Abstract
Hepatitis C virus (HCV) infection was once considered a threat to life but is now curable. This miraculous achievement is the result of years of effort to understand basic HCV biology, which led to the development of HCV cell culture systems eventually enabling drug discovery. Initial studies focused on biochemical characterization of viral proteins and dissected their roles in the virus life cycle. Two of the viral proteins, NS3-4A protease and NS5B polymerase, were selected early on as potential drug targets, and subsequent collaborative efforts of academia and industry led to the development of highly effective inhibitors against these enzymes. Another HCV protein, NS5A that has no known enzymatic activity, was more recently identified as an unexpected target of a highly potent class of anti-HCV inhibitors. Various combinations of these protease, polymerase, and NS5A inhibitors now constitute the current anti-HCV regimens with cure rates of above 95%. This chapter is divided into two parts. The first part begins with a short introduction to HCV and its life cycle and reviews insights into biochemical and functional characteristics of HCV RNA elements and proteins. The second part discusses the HCV animal models and how their use yielded important insights into the viral life cycle, immunity, and disease pathogenesis.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Lohmann V et al (1999) Replication of subgenomic hepatitis C virus RNAs in a hepatoma cell line. Science 285:110–113
Wakita T et al (2005) Production of infectious hepatitis C virus in tissue culture from a cloned viral genome. Nat Med 11:791–796. https://doi.org/10.1038/nm1268
Lindenbach BD et al (2005) Complete replication of hepatitis C virus in cell culture. Science 309:623–626. https://doi.org/10.1126/science.1114016
Choo QL et al (1991) Genetic organization and diversity of the hepatitis C virus. Proc Natl Acad Sci U S A 88:2451–2455
Han JH et al (1991) Characterization of the terminal regions of hepatitis C viral RNA: identification of conserved sequences in the 5′ untranslated region and poly(A) tails at the 3′ end. Proc Natl Acad Sci U S A 88:1711–1715
Kolykhalov AA, Feinstone SM, Rice CM (1996) Identification of a highly conserved sequence element at the 3′ terminus of hepatitis C virus genome RNA. J Virol 70:3363–3371
Tanaka T, Kato N, Cho MJ, Sugiyama K, Shimotohno K (1996) Structure of the 3′ terminus of the hepatitis C virus genome. J Virol 70:3307–3312
Moradpour D, Penin F (2013) Hepatitis C virus proteins: from structure to function. Curr Top Microbiol Immunol 369:113–142. https://doi.org/10.1007/978-3-642-27340-7_5
Wang C, Sarnow P, Siddiqui A (1993) Translation of human hepatitis C virus RNA in cultured cells is mediated by an internal ribosome-binding mechanism. J Virol 67:3338–3344
Bradrick SS, Walters RW, Gromeier M (2006) The hepatitis C virus 3′-untranslated region or a poly(A) tract promote efficient translation subsequent to the initiation phase. Nucleic Acids Res 34:1293–1303. https://doi.org/10.1093/nar/gkl019
Bung C et al (2010) Influence of the hepatitis C virus 3′-untranslated region on IRES-dependent and cap-dependent translation initiation. FEBS Lett 584:837–842. https://doi.org/10.1016/j.febslet.2010.01.015
Song Y et al (2006) The hepatitis C virus RNA 3′-untranslated region strongly enhances translation directed by the internal ribosome entry site. J Virol 80:11579–11588. https://doi.org/10.1128/JVI.00675-06
Friebe P, Boudet J, Simorre JP, Bartenschlager R (2005) Kissing-loop interaction in the 3′ end of the hepatitis C virus genome essential for RNA replication. J Virol 79:380–392. https://doi.org/10.1128/JVI.79.1.380-392.2005
Pirakitikulr N, Kohlway A, Lindenbach BD, Pyle AM (2016) The coding region of the HCV genome contains a network of regulatory RNA structures. Mol Cell 62:111–120. https://doi.org/10.1016/j.molcel.2016.01.024
Hijikata M, Kato N, Ootsuyama Y, Nakagawa M, Shimotohno K (1991) Gene mapping of the putative structural region of the hepatitis C virus genome by in vitro processing analysis. Proc Natl Acad Sci U S A 88:5547–5551
Grakoui A, Wychowski C, Lin C, Feinstone SM, Rice CM (1993) Expression and identification of hepatitis C virus polyprotein cleavage products. J Virol 67:1385–1395
Barth H et al (2006) Viral and cellular determinants of the hepatitis C virus envelope-heparan sulfate interaction. J Virol 80:10579–10590. https://doi.org/10.1128/JVI.00941-06
Jiang J et al (2012) Hepatitis C virus attachment mediated by apolipoprotein E binding to cell surface heparan sulfate. J Virol 86:7256–7267. https://doi.org/10.1128/JVI.07222-11
Lindenbach BD, Rice CM (2013) The ins and outs of hepatitis C virus entry and assembly. Nat Rev Microbiol 11:688–700. https://doi.org/10.1038/nrmicro3098
Ding Q, von Schaewen M, Ploss A (2014) The impact of hepatitis C virus entry on viral tropism. Cell Host Microbe 16:562–568. https://doi.org/10.1016/j.chom.2014.10.009
Blanchard E et al (2006) Hepatitis C virus entry depends on clathrin-mediated endocytosis. J Virol 80:6964–6972. https://doi.org/10.1128/JVI.00024-06
Hsu M et al (2003) Hepatitis C virus glycoproteins mediate pH-dependent cell entry of pseudotyped retroviral particles. Proc Natl Acad Sci U S A 100:7271–7276. https://doi.org/10.1073/pnas.0832180100
Meertens L, Bertaux C, Dragic T (2006) Hepatitis C virus entry requires a critical postinternalization step and delivery to early endosomes via clathrin-coated vesicles. J Virol 80:11571–11578. https://doi.org/10.1128/JVI.01717-06
Lohmann V (2013) Hepatitis C virus RNA replication. Curr Top Microbiol Immunol 369:167–198. https://doi.org/10.1007/978-3-642-27340-7_7
Murray CL, Jones CT, Rice CM (2008) Architects of assembly: roles of Flaviviridae non-structural proteins in virion morphogenesis. Nat Rev Microbiol 6:699–708. https://doi.org/10.1038/nrmicro1928
Paul D, Madan V, Bartenschlager R (2014) Hepatitis C virus RNA replication and assembly: living on the fat of the land. Cell Host Microbe 16:569–579. https://doi.org/10.1016/j.chom.2014.10.008
Miyanari Y et al (2007) The lipid droplet is an important organelle for hepatitis C virus production. Nat Cell Biol 9:1089–1097. https://doi.org/10.1038/ncb1631
Bartenschlager R, Penin F, Lohmann V, Andre P (2011) Assembly of infectious hepatitis C virus particles. Trends Microbiol 19:95–103. https://doi.org/10.1016/j.tim.2010.11.005
Gastaminza P et al (2008) Cellular determinants of hepatitis C virus assembly, maturation, degradation, and secretion. J Virol 82:2120–2129. https://doi.org/10.1128/JVI.02053-07
Vieyres G et al (2010) Characterization of the envelope glycoproteins associated with infectious hepatitis C virus. J Virol 84:10159–10168. https://doi.org/10.1128/JVI.01180-10
Wozniak AL et al (2010) Intracellular proton conductance of the hepatitis C virus p7 protein and its contribution to infectious virus production. PLoS Pathog 6:e1001087. https://doi.org/10.1371/journal.ppat.1001087
Gastaminza P, Kapadia SB, Chisari FV (2006) Differential biophysical properties of infectious intracellular and secreted hepatitis C virus particles. J Virol 80:11074–11081. https://doi.org/10.1128/JVI.01150-06
Bradley D et al (1991) Hepatitis C virus: buoyant density of the factor VIII-derived isolate in sucrose. J Med Virol 34:206–208
Hijikata M et al (1993) Equilibrium centrifugation studies of hepatitis C virus: evidence for circulating immune complexes. J Virol 67:1953–1958
Cai Z et al (2005) Robust production of infectious hepatitis C virus (HCV) from stably HCV cDNA-transfected human hepatoma cells. J Virol 79:13963–13973. https://doi.org/10.1128/JVI.79.22.13963-13973.2005
Aizaki H et al (2008) Critical role of virion-associated cholesterol and sphingolipid in hepatitis C virus infection. J Virol 82:5715–5724. https://doi.org/10.1128/JVI.02530-07
Merz A et al (2011) Biochemical and morphological properties of hepatitis C virus particles and determination of their lipidome. J Biol Chem 286:3018–3032. https://doi.org/10.1074/jbc.M110.175018
Friebe P, Lohmann V, Krieger N, Bartenschlager R (2001) Sequences in the 5′ nontranslated region of hepatitis C virus required for RNA replication. J Virol 75:12047–12057. https://doi.org/10.1128/JVI.75.24.12047-12057.2001
Wang C, Le SY, Ali N, Siddiqui A (1995) An RNA pseudoknot is an essential structural element of the internal ribosome entry site located within the hepatitis C virus 5′ noncoding region. RNA 1:526–537
Pestova TV, Shatsky IN, Fletcher SP, Jackson RJ, Hellen CU (1998) A prokaryotic-like mode of cytoplasmic eukaryotic ribosome binding to the initiation codon during internal translation initiation of hepatitis C and classical swine fever virus RNAs. Genes Dev 12:67–83
Berry KE, Waghray S, Mortimer SA, Bai Y, Doudna JA (2011) Crystal structure of the HCV IRES central domain reveals strategy for start-codon positioning. Structure 19:1456–1466. https://doi.org/10.1016/j.str.2011.08.002
Ji H, Fraser CS, Yu Y, Leary J, Doudna JA (2004) Coordinated assembly of human translation initiation complexes by the hepatitis C virus internal ribosome entry site RNA. Proc Natl Acad Sci U S A 101:16990–16995. https://doi.org/10.1073/pnas.0407402101
Locker N, Easton LE, Lukavsky PJ (2007) HCV and CSFV IRES domain II mediate eIF2 release during 80S ribosome assembly. EMBO J 26:795–805. https://doi.org/10.1038/sj.emboj.7601549
Pestova TV, de Breyne S, Pisarev AV, Abaeva IS, Hellen CU (2008) eIF2-dependent and eIF2-independent modes of initiation on the CSFV IRES: a common role of domain II. EMBO J 27:1060–1072. https://doi.org/10.1038/emboj.2008.49
Jopling CL, Yi M, Lancaster AM, Lemon SM, Sarnow P (2005) Modulation of hepatitis C virus RNA abundance by a liver-specific MicroRNA. Science 309:1577–1581. https://doi.org/10.1126/science.1113329
Jopling CL, Schutz S, Sarnow P (2008) Position-dependent function for a tandem microRNA miR-122-binding site located in the hepatitis C virus RNA genome. Cell Host Microbe 4:77–85. https://doi.org/10.1016/j.chom.2008.05.013
Li Y, Masaki T, Yamane D, McGivern DR, Lemon SM (2013) Competing and noncompeting activities of miR-122 and the 5′ exonuclease Xrn1 in regulation of hepatitis C virus replication. Proc Natl Acad Sci U S A 110:1881–1886. https://doi.org/10.1073/pnas.1213515110
Li Y, Yamane D, Lemon SM (2015) Dissecting the roles of the 5′ exoribonucleases Xrn1 and Xrn2 in restricting hepatitis C virus replication. J Virol 89:4857–4865. https://doi.org/10.1128/JVI.03692-14
Sedano CD, Sarnow P (2014) Hepatitis C virus subverts liver-specific miR-122 to protect the viral genome from exoribonuclease Xrn2. Cell Host Microbe 16:257–264. https://doi.org/10.1016/j.chom.2014.07.006
Henke JI et al (2008) microRNA-122 stimulates translation of hepatitis C virus RNA. EMBO J 27:3300–3310. https://doi.org/10.1038/emboj.2008.244
Jangra RK, Yi M, Lemon SM (2010) Regulation of hepatitis C virus translation and infectious virus production by the microRNA miR-122. J Virol 84:6615–6625. https://doi.org/10.1128/JVI.00417-10
Masaki T et al (2015) miR-122 stimulates hepatitis C virus RNA synthesis by altering the balance of viral RNAs engaged in replication versus translation. Cell Host Microbe 17:217–228. https://doi.org/10.1016/j.chom.2014.12.014
Luna JM et al (2015) Hepatitis C virus RNA functionally sequesters miR-122. Cell 160:1099–1110. https://doi.org/10.1016/j.cell.2015.02.025
Janssen HL et al (2013) Treatment of HCV infection by targeting microRNA. N Engl J Med 368:1685–1694. https://doi.org/10.1056/NEJMoa1209026
Tanaka T, Kato N, Cho MJ, Shimotohno K (1995) A novel sequence found at the 3′ terminus of hepatitis C virus genome. Biochem Biophys Res Commun 215:744–749. https://doi.org/10.1006/bbrc.1995.2526
Friebe P, Bartenschlager R (2002) Genetic analysis of sequences in the 3′ nontranslated region of hepatitis C virus that are important for RNA replication. J Virol 76:5326–5338
Yi M, Lemon SM (2003) 3′ nontranslated RNA signals required for replication of hepatitis C virus RNA. J Virol 77:3557–3568
You S, Rice CM (2008) 3’ RNA elements in hepatitis C virus replication: kissing partners and long poly(U). J Virol 82:184–195. https://doi.org/10.1128/JVI.01796-07
Gwack Y, Kim DW, Han JH, Choe J (1996) Characterization of RNA binding activity and RNA helicase activity of the hepatitis C virus NS3 protein. Biochem Biophys Res Commun 225:654–659. https://doi.org/10.1006/bbrc.1996.1225
Huang L et al (2005) Hepatitis C virus nonstructural protein 5A (NS5A) is an RNA-binding protein. J Biol Chem 280:36417–36428. https://doi.org/10.1074/jbc.M508175200
Lohmann V, Korner F, Herian U, Bartenschlager R (1997) Biochemical properties of hepatitis C virus NS5B RNA-dependent RNA polymerase and identification of amino acid sequence motifs essential for enzymatic activity. J Virol 71:8416–8428
Blight KJ, Rice CM (1997) Secondary structure determination of the conserved 98-base sequence at the 3′ terminus of hepatitis C virus genome RNA. J Virol 71:7345–7352
Yi M, Lemon SM (2003) Structure-function analysis of the 3′ stem-loop of hepatitis C virus genomic RNA and its role in viral RNA replication. RNA 9:331–345
Isken O et al (2003) Members of the NF90/NFAR protein group are involved in the life cycle of a positive-strand RNA virus. EMBO J 22:5655–5665. https://doi.org/10.1093/emboj/cdg562
Weinlich S et al (2009) IGF2BP1 enhances HCV IRES-mediated translation initiation via the 3’UTR. RNA 15:1528–1542. https://doi.org/10.1261/rna.1578409
Santolini E, Migliaccio G, La Monica N (1994) Biosynthesis and biochemical properties of the hepatitis C virus core protein. J Virol 68:3631–3641
McLauchlan J, Lemberg MK, Hope G, Martoglio B (2002) Intramembrane proteolysis promotes trafficking of hepatitis C virus core protein to lipid droplets. EMBO J 21:3980–3988. https://doi.org/10.1093/emboj/cdf414
Oehler V et al (2012) Structural analysis of hepatitis C virus core-E1 signal peptide and requirements for cleavage of the genotype 3a signal sequence by signal peptide peptidase. J Virol 86:7818–7828. https://doi.org/10.1128/JVI.00457-12
Okamoto K et al (2008) Intramembrane processing by signal peptide peptidase regulates the membrane localization of hepatitis C virus core protein and viral propagation. J Virol 82:8349–8361. https://doi.org/10.1128/JVI.00306-08
Kopp M, Murray CL, Jones CT, Rice CM (2010) Genetic analysis of the carboxy-terminal region of the hepatitis C virus core protein. J Virol 84:1666–1673. https://doi.org/10.1128/JVI.02043-09
Lussignol M et al (2016) Proteomics of HCV virions reveals an essential role for the nucleoporin Nup98 in virus morphogenesis. Proc Natl Acad Sci U S A 113:2484–2489. https://doi.org/10.1073/pnas.1518934113
Boulant S, Vanbelle C, Ebel C, Penin F, Lavergne JP (2005) Hepatitis C virus core protein is a dimeric alpha-helical protein exhibiting membrane protein features. J Virol 79:11353–11365. https://doi.org/10.1128/JVI.79.17.11353-11365.2005
Boulant S et al (2006) Structural determinants that target the hepatitis C virus core protein to lipid droplets. J Biol Chem 281:22236–22247. https://doi.org/10.1074/jbc.M601031200
Cristofari G et al (2004) The hepatitis C virus Core protein is a potent nucleic acid chaperone that directs dimerization of the viral (+) strand RNA in vitro. Nucleic Acids Res 32:2623–2631. https://doi.org/10.1093/nar/gkh579
Eng FJ et al (2009) Internal initiation stimulates production of p8 minicore, a member of a newly discovered family of hepatitis C virus core protein isoforms. J Virol 83:3104–3114. https://doi.org/10.1128/JVI.01679-08
Eng FJ et al (2018) Newly discovered hepatitis C virus minicores circulate in human blood. Hepatol Commun 2:21–28. https://doi.org/10.1002/hep4.1125
Branch AD, Stump DD, Gutierrez JA, Eng F, Walewski JL (2005) The hepatitis C virus alternate reading frame (ARF) and its family of novel products: the alternate reading frame protein/F-protein, the double-frameshift protein, and others. Semin Liver Dis 25:105–117. https://doi.org/10.1055/s-2005-864786
Cocquerel L et al (2002) Topological changes in the transmembrane domains of hepatitis C virus envelope glycoproteins. EMBO J 21:2893–2902. https://doi.org/10.1093/emboj/cdf295
Voisset C, Dubuisson J (2004) Functional hepatitis C virus envelope glycoproteins. Biol Cell 96:413–420. https://doi.org/10.1016/j.biolcel.2004.03.008
Khan AG et al (2014) Structure of the core ectodomain of the hepatitis C virus envelope glycoprotein 2. Nature 509:381–384. https://doi.org/10.1038/nature13117
Kong L et al (2013) Hepatitis C virus E2 envelope glycoprotein core structure. Science 342:1090–1094. https://doi.org/10.1126/science.1243876
Krey T et al (2010) The disulfide bonds in glycoprotein E2 of hepatitis C virus reveal the tertiary organization of the molecule. PLoS Pathog 6:e1000762. https://doi.org/10.1371/journal.ppat.1000762
Choukhi A, Ung S, Wychowski C, Dubuisson J (1998) Involvement of endoplasmic reticulum chaperones in the folding of hepatitis C virus glycoproteins. J Virol 72:3851–3858
Goffard A et al (2005) Role of N-linked glycans in the functions of hepatitis C virus envelope glycoproteins. J Virol 79:8400–8409. https://doi.org/10.1128/JVI.79.13.8400-8409.2005
Helle F, Duverlie G, Dubuisson J (2011) The hepatitis C virus glycan shield and evasion of the humoral immune response. Viruses 3:1909–1932. https://doi.org/10.3390/v3101909
Smit JM, Moesker B, Rodenhuis-Zybert I, Wilschut J (2011) Flavivirus cell entry and membrane fusion. Viruses 3:160–171. https://doi.org/10.3390/v3020160
Khan AG, Miller MT, Marcotrigiano J (2015) HCV glycoprotein structures: what to expect from the unexpected. Curr Opin Virol 12:53–58. https://doi.org/10.1016/j.coviro.2015.02.004
El Omari K et al (2014) Unexpected structure for the N-terminal domain of hepatitis C virus envelope glycoprotein E1. Nat Commun 5:4874. https://doi.org/10.1038/ncomms5874
Weiner AJ et al (1992) Evidence for immune selection of hepatitis C virus (HCV) putative envelope glycoprotein variants: potential role in chronic HCV infections. Proc Natl Acad Sci U S A 89:3468–3472
Farci P et al (1996) Prevention of hepatitis C virus infection in chimpanzees by hyperimmune serum against the hypervariable region 1 of the envelope 2 protein. Proc Natl Acad Sci U S A 93:15394–15399
Carrere-Kremer S et al (2002) Subcellular localization and topology of the p7 polypeptide of hepatitis C virus. J Virol 76:3720–3730
Griffin SD et al (2003) The p7 protein of hepatitis C virus forms an ion channel that is blocked by the antiviral drug, amantadine. FEBS Lett 535:34–38
Luik P et al (2009) The 3-dimensional structure of a hepatitis C virus p7 ion channel by electron microscopy. Proc Natl Acad Sci U S A 106:12712–12716. https://doi.org/10.1073/pnas.0905966106
Montserret R et al (2010) NMR structure and ion channel activity of the p7 protein from hepatitis C virus. J Biol Chem 285:31446–31461. https://doi.org/10.1074/jbc.M110.122895
Chandler DE, Penin F, Schulten K, Chipot C (2012) The p7 protein of hepatitis C virus forms structurally plastic, minimalist ion channels. PLoS Comput Biol 8:e1002702. https://doi.org/10.1371/journal.pcbi.1002702
Steinmann E, Pietschmann T (2010) Hepatitis C virus p7-a viroporin crucial for virus assembly and an emerging target for antiviral therapy. Viruses 2:2078–2095. https://doi.org/10.3390/v2092078
Grakoui A, McCourt DW, Wychowski C, Feinstone SM, Rice CM (1993) A second hepatitis C virus-encoded proteinase. Proc Natl Acad Sci U S A 90:10583–10587
Schregel V, Jacobi S, Penin F, Tautz N (2009) Hepatitis C virus NS2 is a protease stimulated by cofactor domains in NS3. Proc Natl Acad Sci U S A 106:5342–5347. https://doi.org/10.1073/pnas.0810950106
Kolykhalov AA, Mihalik K, Feinstone SM, Rice CM (2000) Hepatitis C virus-encoded enzymatic activities and conserved RNA elements in the 3′ nontranslated region are essential for virus replication in vivo. J Virol 74:2046–2051
Pallaoro M et al (2001) Characterization of the hepatitis C virus NS2/3 processing reaction by using a purified precursor protein. J Virol 75:9939–9946. https://doi.org/10.1128/JVI.75.20.9939-9946.2001
Lorenz IC, Marcotrigiano J, Dentzer TG, Rice CM (2006) Structure of the catalytic domain of the hepatitis C virus NS2-3 protease. Nature 442:831–835. https://doi.org/10.1038/nature04975
Hijikata M et al (1993) Two distinct proteinase activities required for the processing of a putative nonstructural precursor protein of hepatitis C virus. J Virol 67:4665–4675
Santolini E, Pacini L, Fipaldini C, Migliaccio G, Monica N (1995) The NS2 protein of hepatitis C virus is a transmembrane polypeptide. J Virol 69:7461–7471
Jirasko V et al (2008) Structural and functional characterization of nonstructural protein 2 for its role in hepatitis C virus assembly. J Biol Chem 283:28546–28562. https://doi.org/10.1074/jbc.M803981200
Jirasko V et al (2010) Structural and functional studies of nonstructural protein 2 of the hepatitis C virus reveal its key role as organizer of virion assembly. PLoS Pathog 6:e1001233. https://doi.org/10.1371/journal.ppat.1001233
Phan T, Beran RK, Peters C, Lorenz IC, Lindenbach BD (2009) Hepatitis C virus NS2 protein contributes to virus particle assembly via opposing epistatic interactions with the E1-E2 glycoprotein and NS3-NS4A enzyme complexes. J Virol 83:8379–8395. https://doi.org/10.1128/JVI.00891-09
Stapleford KA, Lindenbach BD (2011) Hepatitis C virus NS2 coordinates virus particle assembly through physical interactions with the E1-E2 glycoprotein and NS3-NS4A enzyme complexes. J Virol 85:1706–1717. https://doi.org/10.1128/JVI.02268-10
Yi M, Ma Y, Yates J, Lemon SM (2009) Trans-complementation of an NS2 defect in a late step in hepatitis C virus (HCV) particle assembly and maturation. PLoS Pathog 5:e1000403. https://doi.org/10.1371/journal.ppat.1000403
de la Fuente C, Goodman Z, Rice CM (2013) Genetic and functional characterization of the N-terminal region of the hepatitis C virus NS2 protein. J Virol 87:4130–4145. https://doi.org/10.1128/JVI.03174-12
Boson B, Granio O, Bartenschlager R, Cosset FL (2011) A concerted action of hepatitis C virus p7 and nonstructural protein 2 regulates core localization at the endoplasmic reticulum and virus assembly. PLoS Pathog 7:e1002144. https://doi.org/10.1371/journal.ppat.1002144
Popescu CI et al (2011) NS2 protein of hepatitis C virus interacts with structural and non-structural proteins towards virus assembly. PLoS Pathog 7:e1001278. https://doi.org/10.1371/journal.ppat.1001278
De Francesco R, Steinkuhler C (2000) Structure and function of the hepatitis C virus NS3-NS4A serine proteinase. Curr Top Microbiol Immunol 242:149–169
Grakoui A, McCourt DW, Wychowski C, Feinstone SM, Rice CM (1993) Characterization of the hepatitis C virus-encoded serine proteinase: determination of proteinase-dependent polyprotein cleavage sites. J Virol 67:2832–2843
Pietschmann T, Lohmann V, Rutter G, Kurpanek K, Bartenschlager R (2001) Characterization of cell lines carrying self-replicating hepatitis C virus RNAs. J Virol 75:1252–1264. https://doi.org/10.1128/JVI.75.3.1252-1264.2001
Herod MR, Jones DM, McLauchlan J, McCormick CJ (2012) Increasing rate of cleavage at boundary between non-structural proteins 4B and 5A inhibits replication of hepatitis C virus. J Biol Chem 287:568–580. https://doi.org/10.1074/jbc.M111.311407
Brass V et al (2008) Structural determinants for membrane association and dynamic organization of the hepatitis C virus NS3-4A complex. Proc Natl Acad Sci U S A 105:14545–14550. https://doi.org/10.1073/pnas.0807298105
Raney KD, Sharma SD, Moustafa IM, Cameron CE (2010) Hepatitis C virus non-structural protein 3 (HCV NS3): a multifunctional antiviral target. J Biol Chem 285:22725–22731. https://doi.org/10.1074/jbc.R110.125294
Lindenbach BD et al (2007) The C terminus of hepatitis C virus NS4A encodes an electrostatic switch that regulates NS5A hyperphosphorylation and viral replication. J Virol 81:8905–8918. https://doi.org/10.1128/JVI.00937-07
Phan T, Kohlway A, Dimberu P, Pyle AM, Lindenbach BD (2011) The acidic domain of hepatitis C virus NS4A contributes to RNA replication and virus particle assembly. J Virol 85:1193–1204. https://doi.org/10.1128/JVI.01889-10
Morikawa K et al (2011) Nonstructural protein 3-4A: the Swiss army knife of hepatitis C virus. J Viral Hepat 18:305–315. https://doi.org/10.1111/j.1365-2893.2011.01451.x
Gu M, Rice CM (2010) Three conformational snapshots of the hepatitis C virus NS3 helicase reveal a ratchet translocation mechanism. Proc Natl Acad Sci U S A 107:521–528. https://doi.org/10.1073/pnas.0913380107
Levin MK, Patel SS (2002) Helicase from hepatitis C virus, energetics of DNA binding. J Biol Chem 277:29377–29385. https://doi.org/10.1074/jbc.M112315200
Porter DJ et al (1998) Product release is the major contributor to kcat for the hepatitis C virus helicase-catalyzed strand separation of short duplex DNA. J Biol Chem 273:18906–18914
Kim JL et al (1998) Hepatitis C virus NS3 RNA helicase domain with a bound oligonucleotide: the crystal structure provides insights into the mode of unwinding. Structure 6:89–100
Gouttenoire J, Roingeard P, Penin F, Moradpour D (2010) Amphipathic alpha-helix AH2 is a major determinant for the oligomerization of hepatitis C virus nonstructural protein 4B. J Virol 84:12529–12537. https://doi.org/10.1128/JVI.01798-10
Paul D et al (2011) NS4B self-interaction through conserved C-terminal elements is required for the establishment of functional hepatitis C virus replication complexes. J Virol 85:6963–6976. https://doi.org/10.1128/JVI.00502-11
Egger D et al (2002) Expression of hepatitis C virus proteins induces distinct membrane alterations including a candidate viral replication complex. J Virol 76:5974–5984
Gosert R et al (2003) Identification of the hepatitis C virus RNA replication complex in Huh-7 cells harboring subgenomic replicons. J Virol 77:5487–5492
Einav S et al (2008) Discovery of a hepatitis C target and its pharmacological inhibitors by microfluidic affinity analysis. Nat Biotechnol 26:1019–1027. https://doi.org/10.1038/nbt.1490
Einav S, Elazar M, Danieli T, Glenn JS (2004) A nucleotide binding motif in hepatitis C virus (HCV) NS4B mediates HCV RNA replication. J Virol 78:11288–11295. https://doi.org/10.1128/JVI.78.20.11288-11295.2004
Thompson AA et al (2009) Biochemical characterization of recombinant hepatitis C virus nonstructural protein 4B: evidence for ATP/GTP hydrolysis and adenylate kinase activity. Biochemistry 48:906–916. https://doi.org/10.1021/bi801747p
Gouttenoire J, Penin F, Moradpour D (2010) Hepatitis C virus nonstructural protein 4B: a journey into unexplored territory. Rev Med Virol 20:117–129. https://doi.org/10.1002/rmv.640
Yu GY, Lee KJ, Gao L, Lai MM (2006) Palmitoylation and polymerization of hepatitis C virus NS4B protein. J Virol 80:6013–6023. https://doi.org/10.1128/JVI.00053-06
Paul D et al (2018) Glycine zipper motifs in hepatitis C virus nonstructural protein 4B are required for the establishment of viral replication organelles. J Virol 92. https://doi.org/10.1128/JVI.01890-17
Wang Z, Chen X, Wu C, Xu H, Liu H (2016) Current drug discovery for anti-hepatitis C virus targeting NS4B. Curr Top Med Chem 16:1362–1371
Ross-Thriepland D, Harris M (2015) Hepatitis C virus NS5A: enigmatic but still promiscuous 10 years on! J Gen Virol 96:727–738. https://doi.org/10.1099/jgv.0.000009
Tellinghuisen TL, Marcotrigiano J, Gorbalenya AE, Rice CM (2004) The NS5A protein of hepatitis C virus is a zinc metalloprotein. J Biol Chem 279:48576–48587. https://doi.org/10.1074/jbc.M407787200
Tellinghuisen TL, Marcotrigiano J, Rice CM (2005) Structure of the zinc-binding domain of an essential component of the hepatitis C virus replicase. Nature 435:374–379. https://doi.org/10.1038/nature03580
Liang Y, Ye H, Kang CB, Yoon HS (2007) Domain 2 of nonstructural protein 5A (NS5A) of hepatitis C virus is natively unfolded. Biochemistry 46:11550–11558. https://doi.org/10.1021/bi700776e
Verdegem D et al (2011) Domain 3 of NS5A protein from the hepatitis C virus has intrinsic alpha-helical propensity and is a substrate of cyclophilin A. J Biol Chem 286:20441–20454. https://doi.org/10.1074/jbc.M110.182436
Appel N et al (2008) Essential role of domain III of nonstructural protein 5A for hepatitis C virus infectious particle assembly. PLoS Pathog 4:e1000035. https://doi.org/10.1371/journal.ppat.1000035
Moradpour D et al (2004) Insertion of green fluorescent protein into nonstructural protein 5A allows direct visualization of functional hepatitis C virus replication complexes. J Virol 78:7400–7409. https://doi.org/10.1128/JVI.78.14.7400-7409.2004
Schaller T et al (2007) Analysis of hepatitis C virus superinfection exclusion by using novel fluorochrome gene-tagged viral genomes. J Virol 81:4591–4603. https://doi.org/10.1128/JVI.02144-06
Neddermann P, Clementi A, De Francesco R (1999) Hyperphosphorylation of the hepatitis C virus NS5A protein requires an active NS3 protease, NS4A, NS4B, and NS5A encoded on the same polyprotein. J Virol 73:9984–9991
Appel N, Pietschmann T, Bartenschlager R (2005) Mutational analysis of hepatitis C virus nonstructural protein 5A: potential role of differential phosphorylation in RNA replication and identification of a genetically flexible domain. J Virol 79:3187–3194. https://doi.org/10.1128/JVI.79.5.3187-3194.2005
Evans MJ, Rice CM, Goff SP (2004) Phosphorylation of hepatitis C virus nonstructural protein 5A modulates its protein interactions and viral RNA replication. Proc Natl Acad Sci U S A 101:13038–13043. https://doi.org/10.1073/pnas.0405152101
Neddermann P et al (2004) Reduction of hepatitis C virus NS5A hyperphosphorylation by selective inhibition of cellular kinases activates viral RNA replication in cell culture. J Virol 78:13306–13314. https://doi.org/10.1128/JVI.78.23.13306-13314.2004
Bukh J et al (2002) Mutations that permit efficient replication of hepatitis C virus RNA in Huh-7 cells prevent productive replication in chimpanzees. Proc Natl Acad Sci U S A 99:14416–14421. https://doi.org/10.1073/pnas.212532699
Masaki T et al (2014) Involvement of hepatitis C virus NS5A hyperphosphorylation mediated by casein kinase I-alpha in infectious virus production. J Virol 88:7541–7555. https://doi.org/10.1128/JVI.03170-13
Fridell RA et al (2013) Intragenic complementation of hepatitis C virus NS5A RNA replication-defective alleles. J Virol 87:2320–2329. https://doi.org/10.1128/JVI.02861-12
McGivern DR et al (2014) Kinetic analyses reveal potent and early blockade of hepatitis C virus assembly by NS5A inhibitors. Gastroenterology 147:453–462.e457. https://doi.org/10.1053/j.gastro.2014.04.021
Biswas A, Treadaway J, Tellinghuisen TL (2016) Interaction between nonstructural proteins NS4B and NS5A is essential for proper NS5A localization and hepatitis C virus RNA replication. J Virol 90:7205–7218. https://doi.org/10.1128/JVI.00037-16
Gao L, Aizaki H, He JW, Lai MM (2004) Interactions between viral nonstructural proteins and host protein hVAP-33 mediate the formation of hepatitis C virus RNA replication complex on lipid raft. J Virol 78:3480–3488
Wang C et al (2005) Identification of FBL2 as a geranylgeranylated cellular protein required for hepatitis C virus RNA replication. Mol Cell 18:425–434. https://doi.org/10.1016/j.molcel.2005.04.004
Reiss S et al (2011) Recruitment and activation of a lipid kinase by hepatitis C virus NS5A is essential for integrity of the membranous replication compartment. Cell Host Microbe 9:32–45. https://doi.org/10.1016/j.chom.2010.12.002
Liu Z, Yang F, Robotham JM, Tang H (2009) Critical role of cyclophilin A and its prolyl-peptidyl isomerase activity in the structure and function of the hepatitis C virus replication complex. J Virol 83:6554–6565. https://doi.org/10.1128/JVI.02550-08
Gao M et al (2010) Chemical genetics strategy identifies an HCV NS5A inhibitor with a potent clinical effect. Nature 465:96–100. https://doi.org/10.1038/nature08960
Nakamoto S, Kanda T, Wu S, Shirasawa H, Yokosuka O (2014) Hepatitis C virus NS5A inhibitors and drug resistance mutations. World J Gastroenterol 20:2902–2912. https://doi.org/10.3748/wjg.v20.i11.2902
Behrens SE, Tomei L, De Francesco R (1996) Identification and properties of the RNA-dependent RNA polymerase of hepatitis C virus. EMBO J 15:12–22
Simister P et al (2009) Structural and functional analysis of hepatitis C virus strain JFH1 polymerase. J Virol 83:11926–11939. https://doi.org/10.1128/JVI.01008-09
Moradpour D et al (2004) Membrane association of the RNA-dependent RNA polymerase is essential for hepatitis C virus RNA replication. J Virol 78:13278–13284. https://doi.org/10.1128/JVI.78.23.13278-13284.2004
Yamashita T et al (1998) RNA-dependent RNA polymerase activity of the soluble recombinant hepatitis C virus NS5B protein truncated at the C-terminal region. J Biol Chem 273:15479–15486
Ranjith-Kumar CT et al (2002) Mechanism of de novo initiation by the hepatitis C virus RNA-dependent RNA polymerase: role of divalent metals. J Virol 76:12513–12525
Ago H et al (1999) Crystal structure of the RNA-dependent RNA polymerase of hepatitis C virus. Structure 7:1417–1426
Bressanelli S et al (1999) Crystal structure of the RNA-dependent RNA polymerase of hepatitis C virus. Proc Natl Acad Sci U S A 96:13034–13039
Lesburg CA et al (1999) Crystal structure of the RNA-dependent RNA polymerase from hepatitis C virus reveals a fully encircled active site. Nat Struct Biol 6:937–943. https://doi.org/10.1038/13305
Appleby TC et al (2015) Viral replication. Structural basis for RNA replication by the hepatitis C virus polymerase. Science 347:771–775. https://doi.org/10.1126/science.1259210
Hong Z et al (2001) A novel mechanism to ensure terminal initiation by hepatitis C virus NS5B polymerase. Virology 285:6–11. https://doi.org/10.1006/viro.2001.0948
Kim SJ, Kim JH, Kim YG, Lim HS, Oh JW (2004) Protein kinase C-related kinase 2 regulates hepatitis C virus RNA polymerase function by phosphorylation. J Biol Chem 279:50031–50041. https://doi.org/10.1074/jbc.M408617200
Piccininni S et al (2002) Modulation of the hepatitis C virus RNA-dependent RNA polymerase activity by the non-structural (NS) 3 helicase and the NS4B membrane protein. J Biol Chem 277:45670–45679. https://doi.org/10.1074/jbc.M204124200
Shirota Y et al (2002) Hepatitis C virus (HCV) NS5A binds RNA-dependent RNA polymerase (RdRP) NS5B and modulates RNA-dependent RNA polymerase activity. J Biol Chem 277:11149–11155. https://doi.org/10.1074/jbc.M111392200
Patil VM, Gupta SP, Samanta S, Masand N (2011) Current perspective of HCV NS5B inhibitors: a review. Curr Med Chem 18:5564–5597
Choo QL et al (1989) Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome. Science 244:359–362
Blight KJ, Kolykhalov AA, Rice CM (2000) Efficient initiation of HCV RNA replication in cell culture. Science 290:1972–1974
Vilarinho S, Lifton RP (2016) Pioneering a global cure for chronic hepatitis C virus infection. Cell 167:12–15. https://doi.org/10.1016/j.cell.2016.08.038
Shin EC, Sung PS, Park SH (2016) Immune responses and immunopathology in acute and chronic viral hepatitis. Nat Rev Immunol 16:509–523. https://doi.org/10.1038/nri.2016.69
Bukh J (2004) A critical role for the chimpanzee model in the study of hepatitis C. Hepatology 39:1469–1475. https://doi.org/10.1002/hep.20268
Lanford RE, Walker CM, Lemon SM (2017) The Chimpanzee model of viral hepatitis: advances in understanding the immune response and treatment of viral hepatitis. ILAR J 58:172–189. https://doi.org/10.1093/ilar/ilx028
Abe K, Kurata T, Teramoto Y, Shiga J, Shikata T (1993) Lack of susceptibility of various primates and woodchucks to hepatitis C virus. J Med Primatol 22:433–434
Sithebe NP et al (2002) Lack of susceptibility of Chacma baboons (Papio ursinus orientalis) to hepatitis C virus infection. J Med Virol 66:468–471. https://doi.org/10.1002/jmv.2167
Garson JA, Whitby K, Watkins P, Morgan AJ (1997) Lack of susceptibility of the cottontop tamarin to hepatitis C infection. J Med Virol 52:286–288. https://doi.org/10.1002/(SICI)1096-9071(199707)52:3<286::AID-JMV9>3.0.CO;2-Z
Xie ZC et al (1998) Transmission of hepatitis C virus infection to tree shrews. Virology 244:513–520. https://doi.org/10.1006/viro.1998.9127
Billerbeck E, de Jong Y, Dorner M, de la Fuente C, Ploss A (2013) Animal models for hepatitis C. Curr Top Microbiol Immunol 369:49–86. https://doi.org/10.1007/978-3-642-27340-7_3
Hartlage AS, Cullen JM, Kapoor A (2016) The strange, expanding world of animal hepaciviruses. Ann Rev Virol 3:53–75. https://doi.org/10.1146/annurev-virology-100114-055104
Alter HJ, Purcell RH, Holland PV, Popper H (1978) Transmissible agent in non-A, non-B hepatitis. Lancet 1:459–463
Hollinger FB et al (1978) Non-A, non-B hepatitis transmission in chimpanzees: a project of the transfusion-transmitted viruses study group. Intervirology 10:60–68
Tabor E et al (1978) Transmission of non-A, non-B hepatitis from man to chimpanzee. Lancet 1:463–466
Kolykhalov AA et al (1997) Transmission of hepatitis C by intrahepatic inoculation with transcribed RNA. Science 277:570–574
Lindenbach BD et al (2006) Cell culture-grown hepatitis C virus is infectious in vivo and can be recultured in vitro. Proc Natl Acad Sci U S A 103:3805–3809. https://doi.org/10.1073/pnas.0511218103
Cooper S et al (1999) Analysis of a successful immune response against hepatitis C virus. Immunity 10:439–449
Major ME et al (2004) Hepatitis C virus kinetics and host responses associated with disease and outcome of infection in chimpanzees. Hepatology 39:1709–1720. https://doi.org/10.1002/hep.20239
Bigger CB, Brasky KM, Lanford RE (2001) DNA microarray analysis of chimpanzee liver during acute resolving hepatitis C virus infection. J Virol 75:7059–7066. https://doi.org/10.1128/JVI.75.15.7059-7066.2001
Thimme R et al (2002) Viral and immunological determinants of hepatitis C virus clearance, persistence, and disease. Proc Natl Acad Sci U S A 99:15661–15668. https://doi.org/10.1073/pnas.202608299
Abe K, Inchauspe G, Shikata T, Prince AM (1992) Three different patterns of hepatitis C virus infection in chimpanzees. Hepatology 15:690–695
Thomson M et al (2001) Emergence of a distinct pattern of viral mutations in chimpanzees infected with a homogeneous inoculum of hepatitis C virus. Gastroenterology 121:1226–1233
Erickson AL et al (2001) The outcome of hepatitis C virus infection is predicted by escape mutations in epitopes targeted by cytotoxic T lymphocytes. Immunity 15:883–895
Farci P et al (1992) Lack of protective immunity against reinfection with hepatitis C virus. Science 258:135–140
Prince AM et al (1992) Immunity in hepatitis C infection. J Infect Dis 165:438–443
Grakoui A et al (2003) HCV persistence and immune evasion in the absence of memory T cell help. Science 302:659–662. https://doi.org/10.1126/science.1088774302/5645/659
Shoukry NH et al (2003) Memory CD8+ T cells are required for protection from persistent hepatitis C virus infection. J Exp Med 197:1645–1655. https://doi.org/10.1084/jem.20030239jem.20030239
Bukh J et al (2015) Immunoglobulin with high-titer in vitro cross-neutralizing hepatitis C virus antibodies passively protects chimpanzees from homologous, but not heterologous, challenge. J Virol 89:9128–9132. https://doi.org/10.1128/JVI.01194-15
Morin TJ et al (2012) Human monoclonal antibody HCV1 effectively prevents and treats HCV infection in chimpanzees. PLoS Pathog 8:e1002895. https://doi.org/10.1371/journal.ppat.1002895
Olsen DB et al (2011) Sustained viral response in a hepatitis C virus-infected chimpanzee via a combination of direct-acting antiviral agents. Antimicrob Agents Chemother 55:937–939. https://doi.org/10.1128/AAC.00990-10
Lanford RE et al (2010) Therapeutic silencing of microRNA-122 in primates with chronic hepatitis C virus infection. Science 327:198–201. https://doi.org/10.1126/science.1178178
Houghton M (2011) Prospects for prophylactic and therapeutic vaccines against the hepatitis C viruses. Immunol Rev 239:99–108. https://doi.org/10.1111/j.1600-065X.2010.00977.x
Choo QL et al (1994) Vaccination of chimpanzees against infection by the hepatitis C virus. Proc Natl Acad Sci U S A 91:1294–1298
Folgori A et al (2006) A T-cell HCV vaccine eliciting effective immunity against heterologous virus challenge in chimpanzees. Nat Med 12:190–197. https://doi.org/10.1038/nm1353
Callendret B et al (2016) Persistent hepatitis C viral replication despite priming of functional CD8+ T cells by combined therapy with a vaccine and a direct-acting antiviral. Hepatology 63:1442–1454. https://doi.org/10.1002/hep.28309
Ploss A, Rice CM (2009) Towards a small animal model for hepatitis C. EMBO Rep 10:1220–1227. https://doi.org/10.1038/embor.2009.223
Zhu Q et al (2006) Novel robust hepatitis C virus mouse efficacy model. Antimicrob Agents Chemother 50:3260–3268. https://doi.org/10.1128/AAC.00413-06
Levander S et al (2018) Immune-mediated effects targeting hepatitis C virus in a syngeneic replicon cell transplantation mouse model. Gut 67:1525–1535. https://doi.org/10.1136/gutjnl-2016-313579
Long G et al (2011) Mouse hepatic cells support assembly of infectious hepatitis C virus particles. Gastroenterology 141:1057–1066. https://doi.org/10.1053/j.gastro.2011.06.010
Sandgren EP et al (1991) Complete hepatic regeneration after somatic deletion of an albumin-plasminogen activator transgene. Cell 66:245–256
Mercer DF et al (2001) Hepatitis C virus replication in mice with chimeric human livers. Nat Med 7:927–933. https://doi.org/10.1038/90968
Grompe M et al (1993) Loss of fumarylacetoacetate hydrolase is responsible for the neonatal hepatic dysfunction phenotype of lethal albino mice. Genes Dev 7:2298–2307
Grompe M et al (1995) Pharmacological correction of neonatal lethal hepatic dysfunction in a murine model of hereditary tyrosinaemia type I. Nat Genet 10:453–460. https://doi.org/10.1038/ng0895-453
Bissig KD, Le TT, Woods NB, Verma IM (2007) Repopulation of adult and neonatal mice with human hepatocytes: a chimeric animal model. Proc Natl Acad Sci U S A 104:20507–20511. https://doi.org/10.1073/pnas.0710528105
Bissig KD et al (2010) Human liver chimeric mice provide a model for hepatitis B and C virus infection and treatment. J Clin Invest 120:924–930. https://doi.org/10.1172/JCI40094
Azuma H et al (2007) Robust expansion of human hepatocytes in Fah−/−/Rag2−/−/Il2rg−/− mice. Nat Biotechnol 25:903–910. https://doi.org/10.1038/nbt1326
Grompe M, Strom S (2013) Mice with human livers. Gastroenterology 145:1209–1214. https://doi.org/10.1053/j.gastro.2013.09.009
Vercauteren K, de Jong YP, Meuleman P (2015) Animal models for the study of HCV. Curr Opin Virol 13:67–74. https://doi.org/10.1016/j.coviro.2015.04.009
de Jong YP et al (2014) Broadly neutralizing antibodies abrogate established hepatitis C virus infection. Sci Transl Med 6:254ra129. https://doi.org/10.1126/scitranslmed.3009512
Desombere I et al (2016) Monoclonal anti-envelope antibody AP33 protects humanized mice against a patient-derived hepatitis C virus challenge. Hepatology 63:1120–1134. https://doi.org/10.1002/hep.28428
Mailly L et al (2015) Clearance of persistent hepatitis C virus infection in humanized mice using a claudin-1-targeting monoclonal antibody. Nat Biotechnol 33:549–554. https://doi.org/10.1038/nbt.3179
Akazawa D et al (2013) Neutralizing antibodies induced by cell culture-derived hepatitis C virus protect against infection in mice. Gastroenterology 145:447–455.e441–444. https://doi.org/10.1053/j.gastro.2013.05.007
Meuleman P et al (2012) A human monoclonal antibody targeting scavenger receptor class B type I precludes hepatitis C virus infection and viral spread in vitro and in vivo. Hepatology 55:364–372. https://doi.org/10.1002/hep.24692
Kneteman NM et al (2009) HCV796: a selective nonstructural protein 5B polymerase inhibitor with potent anti-hepatitis C virus activity in vitro, in mice with chimeric human livers, and in humans infected with hepatitis C virus. Hepatology 49:745–752. https://doi.org/10.1002/hep.22717
Ohara E et al (2011) Elimination of hepatitis C virus by short term NS3-4A and NS5B inhibitor combination therapy in human hepatocyte chimeric mice. J Hepatol 54:872–878. https://doi.org/10.1016/j.jhep.2010.08.033
Kremsdorf D, Strick-Marchand H (2017) Modeling hepatitis virus infections and treatment strategies in humanized mice. Curr Opin Virol 25:119–125. https://doi.org/10.1016/j.coviro.2017.07.029
Shultz LD, Brehm MA, Garcia-Martinez JV, Greiner DL (2012) Humanized mice for immune system investigation: progress, promise and challenges. Nat Rev Immunol 12:786–798. https://doi.org/10.1038/nri3311
Washburn ML et al (2011) A humanized mouse model to study hepatitis C virus infection, immune response, and liver disease. Gastroenterology. https://doi.org/10.1053/j.gastro.2011.01.001
Strick-Marchand H et al (2015) A novel mouse model for stable engraftment of a human immune system and human hepatocytes. PLoS One 10:e0119820. https://doi.org/10.1371/journal.pone.0119820
Billerbeck E et al (2016) Humanized mice efficiently engrafted with fetal hepatoblasts and syngeneic immune cells develop human monocytes and NK cells. J Hepatol 65:334–343. https://doi.org/10.1016/j.jhep.2016.04.022
Ploss A et al (2009) Human occludin is a hepatitis C virus entry factor required for infection of mouse cells. Nature 457:882–886. https://doi.org/10.1038/nature07684
Dorner M et al (2013) Completion of the entire hepatitis C virus life cycle in genetically humanized mice. Nature 501:237–241. https://doi.org/10.1038/nature12427
Dorner M et al (2011) A genetically humanized mouse model for hepatitis C virus infection. Nature 474:208–211. https://doi.org/10.1038/nature10168
Giang E et al (2012) Human broadly neutralizing antibodies to the envelope glycoprotein complex of hepatitis C virus. Proc Natl Acad Sci U S A 109:6205–6210. https://doi.org/10.1073/pnas.1114927109
Chen J et al (2014) Persistent hepatitis C virus infections and hepatopathological manifestations in immune-competent humanized mice. Cell Res 24:1050–1066. https://doi.org/10.1038/cr.2014.116
Bitzegeio J et al (2010) Adaptation of hepatitis C virus to mouse CD81 permits infection of mouse cells in the absence of human entry factors. PLoS Pathog 6:e1000978. https://doi.org/10.1371/journal.ppat.1000978
von Schaewen M et al (2016) Expanding the host range of hepatitis C virus through viral adaptation. MBio 7:e01915–e01916. https://doi.org/10.1128/mBio.01915-16
Scheel TK, Simmonds P, Kapoor A (2015) Surveying the global virome: identification and characterization of HCV-related animal hepaciviruses. Antivir Res 115:83–93. https://doi.org/10.1016/j.antiviral.2014.12.014
Simmonds P (2013) The origin of hepatitis C virus. Curr Top Microbiol Immunol 369:1–15. https://doi.org/10.1007/978-3-642-27340-7_1
Simons JN et al (1995) Identification of two flavivirus-like genomes in the GB hepatitis agent. Proc Natl Acad Sci U S A 92:3401–3405
Bukh J, Apgar CL, Govindarajan S, Purcell RH (2001) Host range studies of GB virus-B hepatitis agent, the closest relative of hepatitis C virus, in New World monkeys and chimpanzees. J Med Virol 65:694–697. https://doi.org/10.1002/jmv.2092
Martin A et al (2003) Chronic hepatitis associated with GB virus B persistence in a tamarin after intrahepatic inoculation of synthetic viral RNA. Proc Natl Acad Sci U S A 100:9962–9967. https://doi.org/10.1073/pnas.1731505100
Kapoor A et al (2011) Characterization of a canine homolog of hepatitis C virus. Proc Natl Acad Sci U S A 108:11608–11613. https://doi.org/10.1073/pnas.1101794108
Burbelo PD et al (2012) Serology enabled discovery of genetically diverse hepaciviruses in a new host. J Virol 86:6171–6178. https://doi.org/10.1128/JVI.00250-12
Lyons S et al (2014) Viraemic frequencies and seroprevalence of non-primate hepacivirus and equine pegiviruses in horses and other mammalian species. J Gen Virol 95:1701–1711. https://doi.org/10.1099/vir.0.065094-0
Pfaender S et al (2015) Clinical course of infection and viral tissue tropism of hepatitis C virus-like nonprimate hepaciviruses in horses. Hepatology 61:447–459. https://doi.org/10.1002/hep.27440
Scheel TK et al (2015) Characterization of nonprimate hepacivirus and construction of a functional molecular clone. Proc Natl Acad Sci U S A 112:2192–2197. https://doi.org/10.1073/pnas.1500265112
Ramsay JD et al (2015) Experimental transmission of equine hepacivirus in horses as a model for hepatitis C virus. Hepatology 61:1533–1546. https://doi.org/10.1002/hep.27689
Pfaender S et al (2017) Immune protection against reinfection with nonprimate hepacivirus. Proc Natl Acad Sci U S A 114:E2430–E2439. https://doi.org/10.1073/pnas.1619380114
Kapoor A et al (2013) Identification of rodent homologs of hepatitis C virus and pegiviruses. MBio 4:e00216–e00213. https://doi.org/10.1128/mBio.00216-13
Drexler JF et al (2013) Evidence for novel hepaciviruses in rodents. PLoS Pathog 9:e1003438. https://doi.org/10.1371/journal.ppat.1003438
Firth C et al (2014) Detection of zoonotic pathogens and characterization of novel viruses carried by commensal Rattus norvegicus in New York City. MBio 5:e01933–e01914. https://doi.org/10.1128/mBio.01933-14
Trivedi S et al (2017) Viral persistence, liver disease and host response in hepatitis C-like virus rat model. Hepatology. https://doi.org/10.1002/hep.29494
Williams SH et al (2018) Viral diversity of house mice in New York City. MBio 9:e01354–e01317. https://doi.org/10.1128/mBio.01354-17
Billerbeck E et al (2017) Mouse models of acute and chronic hepacivirus infection. Science 357:204–208. https://doi.org/10.1126/science.aal1962
Acknowledgments
We thank William Schneider for critical reading of the manuscript. We apologize to colleagues whose work was not cited due to space constraints.
Compliance with Ethical Standards
Funding We thank NIAID, NIDDK, NCI, the Greenberg Medical Research Institute, and the Starr Foundation for their financial support over the years.
Conflict of Interest
The authors have no conflict of interest.
Ethical Approval
This article does not contain any studies with human participants or animals performed by any of the authors.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2019 Springer Nature Switzerland AG
About this chapter
Cite this chapter
Saeed, M., Billerbeck, E., Rice, C.M. (2019). HCV Molecular Virology and Animal Models. In: Sofia, M. (eds) HCV: The Journey from Discovery to a Cure. Topics in Medicinal Chemistry, vol 31. Springer, Cham. https://doi.org/10.1007/7355_2018_51
Download citation
DOI: https://doi.org/10.1007/7355_2018_51
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-030-28206-6
Online ISBN: 978-3-030-28207-3
eBook Packages: Chemistry and Materials ScienceChemistry and Material Science (R0)