title: Characterization of host-range and cell entry properties of the major genotypes and subtypes of hepatitis C virus.
abstract: Because of the lack of a robust cell culture system, relatively little is known about the molecular details of the cell entry mechanism for hepatitis C virus (HCV). Recently, we described infectious HCV pseudo-particles (HCVpp) that were generated by incorporating unmodified HCV E1E2 glycoproteins into the membrane of retroviral core particles. These initial studies, performed with E1E2 glycoproteins of genotype 1, noted that HCVpp closely mimic the cell entry and neutralization properties of parental HCV. Because sequence variations in E1 and E2 may account for differences in tropism, replication properties, neutralization, and response to treatment in patients infected with different genotypes, we investigated the functional properties of HCV envelope glycoproteins from different genotypes/subtypes. Our studies indicate that hepatocytes were preferential targets of infection in vitro, although HCV replication in extrahepatic sites has been reported in vivo. Receptor competition assays using antibodies against the CD81 ectodomain as well as ectopic expression of CD81 in CD81-deficient HepG2 cells indicated that CD81 is used by all the different genotypes/subtypes analyzed to enter the cells. However, by silencing RNA (siRNA) interference assays, our results show that the level of Scavenger Receptor Class-B Type-I (SR-BI) needed for efficient infection varies between genotypes and subtypes. Finally, sera from chronic HCV carriers were found to exhibit broadly reactive activities that inhibited HCVpp cell entry, but failed to neutralize all the different genotypes. In conclusion, we characterize common steps in the cell entry pathways of the major HCV genotypes that should provide clues for the development of cell entry inhibitors and vaccines.
authors.affiliation: Laboratoire de Vectorologie Rétrovirale et Thérapie Génique, INSERM U412, IFR128, BioSciences Lyon-Gerland, Ecole Normale Supérieure de Lyon, Lyon, France.
authors.forename: Dimitri
authors.initials: D
authors.lastname: Lavillette
authors.forename: Alexander W
authors.initials: AW
authors.lastname: Tarr
authors.forename: Cécile
authors.initials: C
authors.lastname: Voisset
authors.forename: Peggy
authors.initials: P
authors.lastname: Donot
authors.forename: Birke
authors.initials: B
authors.lastname: Bartosch
authors.forename: Christine
authors.initials: C
authors.lastname: Bain
authors.forename: Arvind H
authors.initials: AH
authors.lastname: Patel
authors.forename: Jean
authors.initials: J
authors.lastname: Dubuisson
authors.forename: Jonathan K
authors.initials: JK
authors.lastname: Ball
authors.forename: François-Loïc
authors.initials: FL
authors.lastname: Cosset
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000502:physiology; D001790:Blood Physiological Phenomena; D018955:CD36 Antigens; D002353:Carrier State / Q000097:blood; D002460:Cell Line; D005838:Genotype; D016174:Hepacivirus / Q000235:genetics / Q000502:physiology*; D022781:Hepatocytes / Q000378:metabolism / Q000821:virology*; D006801:Humans; D011971:Receptors, Immunologic / Q000502:physiology; D051116:Receptors, Scavenger; D051122:Scavenger Receptors, Class B; D060225:Tetraspanin 28; D014759:Viral Envelope Proteins / Q000378:metabolism / Q000502:physiology*; D014771:Virion / Q000378:metabolism / Q000502:physiology; D019065:Virus Assembly
chemical_list: D015703:Antigens, CD; D018955:CD36 Antigens; C554798:CD81 protein, human; D011971:Receptors, Immunologic; D051116:Receptors, Scavenger; C495124:SCARB1 protein, human; D051122:Scavenger Receptors, Class B; D060225:Tetraspanin 28; D014759:Viral Envelope Proteins