Oxidized low-density lipoprotein inhibits hepatitis C virus cell entry in human hepatoma cells.
Cell entry of hepatitis C virus, pseudoparticles (HCVpp) and cell culture grown virus (HCVcc), requires the interaction of viral glycoproteins with CD81 and other as yet unknown cellular factors. One of these is likely to be the scavenger receptor class B type I (SR-BI). To further understand the role of SR-BI, we examined the effect of SR-BI ligands on HCVpp and HCVcc infectivity. Oxidized low-density lipoprotein (oxLDL), but not native LDL, potently inhibited HCVpp and HCVcc cell entry. Pseudoparticles bearing unrelated viral glycoproteins or bovine viral diarrhea virus were not affected. A dose-dependent inhibition was observed for HCVpp bearing diverse viral glycoproteins with an approximate IC50 of 1.5 microg/mL apolipoprotein content, which is within the range of oxLDL reported to be present in human plasma. The ability of lipoprotein components to bind to target cells associated with their antiviral activity, suggesting a mechanism of action which targets a cell surface receptor critical for HCV infection of the host cell. However, binding of soluble E2 to SR-BI or CD81 was not affected by oxLDL, suggesting that oxLDL does not act as a simple receptor blocker. At the same time, oxLDL incubation altered the biophysical properties of HCVpp, suggesting a ternary interaction of oxLDL with both virus and target cells. In conclusion, the SR-BI ligand oxLDL is a potent cell entry inhibitor for a broad range of HCV strains in vitro. These findings suggest that SR-BI is an essential component of the cellular HCV receptor complex.
von Hahn
Thomas
T
Center for the Study of Hepatitis C, The Rockefeller University, New York, NY 10021, USA. vonhaht@rockefeller.edu
Lindenbach
Brett D
BD
Boullier
Agnès
A
Quehenberger
Oswald
O
Paulson
Matthew
M
Rice
Charles M
CM
McKeating
Jane A
JA
D018955:CD36 Antigens / Q000502:physiology; D006528:Carcinoma, Hepatocellular / Q000473:pathology / Q000821:virology*; D016174:Hepacivirus / Q000187:drug effects* / Q000472:pathogenicity*; D006801:Humans; D008077:Lipoproteins, LDL / Q000494:pharmacology*; D008113:Liver Neoplasms / Q000473:pathology / Q000821:virology*; D010084:Oxidation-Reduction; D014407:Tumor Cells, Cultured
D018955:CD36 Antigens; D008077:Lipoproteins, LDL; C099252:oxidized low density lipoprotein