title: High-avidity monoclonal antibodies against the human scavenger class B type I receptor efficiently block hepatitis C virus infection in the presence of high-density lipoprotein.
abstract: The human scavenger class B type 1 receptor (SR-B1/Cla1) was identified as a putative receptor for hepatitis C virus (HCV) because it binds to soluble recombinant HCV envelope glycoprotein E2 (sE2). High-density lipoprotein (HDL), a natural SR-B1 ligand, was shown to increase the in vitro infectivity of retroviral pseudoparticles bearing HCV envelope glycoproteins and of cell culture-derived HCV (HCVcc), suggesting that SR-B1 promotes viral entry in an HDL-dependent manner. To determine whether SR-B1 participates directly in HCV infection or facilitates HCV entry through lipoprotein uptake, we generated a panel of monoclonal antibodies (MAbs) against native human SR-B1. Two of them, 3D5 and C167, bound to conformation-dependent SR-B1 determinants and inhibited the interaction of sE2 with SR-B1. These antibodies efficiently blocked HCVcc infection of Huh-7.5 hepatoma cells in a dose-dependent manner. To examine the role of HDL in SR-B1-mediated HCVcc infection, we set up conditions for HCVcc production and infection in serum-free medium. HCVcc efficiently infected Huh-7.5 cells in the absence of serum lipoproteins, and addition of HDL led to a twofold increase in infectivity. However, the HDL-induced enhancement of infection had no impact on the neutralization potency of MAb C167, despite its ability to inhibit both HDL binding to cells and SR-B1-mediated lipid transfer. Of note, MAb C167 also potently blocked Huh-7.5 infection by an HCV strain recovered from HCVcc-infected chimpanzees. These results demonstrate that SR-B1 is essential for infection with HCV produced in vitro and in vivo and suggest the possible use of anti-SR-B1 antibodies as therapeutic agents.
authors.affiliation: Istituto di Ricerche di Biologia Molecolare P. Angeletti, 00040 Pomezia, Rome, Italy.
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Catanese
authors.forename: Rita
authors.initials: R
authors.lastname: Graziani
authors.forename: Thomas
authors.initials: T
authors.lastname: von Hahn
authors.forename: Martine
authors.initials: M
authors.lastname: Moreau
authors.forename: Thierry
authors.initials: T
authors.lastname: Huby
authors.forename: Giacomo
authors.initials: G
authors.lastname: Paonessa
authors.forename: Claudia
authors.initials: C
authors.lastname: Santini
authors.forename: Alessandra
authors.initials: A
authors.lastname: Luzzago
authors.forename: Charles M
authors.initials: CM
authors.lastname: Rice
authors.forename: Riccardo
authors.initials: R
authors.lastname: Cortese
authors.forename: Alessandra
authors.initials: A
authors.lastname: Vitelli
authors.forename: Alfredo
authors.initials: A
authors.lastname: Nicosia
mesh_terms: D000911:Antibodies, Monoclonal / Q000276:immunology*; D000915:Antibody Affinity; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism; D016174:Hepacivirus / Q000276:immunology*; D006526:Hepatitis C / Q000276:immunology / Q000517:prevention & control; D006801:Humans; D008075:Lipoproteins, HDL / Q000378:metabolism*; D051122:Scavenger Receptors, Class B / Q000235:genetics / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D008075:Lipoproteins, HDL; C495124:SCARB1 protein, human; D051122:Scavenger Receptors, Class B; D002784:Cholesterol