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The Hepatitis C Virus Life Cycle as a Target for New Antiviral Therapies

2007; Elsevier BV; Volume: 132; Issue: 5 Linguagem: Inglês

10.1053/j.gastro.2007.03.116

1528-0012

Jean‐Michel Pawlotsky, Stéphane Chevaliez, John G. McHutchison,

Hepatitis B Virus Studies

The burden of disease consequent to hepatitis C virus (HCV) infection has been well described and is expected to increase dramatically over the next decade. Current approved antiviral therapies are effective in eradicating the virus in approximately 50% of infected patients. However, pegylated interferon and ribavirin-based therapy is costly, prolonged, associated with significant adverse effects, and not deemed suitable for many HCV-infected patients. As such, there is a clear and pressing need for the development of additional agents that act through alternate or different mechanisms, in the hope that such regimens could lead to enhanced response rates more broadly applicable to patients with hepatitis C infection. Recent basic science enhancements in HCV cell culture systems and replication assays have led to a broadening of our understanding of many of the mechanisms of HCV replication and, therefore, potential novel antiviral targets. In this article, we have attempted to highlight important new information as it relates to our understanding of the HCV life cycle. These steps broadly encompass viral attachment, entry, and fusion; viral RNA translation; posttranslational processing; HCV replication; and viral assembly and release. In each of these areas, we present up-to-date knowledge of the relevant aspects of that component of the viral life cycle and then describe the preclinical and clinical development targets and pathways being explored in the translational and clinical settings. The burden of disease consequent to hepatitis C virus (HCV) infection has been well described and is expected to increase dramatically over the next decade. Current approved antiviral therapies are effective in eradicating the virus in approximately 50% of infected patients. However, pegylated interferon and ribavirin-based therapy is costly, prolonged, associated with significant adverse effects, and not deemed suitable for many HCV-infected patients. As such, there is a clear and pressing need for the development of additional agents that act through alternate or different mechanisms, in the hope that such regimens could lead to enhanced response rates more broadly applicable to patients with hepatitis C infection. Recent basic science enhancements in HCV cell culture systems and replication assays have led to a broadening of our understanding of many of the mechanisms of HCV replication and, therefore, potential novel antiviral targets. In this article, we have attempted to highlight important new information as it relates to our understanding of the HCV life cycle. These steps broadly encompass viral attachment, entry, and fusion; viral RNA translation; posttranslational processing; HCV replication; and viral assembly and release. In each of these areas, we present up-to-date knowledge of the relevant aspects of that component of the viral life cycle and then describe the preclinical and clinical development targets and pathways being explored in the translational and clinical settings. The current standard of care for patients with chronic hepatitis C, combination therapy with pegylated interferon (IFN) α and ribavirin, is effective in approximately 80% of patients with hepatitis C virus (HCV) genotype 2 or 3 infection but less than 50% of those with HCV genotype 1.1National Institutes of Health Consensus Development Conference Statement: management of hepatitis C: 2002-June 10-12, 2002.Hepatology. 2002; 36: S3-S20Crossref PubMed Scopus (0) Google Scholar Unfortunately, genotype 1 causes approximately 70%–80% of chronic HCV infections in the United States and more than 60% in Europe and Asia, making the current standard of care unsatisfactory for many patients. In addition, therapy with pegylated IFN-α and ribavirin is prolonged, costly, and may be associated with adverse effects that are difficult for many patients to tolerate. Thus, more effective, more tolerable, and/or more tailored therapies are required. In the last decade, insights into the virology of HCV have unraveled several targets for potential novel therapeutics. Unlike IFN-α and ribavirin, many of the putative new therapeutics are specifically targeted to HCV. Specifically targeted antiviral therapy for hepatitis C (STAT-C) has the theoretic potential to be effective in greater proportions of patients and result in fewer adverse effects than the current standard of care. Many drugs are at the preclinical developmental stage, and several are in clinical development, but initial trials using some of these inhibitors alone have raised concerns about their tolerability and the development of viral resistance. A number of specifically targeted therapies are now also being tested in combination with pegylated IFN-α with or without ribavirin. In addition to STAT-C, other immune modulators and therapeutic vaccines are also being developed and tested, as are antifibrotics and caspase inhibitors. This review article focuses on the most recent developments in the understanding of the HCV life cycle, every step of which constitutes a potential target for STAT-C, and a description of compounds in preclinical development as well as molecules that have entered clinical trials against these targets (Figure 1). The early steps of HCV entry involve 2 groups of actors: the HCV structural proteins and the receptor molecules at the surface of target cells (Table 1 and Figure 2).Table 1Principal Putative Viral and Cellular Actors of the HCV Life CycleLife-cycle stepViral actorsCellular actorsViral attachment, entry, and fusionEnvelope glycoprotein E1Envelope glycoprotein E2GlycosaminoglycansCD81 (target of antiproliferative antibody 1)Scavenger receptor B type IClaudin-1Dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN or CD209)Liver/lymph node-specific intercellular adhesion molecule-3 (ICAM-3)-grabbing integrin (L-SIGN or CD209L)Low-density lipoprotein receptorAsialoglycoprotein receptorHCV RNA translationInternal ribosome entry siteDomain I of the 5' untranslated regionHCV open reading frame3' untranslated regionNS4A and NS5BRibosomal subunitsEukaryotic initiation factors 2 and 3tRNAPolypyrimidine tract-binding proteinHeterogeneous nuclear ribonucleoprotein L (hnRNP L)La autoantigenPoly(rC)-binding protein 2NS1-associated protein 1Posttranslational processingNS2 zinc-dependent metalloproteinaseNS3/4A serine proteinaseSignal peptidaseSignal peptide peptidaseHCV replicationNS5B RNA-dependent RNA polymeraseNS5ANS3 helicase-NTPaseNS4BX region of the 3′ untranslated regionDomain I of the 5′ untranslated region5BSL3.2 in the NS5B-coding regionLipid raftsHuman vesicle-associated membrane protein (VAMP)-associated membrane protein A (hVAP-A)Cyclophilin BFBL2Polypyrimidine tract-binding protein (PTB)Micro-RNAVirus assembly and releaseCore proteinE1 and E2 envelope glycoproteinsHCV RNA genomeER membranesGolgi apparatus Open table in a new tab The 2 envelope glycoproteins, E1 and E2, are essential components of the HCV virion envelope and are necessary for viral entry and fusion.2Bartosch B. Dubuisson J. Cosset F.L. Infectious hepatitis C virus pseudo-particles containing functional E1-E2 envelope protein complexes.J Exp Med. 2003; 197: 633-642Crossref PubMed Scopus (621) Google Scholar, 3Nielsen S.U. Bassendine M.F. Burt A.D. Bevitt D.J. Toms G.L. Characterization of the genome and structural proteins of hepatitis C virus resolved from infected human liver.J Gen Virol. 2004; 85: 1497-1507Crossref PubMed Scopus (32) Google Scholar E1 and E2 have molecular weights of 33–35 and 70–72 kilodaltons, respectively, and assemble as noncovalent heterodimers.4Deleersnyder V. Pillez A. Wychowski C. Blight K. Xu J. Hahn Y.S. Rice C.M. Dubuisson J. Formation of native hepatitis C virus glycoprotein complexes.J Virol. 1997; 71: 697-704Crossref PubMed Google Scholar E1 and E2 are type I transmembrane glycoproteins, with N-terminal ectodomains of 160 and 334 amino acids, respectively, and a short C-terminal transmembrane domain of approximately 30 amino acids. The transmembrane domains have numerous functions, including membrane anchoring, endoplasmic reticulum (ER) localization, and heterodimer assembly.5Cocquerel L. Meunier J.C. Pillez A. Wychowski C. Dubuisson J. A retention signal necessary and sufficient for endoplasmic reticulum localization maps to the transmembrane domain of hepatitis C virus glycoprotein E2.J Virol. 1998; 72: 2183-2191Crossref PubMed Google Scholar, 6Cocquerel L. Wychowski C. Minner F. Penin F. Dubuisson J. Charged residues in the transmembrane domains of hepatitis C virus glycoproteins play a major role in the processing, subcellular localization, and assembly of these envelope proteins.J Virol. 2000; 74: 3623-3633Crossref PubMed Scopus (102) Google Scholar They could play an important role in fusion.7Ciczora Y. Callens N. Penin F. Pecheur E.I. Dubuisson J. Transmembrane domains of hepatitis C virus envelope glycoproteins: residues involved in E1E2 heterodimerization and involvement of these domains in virus entry.J Virol. 2007; 81: 2372-2381Crossref PubMed Scopus (48) Google Scholar E1 and E2 are highly glycosylated, containing up to 5 and 11 glycosylation sites, respectively. Hypervariable regions have been identified in the E2 envelope glycoprotein.8Weiner A.J. Christopherson C. Hall J.E. Bonino F. Saracco G. Brunetto M.R. Crawford K. Marion C.D. Crawford K.A. Venkatakrishna S. Houghton M. Sequence variation in hepatitis C viral isolates.J Hepatol. 1991; 13: S6-S14Abstract Full Text PDF PubMed Google Scholar Hypervariable region 1 (HVR1) contains 27 amino acids and is a major (but not the only) HCV neutralizing epitope.9Farci P. Shimoda A. Wong D. Cabezon T. De Gioannis D. Strazzera A. Shimizu Y. Shapiro M. Alter H.J. Purcell R.H. 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. 1996; 93: 15394-15399Crossref PubMed Scopus (421) Google Scholar, 10Zibert A. Kraas W. Meisel H. Jung G. Roggendorf M. Epitope mapping of antibodies directed against hypervariable region 1 in acute self-limiting and chronic infections due to hepatitis C virus.J Virol. 1997; 71: 4123-4127PubMed Google Scholar Despite HVR1 sequence variability, the physicochemical properties of the residues at each position and the overall conformation of HVR1 are highly conserved among all known HCV genotypes, suggesting an important role in the virus life cycle.11Penin F. Combet C. Germanidis G. Frainais P.O. Deleage G. Pawlotsky J.M. Conservation of the conformation and positive charges of hepatitis C virus E2 envelope glycoprotein hypervariable region 1 points to a role in cell attachment.J Virol. 2001; 75: 5703-5710Crossref PubMed Scopus (143) Google Scholar E2 plays a crucial role in the early steps of infection. Viral attachment is thought to be initiated via E2 interaction with one or several components of the receptor complex.12Flint M. McKeating J.A. The role of the hepatitis C virus glycoproteins in infection.Rev Med Virol. 2000; 10: 101-117Crossref PubMed Scopus (55) Google Scholar, 13Rosa D. Campagnoli S. Moretto C. Guenzi E. Cousens L. Chin M. Dong C. Weiner A.J. Lau J.Y. Choo Q.L. Chien D. Pileri P. Houghton M. Abrignani S. A quantitative test to estimate neutralizing antibodies to the hepatitis C virus: cytofluorimetric assessment of envelope glycoprotein 2 binding to target cells.Proc Natl Acad Sci U S A. 1996; 93: 1759-1763Crossref PubMed Scopus (288) Google Scholar The interaction of HVR1, a basic region with positively charged residues at specific sequence positions,11Penin F. Combet C. Germanidis G. Frainais P.O. Deleage G. Pawlotsky J.M. Conservation of the conformation and positive charges of hepatitis C virus E2 envelope glycoprotein hypervariable region 1 points to a role in cell attachment.J Virol. 2001; 75: 5703-5710Crossref PubMed Scopus (143) Google Scholar with negatively charged molecules at the cell surface could play a role in host cell recognition and attachment, as well as in cell or tissue compartmentalization.14Bartosch B. Vitelli A. Granier C. Goujon C. Dubuisson J. Pascale S. Scarselli E. Cortese R. Nicosia A. Cosset F.L. Cell entry of hepatitis C virus requires a set of co-receptors that include the CD81 tetraspanin and the SR-B1 scavenger receptor.J Biol Chem. 2003; 278: 41624-41630Crossref PubMed Scopus (370) Google Scholar, 15Barth H. Schafer C. Adah M.I. Zhang F. Linhardt R.J. Toyoda H. Kinoshita-Toyoda A. Toida T. Van Kuppevelt T.H. Depla E. Von Weizsacker F. Blum H.E. Baumert T.F. Cellular binding of hepatitis C virus envelope glycoprotein E2 requires cell surface heparan sulfate.J Biol Chem. 2003; 278: 41003-41012Crossref PubMed Scopus (244) Google Scholar In addition, it has been recently shown that human serum facilitates infection of Huh7 cells by HCV pseudoparticles, apparently mediated through an interplay among serum high-density lipoproteins (HDL), HVR1, and the scavenger receptor B type I (SR-BI).16Bartosch B. Verney G. Dreux M. Donot P. Morice Y. Penin F. Pawlotsky J.M. Lavillette D. Cosset F.L. An interplay between hypervariable region 1 of the hepatitis C virus E2 glycoprotein, the scavenger receptor BI, and high-density lipoprotein promotes both enhancement of infection and protection against neutralizing antibodies.J Virol. 2005; 79: 8217-8229Crossref PubMed Scopus (178) Google Scholar, 17Voisset C. Callens N. Blanchard E. Op De Beeck A. Dubuisson J. Vu-Dac N. High density lipoproteins facilitate hepatitis C virus entry through the scavenger receptor class B type I.J Biol Chem. 2005; 280: 7793-7799Crossref PubMed Scopus (157) Google Scholar E1 is thought to be involved in intracytoplasmic virus-membrane fusion.12Flint M. McKeating J.A. The role of the hepatitis C virus glycoproteins in infection.Rev Med Virol. 2000; 10: 101-117Crossref PubMed Scopus (55) Google Scholar, 13Rosa D. Campagnoli S. Moretto C. Guenzi E. Cousens L. Chin M. Dong C. Weiner A.J. Lau J.Y. Choo Q.L. Chien D. Pileri P. Houghton M. Abrignani S. A quantitative test to estimate neutralizing antibodies to the hepatitis C virus: cytofluorimetric assessment of envelope glycoprotein 2 binding to target cells.Proc Natl Acad Sci U S A. 1996; 93: 1759-1763Crossref PubMed Scopus (288) Google Scholar More recently, it has been suggested that mutations in the transmembrane domains of E1 and E2 affect the fusion properties of HCV envelope glycoproteins.7Ciczora Y. Callens N. Penin F. Pecheur E.I. Dubuisson J. Transmembrane domains of hepatitis C virus envelope glycoproteins: residues involved in E1E2 heterodimerization and involvement of these domains in virus entry.J Virol. 2007; 81: 2372-2381Crossref PubMed Scopus (48) Google Scholar Several cell surface molecules have been proposed to mediate HCV binding or HCV binding and internalization (Table 1). Conservation of positively charged residues in the N-terminus of E2 is in keeping with a possible interaction with heparan sulfate proteoglycans.15Barth H. Schafer C. Adah M.I. Zhang F. Linhardt R.J. Toyoda H. Kinoshita-Toyoda A. Toida T. Van Kuppevelt T.H. Depla E. Von Weizsacker F. Blum H.E. Baumert T.F. Cellular binding of hepatitis C virus envelope glycoprotein E2 requires cell surface heparan sulfate.J Biol Chem. 2003; 278: 41003-41012Crossref PubMed Scopus (244) Google Scholar E2, in particular its HVR1, has been shown to bind heparan sulfate with a stronger affinity than other viral envelope glycoproteins. However, glycosaminoglycans are ubiquitously expressed cell surface molecules. It is conceivable that they could serve as the initial docking site for HCV attachment and that the virus is subsequently transferred to another high-affinity receptor (or receptor complex) triggering entry.15Barth H. Schafer C. Adah M.I. Zhang F. Linhardt R.J. Toyoda H. Kinoshita-Toyoda A. Toida T. Van Kuppevelt T.H. Depla E. Von Weizsacker F. Blum H.E. Baumert T.F. Cellular binding of hepatitis C virus envelope glycoprotein E2 requires cell surface heparan sulfate.J Biol Chem. 2003; 278: 41003-41012Crossref PubMed Scopus (244) Google Scholar, 18Barth H. Schnober E.K. Zhang F. Linhardt R.J. Depla E. Boson B. Cosset F.L. Patel A.H. Blum H.E. Baumert T.F. Viral and cellular determinants of the hepatitis C virus envelope-heparan sulfate interaction.J Virol. 2006; 80: 10579-10590Crossref PubMed Scopus (109) Google Scholar Human CD81 (target of antiproliferative antibody 1) is a 25-kilodalton molecule belonging to the tetraspanin superfamily. It is found at the surface of numerous cell types, at which it is thought to assemble as homo- and/or heterodimers by means of a conserved hydrophobic interface. CD81 contains 2 extracellular loop domains: the small extracellular loop and the large extracellular loop. The large extracellular loop is variable, except between humans and chimpanzees, the only 2 species permissive to HCV infection.19Walker C.M. Comparative features of hepatitis C virus infection in humans and chimpanzees.Springer Semin Immunopathol. 1997; 19: 85-98Crossref PubMed Scopus (49) Google Scholar, 20Major M.E. Dahari H. Mihalik K. Puig M. Rice C.M. Neumann A.U. Feinstone S.M. Hepatitis C virus kinetics and host responses associated with disease and outcome of infection in chimpanzees.Hepatology. 2004; 39: 1709-1720Crossref PubMed Scopus (84) Google Scholar The CD81 large extracellular loop has been shown to mediate binding of HCV through its envelope glycoprotein E2.21Pileri P. Uematsu Y. Campagnoli S. Galli G. Falugi F. Petracca R. Weiner A.J. Houghton M. Rosa D. Grandi G. Abrignani S. Binding of hepatitis C virus to CD81.Science. 1998; 282: 938-941Crossref PubMed Scopus (1271) Google Scholar, 22Petracca R. Falugi F. Galli G. Norais N. Rosa D. Campagnoli S. Burgio V. Di Stasio E. Giardina B. Houghton M. Abrignani S. Grandi G. 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