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• W2089014790 abstract "Production of infectious hepatitis C virus in tissue culture from a cloned viral genome. Wakita T, Pietschmann T, Kato T, Date T, Miyamoto M, Zhao Z, Murthy K, Habermann A, Krausslich HG, Mizokami M, Bartenschlager R, Liang TJ.Hepatitis C virus (HCV) infection causes chronic liver diseases and is a global public health problem. Detailed analyses of HCV have been hampered by the lack of viral culture systems. Subgenomic replicons of the JFH1 genotype 2a strain cloned from an individual with fulminant hepatitis replicate efficiently in cell culture. Here we show that the JFH1 genome replicates efficiently and supports secretion of viral particles after transfection into a human hepatoma cell line (Huh7).Particles have a density of about 1.15–1.17 g/ml and a spherical morphology with an average diameter of about 55 nm. Secreted virus is infectious for Huh7 cells and infectivity can be neutralized by CD81-specific antibodies and by immunoglobulins from chronically infected individuals. The cell culture-generated HCV is infectious for chimpanzee. This system provides a powerful tool for studying the viral life cycle and developing antiviral strategies.[Abstract reproduced by permission of Nat Med 2005;11(7):791–6]Complete replication of hepatitis C virus in cell culture. Lindenbach BD, Evans MJ, Syder AJ, Wolk B, Tellinghuisen TL, Liu CC, Maruyama T, Hynes RO, Burton DR, McKeating JA, Rice CM.Many aspects of the hepatitis C virus (HCV) life cycle have not been reproduced in cell culture, which has slowed research progress on this important human pathogen. Here, we describe a full-length HCV genome that replicates and produces virus particles that are infectious in cell culture (HCVcc). Replication of HCVcc was robust, producing nearly 10(5) infectious units per milliliter within 48 hours. Virus particles were filterable and neutralized with a monoclonal antibody against the viral glycoprotein E2. Viral entry was dependent on cellular expression of a putative HCV receptor, CD81. HCVcc replication was inhibited by interferon-alpha and by several HCV-specific antiviral compounds, suggesting that this in vitro system will aid in the search for improved antivirals.[Abstract reproduced by permission of Science 2005;309(5734):623–6]Robust hepatitis C virus infection in vitro. Zhong J, Gastaminza P, Cheng G, Kapadia S, Kato T, Burton DR, Wieland SF, Uprichard SL, Wakita T, Chisari FV.The absence of a robust cell culture model of hepatitis C virus (HCV) infection has severely limited analysis of the HCV life cycle and the development of effective antivirals and vaccines. Here we report the establishment of a simple yet robust HCV cell culture infection system based on the HCV JFH-1 molecular clone and Huh-7-derived cell lines that allows the production of virus that can be efficiently propagated in tissue culture. This system provides a powerful tool for the analysis of host-virus interactions that should facilitate the discovery of antiviral drugs and vaccines for this important human pathogen.[Abstract reproduced by permission of Proc Natl Acad Sci USA 2005;102(26):9294–9] Production of infectious hepatitis C virus in tissue culture from a cloned viral genome. Wakita T, Pietschmann T, Kato T, Date T, Miyamoto M, Zhao Z, Murthy K, Habermann A, Krausslich HG, Mizokami M, Bartenschlager R, Liang TJ. Hepatitis C virus (HCV) infection causes chronic liver diseases and is a global public health problem. Detailed analyses of HCV have been hampered by the lack of viral culture systems. Subgenomic replicons of the JFH1 genotype 2a strain cloned from an individual with fulminant hepatitis replicate efficiently in cell culture. Here we show that the JFH1 genome replicates efficiently and supports secretion of viral particles after transfection into a human hepatoma cell line (Huh7). Particles have a density of about 1.15–1.17 g/ml and a spherical morphology with an average diameter of about 55 nm. Secreted virus is infectious for Huh7 cells and infectivity can be neutralized by CD81-specific antibodies and by immunoglobulins from chronically infected individuals. The cell culture-generated HCV is infectious for chimpanzee. This system provides a powerful tool for studying the viral life cycle and developing antiviral strategies. [Abstract reproduced by permission of Nat Med 2005;11(7):791–6] Complete replication of hepatitis C virus in cell culture. Lindenbach BD, Evans MJ, Syder AJ, Wolk B, Tellinghuisen TL, Liu CC, Maruyama T, Hynes RO, Burton DR, McKeating JA, Rice CM. Many aspects of the hepatitis C virus (HCV) life cycle have not been reproduced in cell culture, which has slowed research progress on this important human pathogen. Here, we describe a full-length HCV genome that replicates and produces virus particles that are infectious in cell culture (HCVcc). Replication of HCVcc was robust, producing nearly 10(5) infectious units per milliliter within 48 hours. Virus particles were filterable and neutralized with a monoclonal antibody against the viral glycoprotein E2. Viral entry was dependent on cellular expression of a putative HCV receptor, CD81. HCVcc replication was inhibited by interferon-alpha and by several HCV-specific antiviral compounds, suggesting that this in vitro system will aid in the search for improved antivirals. [Abstract reproduced by permission of Science 2005;309(5734):623–6] Robust hepatitis C virus infection in vitro. Zhong J, Gastaminza P, Cheng G, Kapadia S, Kato T, Burton DR, Wieland SF, Uprichard SL, Wakita T, Chisari FV. The absence of a robust cell culture model of hepatitis C virus (HCV) infection has severely limited analysis of the HCV life cycle and the development of effective antivirals and vaccines. Here we report the establishment of a simple yet robust HCV cell culture infection system based on the HCV JFH-1 molecular clone and Huh-7-derived cell lines that allows the production of virus that can be efficiently propagated in tissue culture. This system provides a powerful tool for the analysis of host-virus interactions that should facilitate the discovery of antiviral drugs and vaccines for this important human pathogen. [Abstract reproduced by permission of Proc Natl Acad Sci USA 2005;102(26):9294–9] 1. Hepatitis C virus: the need for model systemsHepatitis C virus (HCV) is a major cause of posttransfusion and community-acquired hepatitis in the world [[1]Rehermann B. Nascimbeni M. Immunology of hepatitis B virus and hepatitis C virus infection.Nat Rev Immunol. 2005; 5: 215-229Crossref PubMed Scopus (1353) Google Scholar]. The majority of HCV-infected individuals develop chronic hepatitis that may progress to liver cirrhosis and hepatocellular carcinoma. Treatment options for chronic HCV infection are limited and a vaccine to prevent HCV infection is not available [[1]Rehermann B. Nascimbeni M. Immunology of hepatitis B virus and hepatitis C virus infection.Nat Rev Immunol. 2005; 5: 215-229Crossref PubMed Scopus (1353) Google Scholar]. The development of efficient antivirals and a vaccine has been hampered by the lack of an efficient tissue culture model for HCV infection.Several in vitro models for the study of HCV infection have been described. These models include human lymphocytic cell lines, human biliary epithelial cells, and primary hepatocytes from humans, chimpanzees or tree shrews (Tupaia belangeri). Primary hepatocytes can be successfully infected by serum-derived HCV [2Castet V. Fournier C. Soulier A. Brillet R. Coste J. Larrey D. et al.Alpha interferon inhibits hepatitis C virus replication in primary human hepatocytes infected in vitro.J Virol. 2002; 76: 8189-8199Crossref PubMed Scopus (110) Google Scholar, 3Barth H. Cerino R. Arcuri M. Hoffmann M. Schurmann P. Adah M.I. et al.Scavenger receptor class B type I and hepatitis C virus infection of primary tupaia hepatocytes.J Virol. 2005; 79: 5774-5785Crossref PubMed Scopus (73) Google Scholar]. Limitations of these systems are the low level of HCV replication requiring RT-PCR for detection of viral infection, the variable quality of host cells such as human hepatocytes obtained from surgical specimens and the lack of a well-defined viral inoculum.Alternative model systems have been developed for the study of defined aspects of the HCV life cycle such as viral entry, replication, assembly and release (Fig. 1). Recombinant HCV envelope glycoproteins [[4]Pileri P. Uematsu Y. Campagnoli S. Galli G. Falugi F. Petracca R. et al.Binding of hepatitis C virus to CD81.Science. 1998; 282: 938-941Crossref PubMed Scopus (1779) Google Scholar], HCV-like particles (HCV-LPs) [3Barth H. Cerino R. Arcuri M. Hoffmann M. Schurmann P. Adah M.I. et al.Scavenger receptor class B type I and hepatitis C virus infection of primary tupaia hepatocytes.J Virol. 2005; 79: 5774-5785Crossref PubMed Scopus (73) Google Scholar, 5Wellnitz S. Klumpp B. Barth H. Ito S. Depla E. Dubuisson J. et al.Binding of hepatitis C virus-like particles derived from infectious clone H77C to defined human cell lines.J Virol. 2002; 76: 1181-1193Crossref PubMed Scopus (89) Google Scholar] and retroviral HCV pseudotypes (HCVpp) [6Bartosch 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 (942) Google Scholar, 7Hsu M. Zhang J. Flint M. Logvinoff C. Cheng-Mayer C. Rice C.M. et al.Hepatitis C virus glycoproteins mediate pH-dependent cell entry of pseudotyped retroviral particles.Proc Natl Acad Sci USA. 2003; 100: 7271-7276Crossref PubMed Scopus (687) Google Scholar] have been successfully used to analyze virus attachment and entry. These systems allowed the isolation and functional analysis of CD81, scavenger receptor BI and highly sulfated heparan sulfate as cell surface molecules involved in viral attachment and entry [3Barth H. Cerino R. Arcuri M. Hoffmann M. Schurmann P. Adah M.I. et al.Scavenger receptor class B type I and hepatitis C virus infection of primary tupaia hepatocytes.J Virol. 2005; 79: 5774-5785Crossref PubMed Scopus (73) Google Scholar, 4Pileri P. Uematsu Y. Campagnoli S. Galli G. Falugi F. Petracca R. et al.Binding of hepatitis C virus to CD81.Science. 1998; 282: 938-941Crossref PubMed Scopus (1779) Google Scholar, 5Wellnitz S. Klumpp B. Barth H. Ito S. Depla E. Dubuisson J. et al.Binding of hepatitis C virus-like particles derived from infectious clone H77C to defined human cell lines.J Virol. 2002; 76: 1181-1193Crossref PubMed Scopus (89) Google Scholar, 6Bartosch 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 (942) Google Scholar, 7Hsu M. Zhang J. Flint M. Logvinoff C. Cheng-Mayer C. Rice C.M. et al.Hepatitis C virus glycoproteins mediate pH-dependent cell entry of pseudotyped retroviral particles.Proc Natl Acad Sci USA. 2003; 100: 7271-7276Crossref PubMed Scopus (687) Google Scholar]. A major step forward towards the study of viral replication was the development of HCV replicons, based on the self-replication of engineered minigenomes in human hepatoma cell lines [[8]Lohmann V. Körner F. Koch J.O. Herian U. Theilmann L. Bartenschlager R. Replication of subgenomic hepatitis C virus RNAs in a hepatoma cell line.Science. 1999; 285: 110-113Crossref PubMed Scopus (2480) Google Scholar]. Replicon-based-systems have allowed the elucidation and dissection of the viral replication complex, the study of mechanisms of viral resistance and the exploration of novel antiviral approaches. Although extremely useful in the study of HCV genomic replication and screening for antiviral drugs, this system does not yet enable the study of viral infection or virus particle production. Finally, a novel model system for the efficient production of viral particles has been reported very recently [[9]Heller T. Saito S. Auerbach J. Williams T. Moreen T.R. Jazwinski A. et al.An in vitro model of hepatitis C virion production.Proc Natl Acad Sci USA. 2005; 102: 2579-2583Crossref PubMed Scopus (108) Google Scholar]. Whether particles synthesized in this system are infectious is currently under investigation [[9]Heller T. Saito S. Auerbach J. Williams T. Moreen T.R. Jazwinski A. et al.An in vitro model of hepatitis C virion production.Proc Natl Acad Sci USA. 2005; 102: 2579-2583Crossref PubMed Scopus (108) Google Scholar].2. Production of infectious HCV in tissue cultureIn a collaborative approach, several groups now succeeded in establishing the long-sought-after cell culture system for HCV [10Wakita T. Pietschmann T. Kato T. Date T. Miyamoto M. Zhao Z. et al.Production of infectious hepatitis C virus in tissue culture from a cloned viral genome.Nat Med. 2005; Jun 12 ([Epub ahead of print])Google Scholar, 11Lindenbach B.D. Evans M.J. Syder A.J. Wolk B. Tellinghuisen T.L. Liu C.C. et al.Complete replication of hepatitis C virus in cell culture.Science. 2005; Jun 9 ([Epub ahead of print])Google Scholar, 12Zhong J. Gastaminza P. Cheng G. Kapadia S. Kato T. Burton D.R. et al.Robust hepatitis C virus infection in vitro.Proc Natl Acad Sci USA. 2005; 102: 9294-9299Crossref PubMed Scopus (1507) Google Scholar]. The first step towards this breakthrough was the development of a unique HCV genotype 2a replicon (JFH1)—derived from a viral isolate of a patient with fulminant hepatitis C—that replicates efficiently in human hepatoma Huh7 cells without adaptive mutations [[13]Kato T. Date T. Miyamoto M. Furusaka A. Tokushige K. Mizokami M. et al.Efficient replication of the genotype 2a hepatitis C virus subgenomic replicon.Gastroenterology. 2003; 125: 1808-1817Abstract Full Text Full Text PDF PubMed Scopus (495) Google Scholar]. Independently, three papers published almost at the same time showed that transfection of full-length JFH1 or chimeric J6/JFH1 genomes into Huh7 or Huh7-derived cells results in secretion of infectious virus. Successful infection of naïve hepatoma cells with recombinant virions was demonstrated by detection of viral proteins and a highly reproducible time-dependent increase of viral RNA in infected cells [10Wakita T. Pietschmann T. Kato T. Date T. Miyamoto M. Zhao Z. et al.Production of infectious hepatitis C virus in tissue culture from a cloned viral genome.Nat Med. 2005; Jun 12 ([Epub ahead of print])Google Scholar, 11Lindenbach B.D. Evans M.J. Syder A.J. Wolk B. Tellinghuisen T.L. Liu C.C. et al.Complete replication of hepatitis C virus in cell culture.Science. 2005; Jun 9 ([Epub ahead of print])Google Scholar, 12Zhong J. Gastaminza P. Cheng G. Kapadia S. Kato T. Burton D.R. et al.Robust hepatitis C virus infection in vitro.Proc Natl Acad Sci USA. 2005; 102: 9294-9299Crossref PubMed Scopus (1507) Google Scholar]. Using control clones containing a mutation of the NS5B polymerase active site or a deletion of viral envelope glycoproteins, the authors elegantly demonstrated that the synthesis of infectious viral particles was dependent on an active viral polymerase and expression of a functional viral envelope containing HCV envelope glycoproteins E1 and E2 [10Wakita T. Pietschmann T. Kato T. Date T. Miyamoto M. Zhao Z. et al.Production of infectious hepatitis C virus in tissue culture from a cloned viral genome.Nat Med. 2005; Jun 12 ([Epub ahead of print])Google Scholar, 11Lindenbach B.D. Evans M.J. Syder A.J. Wolk B. Tellinghuisen T.L. Liu C.C. et al.Complete replication of hepatitis C virus in cell culture.Science. 2005; Jun 9 ([Epub ahead of print])Google Scholar, 12Zhong J. Gastaminza P. Cheng G. Kapadia S. Kato T. Burton D.R. et al.Robust hepatitis C virus infection in vitro.Proc Natl Acad Sci USA. 2005; 102: 9294-9299Crossref PubMed Scopus (1507) Google Scholar].Using an antibody directed against an epitope of the HCV envelope glycoprotein E2, the Bartenschlager group was able for the first time to visualize cell culture-derived JFH1 virions by immunoelectron microscopy [[10]Wakita T. Pietschmann T. Kato T. Date T. Miyamoto M. Zhao Z. et al.Production of infectious hepatitis C virus in tissue culture from a cloned viral genome.Nat Med. 2005; Jun 12 ([Epub ahead of print])Google Scholar]. HCV particles were 50–65 nm in diameter, the predicted size of HCV. Secreted virions were further characterized biophysically by sucrose density gradient centrifugation: the peak HCV RNA fraction which also contained HCV core, E1 and E2 proteins had a density of about 1.15–1.17 g/ml. Interestingly, viral particles exhibiting the highest infection efficiency had an apparent density of about 1.09–1.10 and 1.105 g/ml as reported by the Rice and Chisari labs, respectively [11Lindenbach B.D. Evans M.J. Syder A.J. Wolk B. Tellinghuisen T.L. Liu C.C. et al.Complete replication of hepatitis C virus in cell culture.Science. 2005; Jun 9 ([Epub ahead of print])Google Scholar, 12Zhong J. Gastaminza P. Cheng G. Kapadia S. Kato T. Burton D.R. et al.Robust hepatitis C virus infection in vitro.Proc Natl Acad Sci USA. 2005; 102: 9294-9299Crossref PubMed Scopus (1507) Google Scholar]. By inoculating supernatant from transfected cells into a chimpanzee, the Liang and Wakita lab investigated the infectivity of this JFH1 clone in vivo [[10]Wakita T. Pietschmann T. Kato T. Date T. Miyamoto M. Zhao Z. et al.Production of infectious hepatitis C virus in tissue culture from a cloned viral genome.Nat Med. 2005; Jun 12 ([Epub ahead of print])Google Scholar]. In deed, the inoculated chimpanzee developed a mild and transient HCV infection, which proved that the recombinant virions were infective in vivo.Although all three groups used JFH1-derived HCV full-length clones for synthesis of viral particles, the studies differed in the hepatoma cell lines used. Whereas Wakita and colleagues transfected and infected native Huh7 cells as well as a highly permissive Huh7-derived cell clone, the Rice and Chisari labs used Huh7.5 and Huh7.5.1 cells for the generation of virions and infectivity studies. Huh7.5 and Huh7.5.1 cells are HCV-adapted cell lines generated by curing replicon expressing-Huh7 and Huh7.5 cells with IFN-α and IFN-γ, respectively [11Lindenbach B.D. Evans M.J. Syder A.J. Wolk B. Tellinghuisen T.L. Liu C.C. et al.Complete replication of hepatitis C virus in cell culture.Science. 2005; Jun 9 ([Epub ahead of print])Google Scholar, 12Zhong J. Gastaminza P. Cheng G. Kapadia S. Kato T. Burton D.R. et al.Robust hepatitis C virus infection in vitro.Proc Natl Acad Sci USA. 2005; 102: 9294-9299Crossref PubMed Scopus (1507) Google Scholar]. Infection efficiencies seemed to be comparable between these different cell lines, although Huh7.5 cells showed faster infection kinetics [11Lindenbach B.D. Evans M.J. Syder A.J. Wolk B. Tellinghuisen T.L. Liu C.C. et al.Complete replication of hepatitis C virus in cell culture.Science. 2005; Jun 9 ([Epub ahead of print])Google Scholar, 12Zhong J. Gastaminza P. Cheng G. Kapadia S. Kato T. Burton D.R. et al.Robust hepatitis C virus infection in vitro.Proc Natl Acad Sci USA. 2005; 102: 9294-9299Crossref PubMed Scopus (1507) Google Scholar]. Interestingly, the authors reported that virus titers decrease upon serial passages in Huh7 cells [[10]Wakita T. Pietschmann T. Kato T. Date T. Miyamoto M. Zhao Z. et al.Production of infectious hepatitis C virus in tissue culture from a cloned viral genome.Nat Med. 2005; Jun 12 ([Epub ahead of print])Google Scholar], whereas no detectable loss in infectivity was observed for Huh7.5.1 cells [[12]Zhong J. Gastaminza P. Cheng G. Kapadia S. Kato T. Burton D.R. et al.Robust hepatitis C virus infection in vitro.Proc Natl Acad Sci USA. 2005; 102: 9294-9299Crossref PubMed Scopus (1507) Google Scholar]. These findings suggest that Huh7.5-derived hepatoma cells may be superior for the efficient production of infectious virions and may allow to define cellular factors modulating HCV infection. In fact, Huh7.5 cells carry a point mutation in the retinoic acid-inducible gene-I (RIG-I) which reduces the cell's innate immune defenses and may contribute to the higher permissiveness. Other, to date unknown, factors may also contribute to favor HCV life cycle in these cells [[14]Bartenschlager R. Pietschmann T. Efficient hepatitis C virus cell culture system: What a difference the host cell makes.Proc Natl Acad Sci USA. 2005; 102: 9739-9740Crossref PubMed Scopus (85) Google Scholar].A current limitation of this new HCV model is its dependence on the JFH1 non-structural genes. Nevertheless, the possibility to create chimeric infectious viruses broadens the scope of this system. The Bartenschlager group recently reported that chimeric viruses composed of the core to NS2 region of the Con1 isolate (genotype 1) and the JFH1 replicase (genotype 2a) are also infectious (T. Pietschmann, G. Koutsoudakis, S. Kallis, T. Kato, S. Foung, T. Wakita and R. Bartenschlager, 11th International symposium on hepatitis C virus and related viruses, Heidelberg, October 2004). Similarly, the analogous chimera composed of the genotype 2a J6 and the JFH1 replicase also supports production of infectious HCV particles [[11]Lindenbach B.D. Evans M.J. Syder A.J. Wolk B. Tellinghuisen T.L. Liu C.C. et al.Complete replication of hepatitis C virus in cell culture.Science. 2005; Jun 9 ([Epub ahead of print])Google Scholar]. However, there seem to be some limitations in creating infectious chimera, as full-length chimeric genomes composed of the core-NS2 region from the infectious H77 (genotype 1a) and JFH1 NS3-NS5B genes are not infectious [[11]Lindenbach B.D. Evans M.J. Syder A.J. Wolk B. Tellinghuisen T.L. Liu C.C. et al.Complete replication of hepatitis C virus in cell culture.Science. 2005; Jun 9 ([Epub ahead of print])Google Scholar]. Further studies are needed to elucidate viral and host factors required for production of infectious particles and for generating of infectious viruses of other genotypes.3. Impact for the study of viral life cycle and the development of antivirals and vaccinesThis cell culture-based model finally allows the study of all aspects of the HCV life cycle including viral attachment, entry, trafficking, replication, assembly and egress (Fig. 1). In a first approach to identify viral and cellular components involved in viral entry, the groups independently showed that viral envelope glycoprotein E2 as well as cellular CD81 appear to be essential for viral infection [10Wakita T. Pietschmann T. Kato T. Date T. Miyamoto M. Zhao Z. et al.Production of infectious hepatitis C virus in tissue culture from a cloned viral genome.Nat Med. 2005; Jun 12 ([Epub ahead of print])Google Scholar, 11Lindenbach B.D. Evans M.J. Syder A.J. Wolk B. Tellinghuisen T.L. Liu C.C. et al.Complete replication of hepatitis C virus in cell culture.Science. 2005; Jun 9 ([Epub ahead of print])Google Scholar, 12Zhong J. Gastaminza P. Cheng G. Kapadia S. Kato T. Burton D.R. et al.Robust hepatitis C virus infection in vitro.Proc Natl Acad Sci USA. 2005; 102: 9294-9299Crossref PubMed Scopus (1507) Google Scholar]. Anti-HCV antibodies in sera from HCV-infected patients were able to neutralize JFH1 viruses in a dose-dependent manner [[10]Wakita T. Pietschmann T. Kato T. Date T. Miyamoto M. Zhao Z. et al.Production of infectious hepatitis C virus in tissue culture from a cloned viral genome.Nat Med. 2005; Jun 12 ([Epub ahead of print])Google Scholar], suggesting that this cell culture model also provides a very valuable tool to study the role of neutralizing antibodies in HCV infection. In addition, this system may be extremely useful for screening and development of antiviral drugs. In fact, Lindenbach and colleagues reported that in vitro HCV infection can be efficiently inhibited by IFN-α and several HCV-specific antiviral compounds, such as NS3 serine protease-inhibitors and a nucleoside analogue targeting the NS5B polymerase [[11]Lindenbach B.D. Evans M.J. Syder A.J. Wolk B. Tellinghuisen T.L. Liu C.C. et al.Complete replication of hepatitis C virus in cell culture.Science. 2005; Jun 9 ([Epub ahead of print])Google Scholar]. Finally, this new HCV infection model may also contribute to HCV vaccine development by gaining novel insights into antiviral innate and adaptive immune responses such as the molecular analysis of antibody-mediated virus neutralization. The future applications of this system clearly demonstrate that the development of this model marks a breakthrough for HCV research. 1. Hepatitis C virus: the need for model systemsHepatitis C virus (HCV) is a major cause of posttransfusion and community-acquired hepatitis in the world [[1]Rehermann B. Nascimbeni M. Immunology of hepatitis B virus and hepatitis C virus infection.Nat Rev Immunol. 2005; 5: 215-229Crossref PubMed Scopus (1353) Google Scholar]. The majority of HCV-infected individuals develop chronic hepatitis that may progress to liver cirrhosis and hepatocellular carcinoma. Treatment options for chronic HCV infection are limited and a vaccine to prevent HCV infection is not available [[1]Rehermann B. Nascimbeni M. Immunology of hepatitis B virus and hepatitis C virus infection.Nat Rev Immunol. 2005; 5: 215-229Crossref PubMed Scopus (1353) Google Scholar]. The development of efficient antivirals and a vaccine has been hampered by the lack of an efficient tissue culture model for HCV infection.Several in vitro models for the study of HCV infection have been described. These models include human lymphocytic cell lines, human biliary epithelial cells, and primary hepatocytes from humans, chimpanzees or tree shrews (Tupaia belangeri). Primary hepatocytes can be successfully infected by serum-derived HCV [2Castet V. Fournier C. Soulier A. Brillet R. Coste J. Larrey D. et al.Alpha interferon inhibits hepatitis C virus replication in primary human hepatocytes infected in vitro.J Virol. 2002; 76: 8189-8199Crossref PubMed Scopus (110) Google Scholar, 3Barth H. Cerino R. Arcuri M. Hoffmann M. Schurmann P. Adah M.I. et al.Scavenger receptor class B type I and hepatitis C virus infection of primary tupaia hepatocytes.J Virol. 2005; 79: 5774-5785Crossref PubMed Scopus (73) Google Scholar]. Limitations of these systems are the low level of HCV replication requiring RT-PCR for detection of viral infection, the variable quality of host cells such as human hepatocytes obtained from surgical specimens and the lack of a well-defined viral inoculum.Alternative model systems have been developed for the study of defined aspects of the HCV life cycle such as viral entry, replication, assembly and release (Fig. 1). Recombinant HCV envelope glycoproteins [[4]Pileri P. Uematsu Y. Campagnoli S. Galli G. Falugi F. Petracca R. et al.Binding of hepatitis C virus to CD81.Science. 1998; 282: 938-941Crossref PubMed Scopus (1779) Google Scholar], HCV-like particles (HCV-LPs) [3Barth H. Cerino R. Arcuri M. Hoffmann M. Schurmann P. Adah M.I. et al.Scavenger receptor class B type I and hepatitis C virus infection of primary tupaia hepatocytes.J Virol. 2005; 79: 5774-5785Crossref PubMed Scopus (73) Google Scholar, 5Wellnitz S. Klumpp B. Barth H. Ito S. Depla E. Dubuisson J. et al.Binding of hepatitis C virus-like particles derived from infectious clone H77C to defined human cell lines.J Virol. 2002; 76: 1181-1193Crossref PubMed Scopus (89) Google Scholar] and retroviral HCV pseudotypes (HCVpp) [6Bartosch 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 (942) Google Scholar, 7Hsu M. Zhang J. Flint M. Logvinoff C. Cheng-Mayer C. Rice C.M. et al.Hepatitis C virus glycoproteins mediate pH-dependent cell entry of pseudotyped retroviral particles.Proc Natl Acad Sci USA. 2003; 100: 7271-7276Crossref PubMed Scopus (687) Google Scholar] have been successfully used to analyze virus attachment and entry. These systems allowed the isolation and functional analysis of CD81, scavenger receptor BI and highly sulfated heparan sulfate as cell surface molecules involved in viral attachment and entry [3Barth H. Cerino R. Arcuri M. Hoffmann M. Schurmann P. Adah M.I. et al.Scavenger receptor class B type I and hepatitis C virus infection of primary tupaia hepatocytes.J Virol. 2005; 79: 5774-5785Crossref PubMed Scopus (73) Google Scholar, 4Pileri P. Uematsu Y. Campagnoli S. Galli G. Falugi F. Petracca R. et al.Binding of hepatitis C virus to CD81.Science. 1998; 282: 938-941Crossref PubMed Scopus (1779) Google Scholar, 5Wellnitz S. Klumpp B. Barth H. Ito S. Depla E. Dubuisson J. et al.Binding of hepatitis C virus-like particles derived from infectious clone H77C to defined human cell lines.J Virol. 2002; 76: 1181-1193Crossref PubMed Scopus (89) Google Scholar, 6Bartosch 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 (942) Google Scholar, 7Hsu M. Zhang J. Flint M. Logvinoff C. Cheng-Mayer C. Rice C.M. et al.Hepatitis C virus glycoproteins mediate pH-dependent cell entry of pseudotyped retroviral particles.Proc Natl Acad Sci USA. 2003; 100: 7271-7276Crossref PubMed Scopus (687) Google Scholar]. A major step forward towards the study of viral replication was the development of HCV replicons, based on the self-replication of engineered minigenomes in human hepatoma cell lines [[8]Lohmann V. Körner F. Koch J.O. Herian U. Theilmann L. Bartenschlager R. Replication of subgenomic hepatitis C virus RNAs in a hepatoma cell line.Science. 1999; 285: 110-113Crossref PubMed Scopus (2480) Google Scholar]. Replicon-based-systems have allowed the elucidation and dissection of the viral replication complex, the study of mechanisms of viral resistance and the exploration of novel antiviral approaches. Although extremely useful in the study of HCV genomic replication and screening for antiviral drugs, this system does not yet enable the study of viral infection or virus particle production. Finally," @default.
• W2089014790 created "2016-06-24" @default.
• W2089014790 creator A5000691119 @default.
• W2089014790 creator A5013323616 @default.
• W2089014790 date "2006-02-01" @default.
• W2089014790 modified "2023-09-27" @default.
• W2089014790 title "Production of infectious hepatitis C virus in tissue culture: A breakthrough for basic and applied research" @default.
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