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.
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.
Catanese
Maria Teresa
MT
Istituto di Ricerche di Biologia Molecolare P. Angeletti, 00040 Pomezia, Rome, Italy.
Graziani
Rita
R
von Hahn
Thomas
T
Moreau
Martine
M
Huby
Thierry
T
Paonessa
Giacomo
G
Santini
Claudia
C
Luzzago
Alessandra
A
Rice
Charles M
CM
Cortese
Riccardo
R
Vitelli
Alessandra
A
Nicosia
Alfredo
A
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*
D000911:Antibodies, Monoclonal; D008075:Lipoproteins, HDL; C495124:SCARB1 protein, human; D051122:Scavenger Receptors, Class B; D002784:Cholesterol