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J. Biol. Chem., Vol. 280, Issue 18, 17737-17748, May 6, 2005

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Hepatitis C Virus Core Protein Acts as a trans-Modulating Factor on Internal Translation Initiation of the Viral RNA^*

Sébastien Boni, Jean-Pierre Lavergne¶, Steeve Boulant¶, and Annie Cahour||

From the Laboratoire de Virologie, Centre Européen de Recherche en Virologie et Immunologie, Unité Propre de Recherche et d'Enseignement Supérier EA 2387, IFR 113 Immunité et Infection, Groupe Hospitalier Pitié-Salpêtrière, 83 Boulevard de l'Hôpital, 75651 Paris Cedex 13 and ^¶Laboratoire de Bioinformatique et RMN Structurale, Institut de Biologie et Chimie des Protéines, UMR5086 CNRS, Université Claude Bernard Lyon I, IFR 128 Biosciences Lyon-Gerland, 7 Passage du Vercors, 69367 Lyon Cedex 07, France

Translation initiation of hepatitis C virus (HCV) RNA occurs through an internal ribosome entry site (IRES) located at its 5' end. As a positive-stranded virus, HCV uses the genomic RNA template for translation and replication, but the transition between these two processes remains poorly understood. HCV core protein (HCV-C) has been proposed as a good candidate to modulate such a regulation. However, current data are still the subject of controversy in attributing any potential role in HCV translation to the HCV core protein. Here we demonstrate that HCV-C displays binding activities toward both HCV IRES and the 40 S ribosomal subunit by using centrifugation on sucrose gradients. To gain further insight into these interactions, we investigated the effect of exogenous addition of purified HCV-C on HCV IRES activity by using an in vitro reporter assay. We found that HCV IRES-mediated translation was specifically modulated by HCV-C provided in trans, in a dose-dependent manner, with up to a 5-fold stimulation of the IRES efficiency upon addition of low amounts of HCV-C, followed by a decrease at high doses. Interestingly, mutations within some domains of the IRES as well as the presence of an upstream reporter gene both lead to changes in the expected effects, consistent with the high dependence of HCV IRES function on its overall structure. Collectively, these results indicate that the HCV core protein is involved in a tight modulation of HCV translation initiation, depending on its concentration, and they suggest an important biological role of this protein in viral gene expression.

Received for publication, February 17, 2005

^* This work was supported in part by the Association pour la Recherche Contre le Cancer Grant 4301 (to J.-P. L.), the Agence Nationale pour la Recherche sur le Sida, the CNRS, and INSERM (ATC Hépatite C). 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.

Recipient of doctoral grant from the Ministère de l'Education Nationale, de la Recherche et de la Technologie.

^|| To whom correspondence should be addressed: Laboratoire de Virologie, Centre Européen de Recherche en Virologie et Immunologie, Unité Propre de Recherche et d'Enseignement Supérieur EA 2387, Groupe Hospitalier Pitié-Salpêtrière, 83 Bd. de l'Hôpital, 75651 Paris Cedex 13, France. Tel.: 33-145-82-6298; Fax: 33-145-82-6314; E-mail: cahour{at}idf.ext.jussieu.fr.

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