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J. Biol. Chem., Vol. 280, Issue 22, 21353-21357, June 3, 2005

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Heparan Sulfate Targets the HIV-1 Envelope Glycoprotein gp120 Coreceptor Binding Site^*

Romain R. Vivès, Anne Imberty, Quentin J. Sattentau¶, and Hugues Lortat-Jacob||

From the Institut de Biologie Structurale, CNRS-Commissariat à l'Energie Atomique-Université Joseph Fourier, UMR 5075, 41 Rue Horowitz, 38027 Grenoble, France, the Centre de Recherches sur les Macromolécules Végétales-CNRS (affiliated with Université Joseph Fourier), 38041 Grenoble, France, and the ^¶Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, United Kingdom

Human immunodeficiency virus (HIV) attachment to host cells is a multi-step process that involves interaction of the viral envelope gp120 with the primary receptor CD4 and coreceptors. HIV gp120 also binds to other cell surface components, including heparan sulfate (HS), a sulfated polysaccharide whose wide interactive properties are exploited by many pathogens for attachment and concentration at the cell surface. To analyze the structural features of gp120 binding to HS, we used soluble CD4 to constrain gp120 in a specific conformation. We first found that CD4 induced conformational change of gp120, dramatically increasing binding to HS. We then showed that HS binding interface on gp120 comprised, in addition to the well characterized V3 loop, a CD4-induced epitope. This epitope is efficiently targeted by nanomolar concentrations of size-defined heparin/HS-derived oligosaccharides. Because this domain of the protein also constitutes the binding site for the viral coreceptors, these results support an implication of HS at late stages of the virus-cell attachment process and suggest potential therapeutic applications.

Received for publication, January 25, 2005 , and in revised form, March 18, 2005.

^* This work was supported by the Agence Nationale de la Recherche sur le SIDA, the CNRS, the Commisariat à l'Energie Atomique, a grant from the Medical Research Council and the Department for International Development, United Kingdom, and a European Union grant to the European Microbicides Project consortium. 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.

^|| To whom correspondence should be addressed. Tel.: 33-438-784-485; Fax: 33-438-785-494; E-mail: Hugues.Lortat-Jacob{at}ibs.fr.

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