title: Different requirements for scavenger receptor class B type I in hepatitis C virus cell-free versus cell-to-cell transmission.
abstract: Hepatitis C virus (HCV) is believed to initially infect the liver through the basolateral side of hepatocytes, where it engages attachment factors and the coreceptors CD81 and scavenger receptor class B type I (SR-BI). Active transport toward the apical side brings the virus in close proximity of additional entry factors, the tight junction molecules claudin-1 and occludin. HCV is also thought to propagate via cell-to-cell spread, which allows highly efficient virion delivery to neighboring cells. In this study, we compared an adapted HCV genome, clone 2, characterized by superior cell-to cell spread, to its parental genome, J6/JFH-1, with the goal of elucidating the molecular mechanisms of HCV cell-to-cell transmission. We show that CD81 levels on the donor cells influence the efficiency of cell-to-cell spread and CD81 transfer between neighboring cells correlates with the capacity of target cells to become infected. Spread of J6/JFH-1 was blocked by anti-SR-BI antibody or in cells knocked down for SR-BI, suggesting a direct role for this receptor in HCV cell-to-cell transmission. In contrast, clone 2 displayed a significantly reduced dependence on SR-BI for lateral spread. Mutations in E1 and E2 responsible for the enhanced cell-to-cell spread phenotype of clone 2 rendered cell-free virus more susceptible to antibody-mediated neutralization. Our results indicate that although HCV can lose SR-BI dependence for cell-to-cell spread, vulnerability to neutralizing antibodies may limit this evolutionary option in vivo. Combination therapies targeting both the HCV glycoproteins and SR-BI may therefore hold promise for effective control of HCV dissemination.
authors.affiliation: Center for the Study of Hepatitis C, Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, New York, USA.
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Catanese
authors.forename: Joana
authors.initials: J
authors.lastname: Loureiro
authors.forename: Christopher T
authors.initials: CT
authors.lastname: Jones
authors.forename: Marcus
authors.initials: M
authors.lastname: Dorner
authors.forename: Thomas
authors.initials: T
authors.lastname: von Hahn
authors.forename: Charles M
authors.initials: CM
authors.lastname: Rice
mesh_terms: D055785:Gene Knockdown Techniques; D016174:Hepacivirus / Q000502:physiology*; D054884:Host-Pathogen Interactions; D006801:Humans; D011991:Receptors, Virus / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051122:Scavenger Receptors, Class B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D060225:Tetraspanin 28 / Q000378:metabolism; D053586:Virus Internalization
chemical_list: C554798:CD81 protein, human; D011991:Receptors, Virus; C495124:SCARB1 protein, human; D051122:Scavenger Receptors, Class B; D060225:Tetraspanin 28