title: Scavenger receptor BI and BII expression levels modulate hepatitis C virus infectivity.
abstract: Hepatitis C virus (HCV) enters cells via a pH- and clathrin-dependent endocytic pathway. Scavenger receptor BI (SR-BI) and CD81 are important entry factors for HCV internalization into target cells. The SR-BI gene gives rise to at least two mRNA splice variants, SR-BI and SR-BII, which differ in their C termini. SR-BI internalization remains poorly understood, but SR-BII is reported to endocytose via a clathrin-dependent pathway, making it an attractive target for HCV internalization. We demonstrate that HCV soluble E2 can interact with human SR-BI and SR-BII. Increased expression of SR-BI and SR-BII in the Huh-7.5 hepatoma cell line enhanced HCV strain J6/JFH and JFH infectivity, suggesting that endogenous levels of these receptors limit infection. Elevated expression of SR-BI, but not SR-BII, increased the rate of J6/JFH infection, which may reflect altered intracellular trafficking of the splice variants. In human plasma, HCV particles have been reported to be complexed with lipoproteins, suggesting an indirect interaction of the virus with SR-BI and other lipoprotein receptors. Plasma from J6/JFH-infected uPA-SCID mice transplanted with human hepatocytes demonstrates an increased infectivity for SR-BI/II-overexpressing Huh-7.5 cells. Plasma-derived J6/JFH infectivity was inhibited by an anti-E2 monoclonal antibody, suggesting that plasma virus interaction with SR-BI was glycoprotein dependent. Finally, anti-SR-BI antibodies inhibited the infectivity of cell culture- and plasma-derived J6/JFH, suggesting a critical role for SR-BI/II in HCV infection.
authors.affiliation: Division of Immunity and Infection, Institute for Biomedical Research, The Medical School, Birmingham University, Edgbaston B14 2TT, United Kingdom.
authors.forename: Joe
authors.initials: J
authors.lastname: Grove
authors.forename: Thierry
authors.initials: T
authors.lastname: Huby
authors.forename: Zania
authors.initials: Z
authors.lastname: Stamataki
authors.forename: Thomas
authors.initials: T
authors.lastname: Vanwolleghem
authors.forename: Philip
authors.initials: P
authors.lastname: Meuleman
authors.forename: Michelle
authors.initials: M
authors.lastname: Farquhar
authors.forename: Anne
authors.initials: A
authors.lastname: Schwarz
authors.forename: Martine
authors.initials: M
authors.lastname: Moreau
authors.forename: James S
authors.initials: JS
authors.lastname: Owen
authors.forename: Geert
authors.initials: G
authors.lastname: Leroux-Roels
authors.forename: Peter
authors.initials: P
authors.lastname: Balfe
authors.forename: Jane A
authors.initials: JA
authors.lastname: McKeating
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology; D002460:Cell Line; D006224:Cricetinae; D005786:Gene Expression Regulation; D016174:Hepacivirus / Q000502:physiology*; D006801:Humans; D051907:Lysosomal Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D051116:Receptors, Scavenger / Q000235:genetics / Q000378:metabolism*; D051122:Scavenger Receptors, Class B / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D012995:Solubility; D014759:Viral Envelope Proteins / Q000378:metabolism
chemical_list: D000906:Antibodies; D051907:Lysosomal Membrane Proteins; D051116:Receptors, Scavenger; C495124:SCARB1 protein, human; C074299:SCARB2 protein, human; D051122:Scavenger Receptors, Class B; D014759:Viral Envelope Proteins; C091015:glycoprotein E2, Hepatitis C virus