Role of scavenger receptor class B type I in hepatitis C virus entry: kinetics and molecular determinants.

Abstract

Scavenger receptor class B type I (SR-BI) is an essential receptor for hepatitis C virus (HCV) and a cell surface high-density-lipoprotein (HDL) receptor. The mechanism of SR-BI-mediated HCV entry, however, is not clearly understood, and the specific protein determinants required for the recognition of the virus envelope are not known. HCV infection is strictly linked to lipoprotein metabolism, and HCV virions may initially interact with SR-BI through associated lipoproteins before subsequent direct interactions of the viral glycoproteins with SR-BI occur. The kinetics of inhibition of cell culture-derived HCV (HCVcc) infection with an anti-SR-BI monoclonal antibody imply that the recognition of SR-BI by HCV is an early event of the infection process. Swapping and single-substitution mutants between mouse and human SR-BI sequences showed reduced binding to the recombinant soluble E2 (sE2) envelope glycoprotein, thus suggesting that the SR-BI interaction with the HCV envelope is likely to involve species-specific protein elements. Most importantly, SR-BI mutants defective for sE2 binding, although retaining wild-type activity for receptor oligomerization and binding to the physiological ligand HDL, were impaired in their ability to fully restore HCVcc infectivity when transduced into an SR-BI-knocked-down Huh-7.5 cell line. These findings suggest a specific and direct role for the identified residues in binding HCV and mediating virus entry. Moreover, the observation that different regions of SR-BI are involved in HCV and HDL binding supports the hypothesis that new therapeutic strategies aimed at interfering with virus/SR-BI recognition are feasible.

• Authors: Maria Teresa Catanese, Helenia Ansuini, Rita Graziani, Thierry Huby, Martine Moreau, Jonathan K Ball, Giacomo Paonessa, Charles M Rice, Riccardo Cortese, Alessandra Vitelli, Alfredo Nicosia
• Journal: Journal of virology (J Virol) Vol. 84 Issue 1 Pg. 34-43 (Jan 2010) ISSN: 1098-5514 [Electronic] United States
• PMID: 19828610 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• Lipoproteins, HDL
• Receptors, Virus
• Scavenger Receptors, Class B

Topics

• Animals
• Antibodies, Monoclonal
• Cells, Cultured
• Hepacivirus (immunology, physiology)
• Hepatitis C (immunology)
• Humans
• Kinetics
• Lipoproteins, HDL (metabolism)
• Mice
• Receptors, Virus
• Scavenger Receptors, Class B (metabolism, physiology)
• Species Specificity
• Virus Internalization