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J. Biol. Chem., Vol. 282, Issue 44, 32357-32369, November 2, 2007

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The Exchangeable Apolipoprotein ApoC-I Promotes Membrane Fusion of Hepatitis C Virus^*

Marlène Dreux¹, Bertrand Boson², Sylvie Ricard-Blum², Jennifer Molle, Dimitri Lavillette, Birke Bartosch, Eve-Isabelle Pécheur, and Francois-Loïc Cosset³

From the Université de Lyon, (UCB-Lyon1), IFR128, INSERM, U758, and Ecole Normale Supérieure de Lyon, Lyon, F-69007, France and IBCP, UMR5086 CNRS-UCB, Lyon-I, F-69007, France

Cell entry of hepatitis C virus (HCV) is strikingly linked to lipoproteins and their receptors. Particularly, high density lipoprotein (HDL) enhances infectivity of HCV by involving the lipid-transfer function of the scavenger receptor BI, a receptor for both HDL and HCV. Here, we demonstrate that apoC-I, an exchangeable apolipoprotein that predominantly resides in HDL, specifically enhances HCVcc and HCVpp infectivity and increases the fusion rates between viral and target membranes via a direct interaction with the HCV surface. We identify the hypervariable region 1, located at the N terminus of the HCV E2 glycoprotein, as an essential viral component that modulates apoC-I-mediated enhancement of HCV fusion properties. The affinity of apoC-I for the HCV membrane may predispose it for fusion with a target membrane via alterations of its outer phospholipid layer. Conversely, we found that excess apoC-I provided as lipoprotein-free protein induces the disruption of the HCV membrane and subsequent loss of infectivity. Furthermore, our data indicate that HDL neither interacts nor spontaneously exchanges apoC-I with HCV virions. Because apoC-I is not present in serum as a lipoprotein-free form, our results suggest that HDL-embedded apoC-I could be released from the lipoprotein particle through a fine-tuned mechanism regulated via a triple interplay between hypervariable region 1, HDL, and scavenger receptor BI, resulting in optimal apoC-I recruitment on the viral membrane. These results provide the first description of a host serum factor helping the fusion process of an enveloped virus.

Received for publication, June 29, 2007 , and in revised form, August 29, 2007.

^* This work was supported in part by INSERM, ENS Lyon, CNRS, and UCB Lyon-I and by grants from the Ligue Nationale Contre le Cancer, the European Union (LSHB-CT-2004-005246 "COMPUVAC"), and the Agence Nationale de Recherches sur le SIDA et les Hépatites Virales. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1-3.

¹ Supported by a fellowship from the Région Rhône-Alpes.

² These are equal contributions.

³ To whom correspondence should be addressed: ENS de Lyon, 46 Allée d'Italie, 69007 Lyon, France. Tel.: 33472728732; Fax: 33472728137; E-mail: flcosset{at}ens-lyon.fr.

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