leu Ser Cys Leu Thr Ile Pro Ala Ser Ala Tyr 180 185 190 Glu Val Arg Asn Val Ser Gly Ile Tyr His Val Thr Asn Asp Cys Ser 195 200 205 Asn Ser Ser Ile Val Tyr Glu Ala Ala Asp Val Ile Met His Thr Pro 210 215 220 Gly Cys Val Pro Cys Val Arg Glu Gly Asn Ser Ser Arg Cys Trp Val 225 230 235 240 Ala Leu Thr Pro Thr Leu Ala Ala Arg Asp Ala Ser Val Pro Thr Thr 245 250 255 Thr Ile Arg Arg His Val Asp Leu Leu Val Gly Thr Ala Ala Phe Cys 260 265 270 Ser Ala Met Tyr Val Gly Asp Leu Cys Gly Ser Ile Phe Leu Val Ser 275 280 285 Gln Leu Phe Thr Phe Ser Pro Arg Arg His Glu Thr Val Gln Asp Cys 290 295 300 Asn Cys Ser Ile Tyr Pro Gly His Val Ser Gly His Arg Met Ala Trp 305 310 315 320 Asp Met Met Met Asn Trp Ser Pro Thr Thr Ala Leu Val Val Ser Gln 325 330 335 Leu Leu Arg Ile Pro Gln Ala Val Val Asp Met Val Ala Gly Ala His 340 345 350 Trp Gly Val Leu Ala Gly Leu Ala Tyr Tyr Ser Met Val Gly Asn Trp 355 360 365 Ala Lys Val Leu Ile Val Ala Leu Leu Phe Ala Gly Val Asp Gly Glu 370 375 380 Thr His Thr Thr Gly Arg Val Val Gly Arg Thr Thr Ser Gly Phe Thr 385 390 395 400 Ser Leu Phe Ser Ser Gly Ala Ser Gln Lys Ile Gln Leu Val Asn Thr 405 410 415 Asn Gly Ser Trp His Ile Asn Arg Thr Ala Leu Asn Cys Asn Asp Ser 420 425 430 Leu Gln Thr Gly Phe Leu Ala Ala Leu Phe Tyr Thr His Lys Phe Asn 435 440 445 Ser Pro Gly Cys Pro Glu Arg Met Ala Ser Cys Arg Pro Ile Asp Trp 450 455 460 Phe Ala Gln Gly Trp Gly Pro Ile Thr Tyr Thr Glu Pro Asn Ser Ser 465 470 475 480 Asp Gln Arg Pro Tyr Cys Trp His Tyr Ala Pro Arg Pro Cys Gly Ile 485 490 495 Val Pro Ala Ser Gln Val Cys Gly Pro Val Tyr Cys Phe Thr Pro Ser 500 505 510 Pro Val Val Val Gly Thr Thr Asp Arg Ser Gly Val Pro Thr Tyr Ser 515 520 525 Trp Gly Glu Asn Glu Thr Asp Val Met Leu Leu Asn Asn Thr Arg Pro 530 535 540 Pro Gln Gly Asn Trp Phe Gly Cys Thr Trp Met Asn Ser Thr Gly Phe 545 550 555 560 Thr Lys Thr Cys Gly Gly Pro Pro Cys Asn Ile Gly Gly Val Gly Asn 565 570 575 Arg Thr Leu Ile Cys Pro Thr Asp Cys Phe Arg Lys His Pro Glu Ala 580 585 590 Thr Tyr Thr Lys Cys Gly Ser Gly Pro Trp Leu Thr Pro Arg Cys Leu 595 600 605 Val Asp Tyr Pro Tyr Arg Leu Trp His Tyr Pro Cys Thr Leu Asn Phe 610 615 620 Ser Ile Phe Lys Val Arg Met Tyr Val Gly Gly Val Glu His Arg Leu 625 630 635 640 Asn Ala Ala Cys Asn Trp Thr Arg Gly Glu Arg Cys Asn Leu Glu Asp 645 650 655 Arg Asp Arg Ser Glu Leu Ser Pro Leu Leu Leu Ser Thr Thr Glu Trp 660 665 670 Gln Ile Leu Pro Cys Ala Phe Thr Thr Leu Pro Ala Leu Ser Thr Gly 675 680 685 Leu Ile His Leu His Gln Asn Ile Val Asp Val Gln Tyr Leu Tyr Gly 690 695 700 Val Gly Ser Ala Phe Val Ser Phe Ala Ile Lys Trp Glu Tyr Ile Leu 705 710 715 720 Leu Leu Phe Leu Leu Leu Ala Asp Ala Arg Val Cys Ala Cys Leu Trp 725 730 735 Met Met Leu Leu Ile Ala Gln Ala Glu Ala Ala Leu Glu Asn Leu Val 740 745 750 Val Leu Asn Ala Ala Ser Val Ala Gly Ala His Gly Ile Leu Ser Phe 755 760 765 Leu Val Phe Phe Cys Ala Ala Trp Tyr Ile Lys Gly Arg Leu Ala Pro 770 775 780 Gly Ala Ala Tyr Ala Phe Tyr Gly Val Trp Pro Leu Leu Leu Leu Leu 785 790 795 800 Leu Ala Leu Pro Pro Arg Ala Tyr Ala Leu Asp Arg Glu Met Ala Ala 805 810 815 Ser Cys Gly Gly Ala Val Leu Val Gly Leu Val Phe Leu Thr Leu Ser 820 825 830 Pro Tyr Tyr Lys Val Phe Leu Thr Arg Leu Ile Trp Trp Leu Gln Tyr 835 840 845 Phe Ile Thr Arg Ala Glu Ala His Met Gln Val Trp Val Pro Pro Leu 850 855 860 Asn Val Arg Gly Gly Arg Asp Ala Ile Ile Leu Leu Thr Cys Ala Val 865 870 875 880 His Pro Glu Leu Ile Phe Asp Ile Thr Lys Leu Leu Leu Ala Ile Leu 885 890 895 Gly Pro Leu Met Val Leu Gln Ala Gly Ile Thr Arg Val Pro Tyr Phe 900 905 910 Val Arg Ala Gln Gly Leu Ile Arg Ala Cys Met Leu Val Arg Lys Val 915 920 925 Ala Gly Gly His Tyr Val Gln Met Ala Phe Met Lys Leu Gly Ala Leu 930 935 940 Thr Gly Thr Tyr Val Tyr Asn His Leu Thr Pro Leu Arg Asp Trp Ala 945 950 955 960 His Ala Gly Leu Arg Asp Leu Ala Val Ala Val Glu Pro Val Val Phe 965 970 975 Ser Ala Met Glu Thr Lys Val Ile Thr Trp Gly Ala Asp Thr Ala Ala 980 985 990 Cys Gly Asp Ile Ile Leu Gly Leu Pro Val Ser Ala Arg Arg Gly Lys 995 1000 1005 Glu Ile Phe Leu Gly Pro Ala Asp Ser Leu Glu Gly Gln Gly Trp Arg 1010 1015 1020 Leu Leu Ala Pro Ile Thr Ala Tyr Ser Gln Gln Thr Arg Gly Val Leu 1025 1030 1035 1040 Gly Cys Val Ile Thr Ser Leu Thr Gly Arg Asp Lys Asn Gln Val Glu 1045 1050 1055 Gly Glu Val Gln Val Val Ser Thr Ala Thr Gln Ser Phe Leu Ala Thr 1060 1065 1070 Cys Ile Asn Gly Val Cys Trp Thr Val Tyr His Gly Ala Gly Ser Lys 1075 1080 1085 Thr Leu Ala Gly Pro Lys Gly Pro Ile Thr Gln Met Tyr Thr Asn Val 1090 1095 1100 Asp Leu Asp Leu Val Gly Trp Gln Ala Pro Pro Gly Ala Arg Ser Met 1105 1110 1115 1120 Thr Pro Cys Ser Cys Gly Ser Ser Asp Leu Tyr Leu Val Thr Arg His 1125 1130 1135 Ala Asp Val Ile Pro Val Arg Arg Arg Gly Asp Ser Arg Gly Ser Leu 1140 1145 1150 Leu Ser Pro Arg Pro Val Ser Tyr Leu Lys Gly Ser Ser Gly Gly Pro 1155 1160 1165 Leu Leu Cys Pro Ser Gly His Val Val Gly Val Phe Arg Ala Ala Val 1170 1175 1180 Cys Thr Arg Gly Val Ala Lys Ala Val Asp Phe Ile Pro Val Glu Ser 1185 1190 1195 1200 Met Glu Thr Thr Met Arg Ser Pro Val Phe Thr Asp Asn Ser Ser Pro 1205 1210 1215 Pro Ala Val Pro Gln Thr Phe Gln Val Ala His Leu His Ala Pro Thr 1220 1225 1230 Gly Ser Gly Lys Ser Thr Lys Val Pro Ala Ala Tyr Ala Ala Gln Gly 1235 1240 1245 Tyr Lys Val Leu Val Leu Asn Pro Ser Val Ala Ala Thr Leu Gly Phe 1250 1255 1260 Gly Ala Tyr Met Ser Lys Ala His Gly Ile Asp Pro Asn Ile Arg Thr 1265 1270 1275 1280 Gly Val Arg Thr Ile Thr Thr Gly Gly Ser Ile Thr Tyr Ser Thr Tyr 1285 1290 1295 Gly Lys Phe Leu Ala Asp Gly Gly Cys Ser Gly Gly Ala Tyr Asp Ile 1300 1305 1310 Ile Ile Cys Asp Glu Cys His Ser Thr Asp Ser Thr Thr Ile Leu Gly 1315 1320 1325 Ile Gly Thr Val Leu Asp Gln Ala Glu Thr Ala Gly Ala Arg Leu Val 1330 1335 1340 Val Leu Ala Thr Ala Thr Pro Pro Gly Ser Val Thr Val Pro His Pro 1345 1350 1355 1360 Asn Ile Glu Glu Ile Gly Leu Ser Asn Asn Gly Glu Ile Pro Phe Tyr 1365 1370 1375 Gly Lys Ala Ile Pro Ile Glu Ala Ile Lys Gly Gly Arg His Leu Ile 1380 1385 1390 Phe Cys His Ser Lys Lys Lys Cys Asp Glu Leu Ala Ala Lys Leu Thr 1395 1400 1405 Gly Leu Gly Leu Asn Ala Val Ala Tyr Tyr Arg Gly Leu Asp Val Ser 1410 1415 1420 Val Ile Pro Pro Ile Gly Asp Val Val Val Val Ala Thr Asp Ala Leu 1425 1430 1435 1440 Met Thr Gly Phe Thr Gly Asp Phe Asp Ser Val Ile Asp Cys Asn Thr 1445 1450 1455 Cys Val Thr Gln Thr Val Asp Phe Ser Leu Asp Pro Thr Phe Thr Ile 1460 1465 1470 Glu Thr Thr Thr Val Pro Gln Asp Ala Val Ser Arg Ser Gln Arg Arg 1475 1480 1485 Gly Arg Thr Gly Arg Gly Arg Ser Gly Ile Tyr Arg Phe Val Thr Pro 1490 1495 1500 Gly Glu Arg Pro Ser Gly Met Phe Asp Ser Ser Val Leu Cys Glu Cys 1505 1510 1515 1520 Tyr Asp Ala Gly Cys Ala Trp His Glu Leu Thr Pro Ala Glu Thr Ser 1525 1530 1535 Val Arg Leu Arg Ala Tyr Leu Asn Thr Pro Gly Leu Pro Val Cys Gln 1540 1545 1550 Asp His Leu Glu Phe Trp Glu Ser Val Phe Thr Gly Leu Thr His Ile 1555 1560 1565 Asp Ala His Phe Leu Ser Gln Thr Lys Gln Ala Gly Asp Asn Phe Pro 1570 1575 1580 Tyr Leu Val Ala Tyr Gln Ala Thr Val Cys Ala Arg Ala Gln Ala Pro 1585 1590 1595 1600 Pro Pro Ser Trp Asp Gln Met Trp Lys Cys Leu Ile Arg Leu Lys Pro 1605 1610 1615 Thr Leu His Gly Pro Thr Pro Leu Leu Tyr Arg Leu Gly Ala Val Gln 1620 1625 1630 Asn Glu Val Ile Leu Thr His Pro Ile Thr Lys Tyr Ile Met Ala Cys 1635 1640 1645 Met Ser Ala Asp Leu Glu Val Val Thr Ser Thr Trp Val Leu Val Gly 1650 1655 1660 Gly Val Leu Ala Ala Leu Ala Ala Tyr Cys Leu Thr Thr Gly Ser Val 1665 1670 1675 1680 Val Ile Val Gly Arg Ile Ile Leu Ser Gly Lys Pro Ala Val Val Pro 1685 1690 1695 Asp Arg Glu Val Leu Tyr Gln Glu Phe Asp Glu Met Glu Glu Cys Ala 1700 1705 1710 Ser Gln Leu Pro Tyr Ile Glu Gln Gly Met Gln Leu Ala Glu Gln Phe 1715 1720 1725 Lys Gln Lys Ala Leu Gly Leu Leu Gln Thr Ala Thr Lys Gln Ala Glu 1730 1735 1740 Ala Ala Ala Pro Val Val Glu Ser Lys Trp Arg Ala Leu Glu Thr Phe 1745 1750 1755 1760 Trp Ala Lys His Met Trp Asn Phe Ile Ser Gly Ile Gln Tyr Leu Ala 1765 1770 1775 Gly Leu Ser Thr Leu Pro Gly Asn Pro Ala Ile Ala Ser Leu Met Ala 1780 1785 1790 Phe Thr Ala Ser Ile Thr Ser Pro Leu Thr Thr Gln Asn Thr Leu Leu 1795 1800 1805 Phe Asn Ile Leu Gly Gly Trp Val Ala Ala Gln Leu Ala Pro Pro Ser 1810 1815 1820 Ala Ala Ser Ala Phe Val Gly Ala Gly Ile Ala Gly Ala Ala Val Gly 1825 1830 1835 1840 Ser Ile Gly Leu Gly Lys Val Leu Val Asp Ile Leu Ala Gly Tyr Gly 1845 1850 1855 Ala Gly Val Ala Gly Ala Leu Val Ala Phe Lys Val Met Ser Gly Glu 1860 1865 1870 Val Pro Ser Thr Glu Asp Leu Val Asn Leu Leu Pro Ala Ile Leu Ser 1875 1880 1885 Pro Gly Ala Leu Val Val Gly Val Val Cys Ala Ala Ile Leu Arg Arg 1890 1895 1900 His Val Gly Pro Gly Glu Gly Ala Val Gln Trp Met Asn Arg Leu Ile 1905 1910 1915 1920 Ala Phe Ala Ser Arg Gly Asn His Val Ser Pro Thr His Tyr Val Pro 1925 1930 1935 Glu Ser Asp Ala Ala Ala Arg Val Thr Gln Ile Leu Pro Ser Leu Thr 1940 1945 1950 Ile Thr Gln Leu Leu Lys Arg Leu His Gln Trp Ile Asn Glu Asp Cys 1955 1960 1965 Ser Thr Pro Cys Ser Gly Ser Trp Leu Arg Asp Val Trp Asp Trp Ile 1970 1975 1980 Cys Thr Val Leu Thr Asp Phe Lys Thr Trp Leu Gln Ser Lys Leu Leu 1985 1990 1995 2000 Pro Arg Leu Pro Gly Val Pro Phe Leu Ser Cys Gln Arg Gly Tyr Lys 2005 2010 2015 Gly Val Trp Arg Gly Asp Gly Ile Met Gln Thr Thr Cys Pro Cys Gly 2020 2025 2030 Ala Gln Ile Ala Gly His Val Lys Asn Gly Ser Met Arg Ile Val Gly 2035 2040 2045 Pro Arg Thr Cys Ser Asn Thr Trp His Gly Thr Phe Pro Ile Asn Ala 2050 2055 2060 Tyr Thr Thr Gly Pro Cys Thr Pro Ser Pro Ala Pro Asn Tyr Ser Arg 2065 2070 2075 2080 Ala Leu Trp Arg Val Ala Ala Glu Glu Tyr Val Glu Val Thr Arg Val 2085 2090 2095 Gly Asp Phe His Tyr Val Thr Gly Met Thr Thr Asp Asn Val Lys Cys 2100 2105 2110 Pro Cys Gln Val Pro Ala Pro Glu Phe Phe Thr Glu Val Asp Gly Val 2115 2120 2125 Arg Leu His Arg Tyr Ala Pro Ala Cys Arg Pro Leu Leu Arg Glu Asp 2130 2135 2140 Val Thr Phe Gln Val Gly Leu Asn Gln Tyr Leu Val Gly Ser Gln Leu 2145 2150 2155 2160 Pro Cys Glu Pro Glu Pro Asp Val Thr Val Leu Thr Ser Met Leu Thr 2165 2170 2175 Asp Pro Ser His Ile Thr Ala Glu Thr Ala Lys Arg Arg Leu Ala Arg 2180 2185 2190 Gly Ser Pro Pro Ser Leu Ala Ser Ser Ser Ala Ser Gln Leu Ser Ala 2195 2200 2205 Pro Ser Leu Lys Ala Thr Cys Thr Thr His His Asp Ser Pro Asp Ala 2210 2215 2220 Asp Leu Ile Glu Ala Asn Leu Leu Trp Arg Gln Glu Met Gly Gly Asn 2225 2230 2235 2240 Ile Thr Arg Val Glu Ser Glu Asn Lys Val Val Ile Leu Asp Ser Phe 2245 2250 2255 Glu Pro Leu His Ala Glu Gly Asp Glu Arg Glu Ile Ser Val Ala Ala 2260 2265 2270 Glu Ile Leu Arg Lys Ser Arg Lys Phe Pro Ser Ala Leu Pro Ile Trp 2275 2280 2285 Ala Arg Pro Asp Tyr Asn Pro Pro Leu Leu Glu Ser Trp Lys Asp Pro 2290 2295 2300 Asp Tyr Val Pro Pro Val Val His Gly Cys Pro Leu Pro Pro Thr Lys 2305 2310 2315 2320 Ala Pro Pro Ile Pro Pro Pro Arg Arg Lys Arg Thr Val Val Leu Thr 2325 2330 2335 Glu Ser Asn Val Ser Ser Ala Leu Ala Glu Leu Ala Thr Lys Thr Phe 2340 2345 2350 Gly Ser Ser Gly Ser Ser Ala Val Asp Ser Gly Thr Ala Thr Ala Leu 2355 2360 2365 Pro Asp Leu Ala Ser Asp Asp Gly Asp Lys Gly Ser Asp Val Glu Ser 2370 2375 2380 His Ser Ser Met Pro Pro Leu Glu Gly Glu Pro Gly Asp Pro Asp Leu 2385 2390 2395 2400 Ser Asp Gly Ser Trp Ser Thr Val Ser Glu Glu Ala Ser Glu Asp Val 2405 2410 2415 Val Cys Cys Ser Met Ser Tyr Thr Trp Thr Gly Ala Leu Ile Thr Pro 2420 2425 2430 Cys Ala Ala Glu Glu Ser Lys Leu Pro Ile Asn Pro Leu Ser Asn Ser 2435 2440 2445 Leu Leu Arg His His Asn Met Val Tyr Ala Thr Thr Ser Arg Ser Ala 2450 2455 2460 Ser Leu Arg Gln Lys Lys Val Thr Phe Asp Arg Leu Gln Val Leu Asp 2465 2470 2475 2480 Asp His Tyr Arg Asp Val Leu Lys Glu Met Lys Ala Lys Ala Ser Thr 2485 2490 2495 Val Lys Ala Lys Leu Leu Ser Ile Glu Glu Ala Cys Lys Leu Thr Pro 2500 2505 2510 Pro His Ser Ala Lys Ser Lys Phe Gly Tyr Gly Ala Lys Asp Val Arg 2515 2520 2525 Asn Leu Ser Ser Arg Ala Val Asn His Ile Arg Ser Val Trp Glu Asp 2530 2535 2540 Leu Leu Glu Asp Thr Glu Thr Pro Ile Asp Thr Thr Ile Met Ala Lys 2545 2550 2555 2560 Ser Glu Val Phe Cys Val Gln Pro Glu Lys Gly Gly Arg Lys Pro Ala 2565 2570 2575 Arg Leu Ile Val Phe Pro Asp Leu Gly Val Arg Val Cys Glu Lys Met 2580 2585

2590 Ala Leu Tyr Asp Val Val Ser Thr Leu Pro Gln Ala Val Met Gly Ser 2595 2600 2605 Ser Tyr Gly Phe Gln Tyr Ser Pro Lys Gln Arg Val Glu Phe Leu Val 2610 2615 2620 Asn Thr Trp Lys Ser Lys Lys Cys Pro Met Gly Phe Ser Tyr Asp Thr 2625 2630 2635 2640 Arg Cys Phe Asp Ser Thr Val Thr Glu Ser Asp Ile Arg Val Glu Glu 2645 2650 2655 Ser Ile Tyr Gln Cys Cys Asp Leu Ala Pro Glu Ala Arg Gln Ala Ile 2660 2665 2670 Arg Ser Leu Thr Glu Arg Leu Tyr Ile Gly Gly Pro Leu Thr Asn Ser 2675 2680 2685 Lys Gly Gln Asn Cys Gly Tyr Arg Arg Cys Arg Ala Ser Gly Val Leu 2690 2695 2700 Thr Thr Ser Cys Gly Asn Thr Leu Thr Cys Tyr Leu Lys Ala Thr Ala 2705 2710 2715 2720 Ala Cys Arg Ala Ala Lys Leu Gln Asp Cys Thr Met Leu Val Asn Gly 2725 2730 2735 Asp Asp Leu Val Val Ile Cys Glu Ser Ala Gly Thr Gln Glu Asp Ala 2740 2745 2750 Ala Ala Leu Arg Ala Phe Thr Glu Ala Met Thr Arg Tyr Ser Ala Pro 2755 2760 2765 Pro Gly Asp Pro Pro Gln Pro Glu Tyr Asp Leu Glu Leu Ile Thr Ser 2770 2775 2780 Cys Ser Ser Asn Val Ser Val Ala His Asp Ala Ser Gly Lys Arg Val 2785 2790 2795 2800 Tyr Tyr Leu Thr Arg Asp Pro Thr Thr Pro Leu Ala Arg Ala Ala Trp 2805 2810 2815 Glu Thr Ala Arg His Thr Pro Ile Asn Ser Trp Leu Gly Asn Ile Ile 2820 2825 2830 Met Tyr Ala Pro Thr Leu Trp Ala Arg Met Ile Leu Met Thr His Phe 2835 2840 2845 Phe Ser Ile Leu Leu Ala Gln Glu Gln Leu Glu Lys Ala Leu Asp Cys 2850 2855 2860 Gln Ile Tyr Gly Ala Cys Tyr Ser Ile Glu Pro Leu Asp Leu Pro Gln 2865 2870 2875 2880 Ile Ile Glu Arg Leu His Gly Leu Ser Ala Phe Thr Leu His Ser Tyr 2885 2890 2895 Ser Pro Gly Glu Ile Asn Arg Val Ala Ser Cys Leu Arg Lys Leu Gly 2900 2905 2910 Val Pro Pro Leu Arg Thr Trp Arg His Arg Ala Arg Ser Val Arg Ala 2915 2920 2925 Lys Leu Leu Ser Gln Gly Gly Arg Ala Ala Thr Cys Gly Arg Tyr Leu 2930 2935 2940 Phe Asn Trp Ala Val Arg Thr Lys Leu Lys Leu Thr Pro Ile Pro Ala 2945 2950 2955 2960 Ala Ser Gln Leu Asp Leu Ser Gly Trp Phe Val Ala Gly Tyr Ser Gly 2965 2970 2975 Gly Asp Ile Tyr His Ser Leu Ser Arg Ala Arg Pro Arg Trp Phe Pro 2980 2985 2990 Leu Cys Leu Leu Leu Leu Ser Val Gly Val Gly Ile Tyr Leu Leu Pro 2995 3000 3005 Asn Arg 3010

Claims

1.-37. (canceled)

38. A purified and isolated nucleic acid molecule which encodes human hepatitis C virus of genotype 2a, said molecule capable of expressing said virus when transfected into cells and further capable of infectivity in vivo, wherein said molecule encodes an amino acid sequence that differs from that of SEQ ID NO: 2 by <2.2% at the amino acid level.

39. The nucleic acid molecule of claim 38, wherein said molecule comprises a nucleic acid sequence that differs from that of SEQ ID NO: 1 from nucleotide 341 to 9439, which corresponds to the ORF, by <4.1% at the nucleotide level.

40. A DNA construct comprising a nucleic acid molecule according to claim 38.

41. A DNA construct comprising a nucleic acid molecule according to claim 39.

42. An RNA transcript of the DNA construct of claim 40.

43. An RNA transcript of the DNA construct of claim 41.

44. An in vitro cell transfected with the DNA construct of claim 40.

45. An in vitro cell transfected with the DNA construct of claim 41.

46. An in vitro cell transfected with the RNA transcript of claim 42.

47. An in vitro cell transfected with the RNA transcript of claim 43.

48. A composition comprising a nucleic acid molecule of claim 38 suspended in a suitable amount of a pharmaceutically acceptable diluent or excipient.

49. A composition comprising a nucleic acid molecule of claim 39 suspended in a suitable amount of a pharmaceutically acceptable diluent or excipient.