Hepatitis C Virus Entry

Hepatitis C virus (HCV) 3The abbreviations used are: HCVhepatitis C virussE2soluble E2HCVgpHCV glycoproteinHCVppHCV pseudoparticle(s)HCVcccell culture-grown HCVSR-BIscavenger receptor class B, type ILDLlow density lipoproteinVLDLvery LDLCLDN1claudin-1GAGsglycosaminoglycansCD81LELCD81 large extracellular loopHDLhigh density lipoproteinHSheparan sulfateLDLrLDL receptorCVBcoxsackievirus group B. is a leading cause of chronic hepatitis, cirrhosis, and liver cancer. There are currently ∼120 million individuals infected worldwide, with the majority remaining undiagnosed or untreated (1Shepard C.W. Finelli L. Alter M.J. Lancet Infect. Dis. 2005; 5: 558-567Abstract Full Text Full Text PDF PubMed Scopus (2213) Google Scholar). The available therapy, a combination of pegylated interferon and ribavirin, has limited efficacy and significant side effects; drugs that specifically target viral enzymes have yet to reach the market (2De Francesco R. Migliaccio G. Nature. 2005; 436: 953-960Crossref PubMed Scopus (398) Google Scholar). hepatitis C virus soluble E2 HCV glycoprotein HCV pseudoparticle(s) cell culture-grown HCV scavenger receptor class B, type I low density lipoprotein very LDL claudin-1 glycosaminoglycans CD81 large extracellular loop high density lipoprotein heparan sulfate LDL receptor coxsackievirus group B. HCV is a small, enveloped virus with a single-stranded RNA genome of positive polarity that replicates primarily, if not exclusively, within hepatocytes (3Lindenbach B.D. Thiel H.-J. Rice C.M. Knipe D.M. Howley P.M. 5th Ed. Fields Virology. Lippincott-Raven, Philadelphia2007: 1101-1152Google Scholar). Host cell infection is initiated by binding of the virion to cell-surface receptors, followed by endocytosis, low pH-induced fusion of viral and cell membranes, and release of nucleocapsid into the cytosol (Fig. 1, left). The 9.6-kb RNA genome is translated by cellular ribosomes to yield a single polyprotein of ∼3000 amino acids, which is cleaved by host and viral proteases into the final gene products core, E1, E2, p7, NS2, NS3, NS4A, NS4B, NS5A, NS5B, and possibly an alternative reading frame protein termed ARFP (3Lindenbach B.D. Thiel H.-J. Rice C.M. Knipe D.M. Howley P.M. 5th Ed. Fields Virology. Lippincott-Raven, Philadelphia2007: 1101-1152Google Scholar, 4Appel N. Schaller T. Penin F. Bartenschlager R. J. Biol. Chem. 2006; 281: 9833-9836Abstract Full Text Full Text PDF PubMed Scopus (172) Google Scholar). The structural proteins core, E1, and E2 are components of the viral particle, whereas the NS gene products mediate genome replication, a process that occurs exclusively in cytoplasm (4Appel N. Schaller T. Penin F. Bartenschlager R. J. Biol. Chem. 2006; 281: 9833-9836Abstract Full Text Full Text PDF PubMed Scopus (172) Google Scholar). Progeny virions are thought to bud at intracellular membranes and egress via the cellular secretory pathway before going on to infect a naïve cell. This review describes the mechanisms of HCV cell entry, beginning with the infectious virion in plasma and ending with fusion of the viral envelope and endosomal membrane. For unknown reasons, HCV derived from the plasma of infected individuals replicates poorly in cultured cells, forcing researchers to employ strand-specific reverse transcription-PCR as a readout for infection. This approach is cumbersome, and its ability to discriminate reliably between replicating genomes and nucleic acid material from input virus in everyday use is questionable (5Takyar S.T. Li D. Wang Y. Trowbridge R. Gowans E.J. Hepatology. 2000; 32: 382-387Crossref PubMed Scopus (32) Google Scholar, 6Lanford R.E. Sureau C. Jacob J.R. White R. Fuerst T.R. Virology. 1994; 202: 606-614Crossref PubMed Scopus (282) Google Scholar). This problem has limited the usefulness of plasma-derived HCV and triggered the development of several in vitro systems for the study of HCV entry. sE2, a form of the HCVgp E2 from which the transmembrane domain has been deleted (7Michalak J.P. Wychowski C. Choukhi A. Meunier J.C. Ung S. Rice C.M. Dubuisson J. J. Gen. Virol. 1997; 78: 2299-2306Crossref PubMed Scopus (150) Google Scholar), has been extremely useful with regard to receptor discovery (8Scarselli E. Ansuini H. Cerino R. Roccasecca R.M. Acali S. Filocamo G. Traboni C. Nicosia A. Cortese R. Vitelli A. EMBO J. 2002; 21: 5017-5025Crossref PubMed Scopus (940) Google Scholar, 9Pileri P. Uematsu Y. Campagnoli S. Galli G. Falugi F. Petracca R. Weiner A.J. Houghton M. Rosa D. Grandi G. Abrignani S. Science. 1998; 282: 938-941Crossref PubMed Scopus (1776) Google Scholar). On the viral particle, however, the HCVgps E1 and E2 are thought to function as a noncovalently linked heterodimer (10Deleersnyder V. Pillez A. Wychowski C. Blight K. Xu J. Hahn Y.S. Rice C.M. Dubuisson J. J. Virol. 1997; 71: 697-704Crossref PubMed Google Scholar, 11Op De Beeck A. Voisset C. Bartosch B. Ciczora Y. Cocquerel L. Keck Z. Foung S. Cosset F.-L. Dubuisson J. J. Virol. 2004; 78: 2994-3002Crossref PubMed Scopus (190) Google Scholar), making it unlikely that sE2 recapitulates all characteristics and functions of the native envelope proteins. HCVpp, retroviral particles that display HCV E1/E2 heterodimers instead of retroviral glycoproteins, were the first robust in vitro assay of HCVgp-mediated entry (12Drummer H.E. Maerz A. Poumbourios P. FEBS Lett. 2003; 546: 385-390Crossref PubMed Scopus (167) Google Scholar, 13Bartosch B. Dubuisson J. Cosset F.-L. J. Exp. Med. 2003; 197: 633-642Crossref PubMed Scopus (938) Google Scholar, 14Hsu M. Zhang J. Flint M. Logvinoff C. Cheng-Mayer C. Rice C.M. McKeating J.A. Proc. Natl. Acad. Sci. U. S. A. 2003; 100: 7271-7276Crossref PubMed Scopus (686) Google Scholar). Pseudotyping takes advantage of the ability of retroviruses to incorporate heterologous glycoproteins into their envelope during budding. Specifically, HCVpp are generated by cotransfection of three plasmids into 293T producer cells: 1) the gag-pol genes of either human immunodeficiency virus or murine leukemia virus, 2) a gutted retrovirus genome retaining only the long terminal repeats and packaging signal and encoding a reporter gene such as green fluorescent protein or and the HCVpp entry is and is by reporter gene development of an HCV that in vitro HCVpp to their use is of replication, are not to the cell that robust HCV RNA a for HCV an HCV termed hepatitis to to high of in cell and to infectious B.D. M.J. A.J. B. T. McKeating J.A. Rice C.M. Science. 2005; PubMed Scopus Google Scholar, T. T. T. T. M. Z. K. A. M. Bartenschlager R. Med. 2005; PubMed Scopus Google Scholar, J. P. G. S. T. T. Proc. Natl. Acad. Sci. U. S. A. 2005; PubMed Scopus Google Scholar). the HCV entry, and in is infectious in and in with human in to plasma-derived virus from is of robust in cell B.D. P. A. T. A.J. McKeating J.A. R.E. G. Rice C.M. Proc. Natl. Acad. Sci. U. S. A. 2006; PubMed Scopus Google Scholar). remaining is that viral is only in cell such as and on the limited available T. T. T. T. M. Z. K. A. M. Bartenschlager R. Med. 2005; PubMed Scopus Google and by to the HCV is thought to have a of The nucleocapsid is from of the protein and the RNA genome and is by a host with E1/E2 heterodimers (3Lindenbach B.D. Thiel H.-J. Rice C.M. Knipe D.M. Howley P.M. 5th Ed. Fields Virology. Lippincott-Raven, Philadelphia2007: 1101-1152Google Scholar, T. T. T. T. M. Z. K. A. M. Bartenschlager R. Med. 2005; PubMed Scopus Google Scholar). sE2 to of the viral scavenger receptor class B, type I (8Scarselli E. Ansuini H. Cerino R. Roccasecca R.M. Acali S. Filocamo G. Traboni C. Nicosia A. Cortese R. Vitelli A. EMBO J. 2002; 21: 5017-5025Crossref PubMed Scopus (940) Google Scholar), and CD81 P. Uematsu Y. Campagnoli S. Galli G. Falugi F. Petracca R. Weiner A.J. Houghton M. Rosa D. Grandi G. Abrignani S. Science. 1998; 282: 938-941Crossref PubMed Scopus (1776) Google Scholar), E2 is thought to for receptor acid at the very of E2, termed 1, to the (8Scarselli E. Ansuini H. Cerino R. Roccasecca R.M. Acali S. Filocamo G. Traboni C. Nicosia A. Cortese R. Vitelli A. EMBO J. 2002; 21: 5017-5025Crossref PubMed Scopus (940) Google Scholar). in E2 have been in CD81 a binding A. K. J. Virol. 2006; PubMed Scopus Google Scholar, H.E. Maerz Poumbourios P. J. Virol. 2006; PubMed Scopus Google Scholar, R. Ansuini H. Vitelli A. A. E. Acali S. M. McKeating J. A. A. A. Cortese R. Nicosia A. J. Virol. 2003; PubMed Scopus Google Scholar). have that plasma-derived HCV is with LDL and and is that with in Hahn T. McKeating J.A. J. Full Text Full Text PDF PubMed Scopus Google Scholar). of a host cell is initiated between the HCVgps and several cell-surface three host and claudin-1 are thought to for HCV entry. glycosaminoglycans virus and several have been cell that all of the entry that at the of the HCV the CD81 is a acid protein with transmembrane and intracellular and C The function of CD81 is only it is of the receptor not for function S. T. 2005; 5: PubMed Scopus Google Scholar). to not fusion E. A. J.P. F. C. Biol. 2006; PubMed Scopus Google Scholar). CD81 has been to for of hepatocytes by of the of E. M. E. L. L. S. C. D. Med. 2003; PubMed Scopus Google Scholar). CD81 as an HCV receptor of its sE2 binding P. Uematsu Y. Campagnoli S. Galli G. Falugi F. Petracca R. Weiner A.J. Houghton M. Rosa D. Grandi G. Abrignani S. Science. 1998; 282: 938-941Crossref PubMed Scopus (1776) Google Scholar), and its in CD81 and soluble of the CD81 large extracellular loop infection by HCVpp of all HCV B. Dubuisson J. 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PubMed Scopus Google Scholar). the of the HCVpp it been that of the and CD81 to HCV entry. This to the that at M. Zhang J. Flint M. Logvinoff C. Cheng-Mayer C. Rice C.M. McKeating J.A. Proc. Natl. Acad. Sci. U. S. A. 2003; 100: 7271-7276Crossref PubMed Scopus (686) Google Scholar, B. Vitelli A. C. C. Dubuisson J. S. E. Cortese R. Nicosia A. Cosset F.-L. J. Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). The has been to for HCV entry an approach M.J. Hahn T. D.M. A.J. M. B. T. McKeating J.A. Rice C.M. Nature. PubMed Scopus Google Scholar). it that HCV the and A. F. Li Y. F. P. Li J. M. H. J. Virol. PubMed Scopus Google Scholar). of HCVpp to the and yet cell 293T and M.J. Hahn T. D.M. A.J. M. B. T. McKeating J.A. Rice C.M. Nature. PubMed Scopus Google Scholar). in cells, such as and of viral entry. the of the which the and in M. S. Biol. 2006; Full Text Full Text PDF PubMed Scopus Google Scholar). of the is in all in the plasma that in a with on cells, the and the not been in the extracellular of and are to the of in the M. S. Biol. 2006; Full Text Full Text PDF PubMed Scopus Google Scholar). is a amino cell-surface protein with transmembrane and intracellular and C There however, between and The extracellular loop of is for HCV entry M.J. Hahn T. D.M. A.J. M. B. T. McKeating J.A. Rice C.M. Nature. PubMed Scopus Google Scholar), it not sE2 or and in between and viral has been are available extracellular by of a in the first extracellular a has been generated that HCV entry it to by M.J. Hahn T. D.M. A.J. M. B. T. McKeating J.A. Rice C.M. Nature. PubMed Scopus Google Scholar). that HCV infection to with an extracellular that is the an to at a in the HCV entry of CD81 M.J. Hahn T. D.M. A.J. M. B. T. McKeating J.A. Rice C.M. Nature. PubMed Scopus Google Scholar). it has been that HCV between in a that not CD81 J. 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