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Journal of Virology, July 2005, p. 8217-8229, Vol. 79, No. 13
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.13.8217-8229.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

An Interplay between Hypervariable Region 1 of the Hepatitis C Virus E2 Glycoprotein, the Scavenger Receptor BI, and High-Density Lipoprotein Promotes both Enhancement of Infection and Protection against Neutralizing Antibodies

Birke Bartosch,1 Géraldine Verney,1,{dagger} Marlène Dreux,1,{dagger} Peggy Donot,1 Yoann Morice,2 François Penin,3 Jean-Michel Pawlotsky,2 Dimitri Lavillette,1 and Francois-Loïc Cosset1*

Laboratoire de Vectorologie Rétrovirale et Thérapie Génique, INSERM U412, Ecole Normale Supérieure de Lyon, IFR128 BioSciences Lyon-Gerland, 46 allée d'Italie, 69364 Lyon cedex 07, France,1 Department of Virology, INSERM U635, Hôpital Henri Mondor, Université Paris XII, 51 avenue du Maréchal de Lattre de Tassigny, 94010 Créteil, France,2 Institut de Biologie et Chimie des Protéines, UMR 5086 CNRS-Université Claude Bernard Lyon-I, IFR128 BioSciences Lyon-Gerland, 7 passage du Vercors, 69367 Lyon Cedex 07, France3

Received 16 January 2005/ Accepted 19 March 2005

Hepatitis C virus (HCV) circulates in the bloodstream in different forms, including complexes with immunoglobulins and/or lipoproteins. To address the significance of such associations, we produced or treated HCV pseudoparticles (HCVpp), a valid model of HCV cell entry and its inhibition, with naïve or patient-derived sera. We demonstrate that infection of hepatocarcinoma cells by HCVpp is increased more than 10-fold by human serum factors, of which high-density lipoprotein (HDL) is a major component. Infection enhancement requires scavenger receptor BI, a molecule known to mediate HDL uptake into cells as well as HCVpp entry, and involves conserved amino acid positions in hypervariable region 1 (HVR1) of the E2 glycoprotein. Additionally, we show that the interaction with human serum or HDL, but not with low-density lipoprotein, leads to the protection of HCVpp from neutralizing antibodies, including monoclonal antibodies and antibodies present in patient sera. Finally, the deletion or mutation of HVR1 in HCVpp abolishes infection enhancement and leads to increased sensitivity to neutralizing antibodies/sera compared to that of parental HCVpp. Altogether, these results assign to HVR1 new roles which are complementary in helping HCV to survive within its host. Besides immune escape by mutation, HRV1 can mediate the enhancement of cell entry and the protection of virions from neutralizing antibodies. By preserving a balance between these functions, HVR1 may be essential for the viral persistence of HCV.

* Corresponding author. Mailing address: LVRTG, ENS de Lyon, 46 Allée d'Italie, 69364 Lyon Cedex 07, France. Phone: 33 472 72 87 32. Fax: 33 472 72 80 80. E-mail: flcosset{at}ens-lyon.fr.

{dagger} These authors contributed equally to this work.

Journal of Virology, July 2005, p. 8217-8229, Vol. 79, No. 13
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.13.8217-8229.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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