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J. Biol. Chem., Vol. 281, Issue 35, 25177-25183, September 1, 2006

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Cyanovirin-N Inhibits Hepatitis C Virus Entry by Binding to Envelope Protein Glycans^*

François Helle¹, Czeslaw Wychowski, Ngoc Vu-Dac, Kirk R. Gustafson, Cécile Voisset¹², and Jean Dubuisson²³

From the Centre National de la Recherche Scientifique, Institut de Biologie de Lille (Unité Mixte de Recherche 8161), Institut Pasteur de Lille, 59021 Lille cedex, France and Molecular Targets Development Program, Center for Cancer Research, National Institutes of Health, National Cancer Institute, Frederick, Maryland 21702-1201

Inhibition of viruses at the stage of viral entry provides a route for therapeutic intervention. Because of difficulties in propagating hepatitis C virus (HCV) in cell culture, entry inhibitors have not yet been reported for this virus. However, with the development of retroviral particles pseudotyped with HCV envelope glycoproteins (HCVpp) and the recent progress in amplification of HCV in cell culture (HCVcc), studying HCV entry is now possible. In addition, these systems are essential for the identification and the characterization of molecules that block HCV entry. The lectin cyanovirin-N (CV-N) has initially been discovered based on its potent activity against human immunodeficiency virus. Because HCV envelope glycoproteins are highly glycosylated, we sought to determine whether CV-N has an antiviral activity against this virus. CV-N inhibited the infectivity of HCVcc and HCVpp at low nanomolar concentrations. This inhibition is attributed to the interaction of CV-N with HCV envelope glycoproteins. In addition, we showed that the carbohydrate binding property of CV-N is involved in the anti-HCV activity. Finally, CV-N bound to HCV envelope glycoproteins and blocked the interaction between the envelope protein E2 and CD81, a cell surface molecule involved in HCV entry. These data demonstrate that targeting the glycans of HCV envelope proteins is a promising approach in the development of antiviral therapies to combat a virus that is a major cause of chronic liver diseases. Furthermore, CV-N is a new invaluable tool to further dissect the early steps of HCV entry into host cells.

Received for publication, March 15, 2006 , and in revised form, June 16, 2006.

^* This work was supported by the "Agence Nationale de Recherche sur le Sida et les Hépatites Virales" (ANRS) and the "Association pour la Recherche sur le Cancer" (ARC). This research was also supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. 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.

¹ Supported by fellowships from the French Ministry of Research and the ANRS, respectively.

² Both authors contributed equally to this work.

³ An international scholar of the Howard Hughes Medical Institute. To whom correspondence should be addressed: J. Dubuisson, Hepatitis C Laboratory, CNRS-UMR8161, Institut de Biologie de Lille, 1 rue Calmette, BP447, 59021 Lille cedex, France. Tel.: 33-3-20-87-11-60; Fax: 33-3-20-87-12-01; E-mail: jean.dubuisson{at}ibl.fr.

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