title: Functional and Biochemical Characterization of Hepatitis C Virus (HCV) Particles Produced in a Humanized Liver Mouse Model.
abstract: Lipoprotein components are crucial factors for hepatitis C virus (HCV) assembly and entry. As hepatoma cells producing cell culture-derived HCV (HCVcc) particles are impaired in some aspects of lipoprotein metabolism, it is of upmost interest to biochemically and functionally characterize the in vivo produced viral particles, particularly regarding how lipoprotein components modulate HCV entry by lipid transfer receptors such as scavenger receptor BI (SR-BI). Sera from HCVcc-infected liver humanized FRG mice were separated by density gradients. Viral subpopulations, termed HCVfrg particles, were characterized for their physical properties, apolipoprotein association, and infectivity. We demonstrate that, in contrast to the widely spread distribution of apolipoproteins across the different HCVcc subpopulations, the most infectious HCVfrg particles are highly enriched in apoE, suggesting that such apolipoprotein enrichment plays a role for entry of in vivo derived infectious particles likely via usage of apolipoprotein receptors. Consistent with this salient feature, we further reveal previously undefined functionalities of SR-BI in promoting entry of in vivo produced HCV. First, unlike HCVcc, SR-BI is a particularly limiting factor for entry of HCVfrg subpopulations of very low density. Second, HCVfrg entry involves SR-BI lipid transfer activity but not its capacity to bind to the viral glycoprotein E2. In conclusion, we demonstrate that composition and biophysical properties of the different subpopulations of in vivo produced HCVfrg particles modulate their levels of infectivity and receptor usage, hereby featuring divergences with in vitro produced HCVcc particles and highlighting the powerfulness of this in vivo model for the functional study of the interplay between HCV and liver components.
authors.forename: Sara
authors.initials: S
authors.lastname: Calattini
authors.forename: Floriane
authors.initials: F
authors.lastname: Fusil
authors.forename: Jimmy
authors.initials: J
authors.lastname: Mancip
authors.forename: Viet Loan
authors.initials: VL
authors.lastname: Dao Thi
authors.forename: Christelle
authors.initials: C
authors.lastname: Granier
authors.affiliation: Structure Fédérative de Recherche (SFR) Lyon-Est, ANIPATH-Centre d'Histopathologie du Petit Animal de laboratoire, CNRS UMS3453-INSERM US7, 69372 Lyon, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Gadot
authors.affiliation: Structure Fédérative de Recherche (SFR) Lyon-Est, ANIPATH-Centre d'Histopathologie du Petit Animal de laboratoire, CNRS UMS3453-INSERM US7, 69372 Lyon, France.
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Scoazec
authors.affiliation: INSERM, U1110, Institut des Maladies Virales et Hépatiques, 67000 Strasbourg, France, University of Strasbourg, 67000 Strasbourg, France, and.
authors.forename: Mirjam B
authors.initials: MB
authors.lastname: Zeisel
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Baumert
authors.forename: Dimitri
authors.initials: D
authors.lastname: Lavillette
authors.affiliation: marlene.dreux@ens-lyon.fr.
authors.forename: Marlène
authors.initials: M
authors.lastname: Dreux
authors.affiliation: flcosset@ens-lyon.fr.
authors.forename: François-Loïc
authors.initials: FL
authors.lastname: Cosset
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D004195:Disease Models, Animal; D016174:Hepacivirus / Q000235:genetics / Q000378:metabolism*; D006526:Hepatitis C / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D051379:Mice; D018345:Mice, Knockout; D051122:Scavenger Receptors, Class B / Q000235:genetics / Q000378:metabolism; D014759:Viral Envelope Proteins / Q000235:genetics / Q000378:metabolism; D053586:Virus Internalization
chemical_list: D001057:Apolipoproteins E; C454739:Scarb1 protein, mouse; D051122:Scavenger Receptors, Class B; D014759:Viral Envelope Proteins; C091015:glycoprotein E2, Hepatitis C virus
keywords: animal model; apolipoprotein; hepatitis C virus (HCV); in vivo study; lipoprotein; scavenger receptor; virus entry