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J. Biol. Chem., Vol. 281, Issue 49, 37921-37929, December 8, 2006

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CD4 and CCR5 Constitutively Interact at the Plasma Membrane of Living Cells

A CONFOCAL FLUORESCENCE RESONANCE ENERGY TRANSFER-BASED APPROACH^*

Gérald Gaibelet¹, Thierry Planchenault¹, Serge Mazères, Fabrice Dumas, Fernando Arenzana-Seisdedos, André Lopez², Bernard Lagane, and Françoise Bachelerie³

From the IPBS/CNRS, 205 Route de Narbonne, 31062 Toulouse cedex, France and the Unité de Pathogénie Virale Moléculaire, Institut Pasteur, 75015 Paris, France

Human immunodeficiency virus entry into target cells requires sequential interactions of the viral glycoprotein envelope gp120 with CD4 and chemokine receptors CCR5 or CXCR4. CD4 interaction with the chemokine receptor is suggested to play a critical role in this process but to what extent such a mechanism takes place at the surface of target cells remains elusive. To address this issue, we used a confocal microspectrofluorimetric approach to monitor fluorescence resonance energy transfer at the cell plasma membrane between enhanced blue and green fluorescent proteins fused to CD4 and CCR5 receptors. We developed an efficient fluorescence resonance energy transfer analysis from experiments carried out on individual cells, revealing that receptors constitutively interact at the plasma membrane. Binding of R5-tropic HIV gp120 stabilizes these associations thus highlighting that ternary complexes between CD4, gp120, and CCR5 occur before the fusion process starts. Furthermore, the ability of CD4 truncated mutants and CCR5 ligands to prevent association of CD4 with CCR5 reveals that this interaction notably engages extracellular parts of receptors. Finally, we provide evidence that this interaction takes place outside raft domains of the plasma membrane.

Received for publication, July 26, 2006 , and in revised form, October 11, 2006.

^* This work was supported by the Agence Nationale de Recherches sur le SIDA (ANRS), Ensemble Contre le SIDA (SIDACTION), Institut National de la Santé Et de la Recherche Médicale (INSERM), and the Centre National de la Recherche Scientifique (CNRS). 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 Fig. S1.

¹ Both authors contributed equally to this work.

² To whom correspondence may be addressed: IPBS/CNRS, 205 route de Narbonne, Toulouse Cedex 31062, France. E-mail: Andre.Lopez{at}ipbs.fr.

³ To whom correspondence may be addressed: Unité de Pathogénie Virale Moléculaire, Institut Pasteur, 28 rue du Dr Roux, Paris 75015, France. Tel.: 33-0-1-40613467; Fax: 33-0-1-45688941; E-mail: fbachele{at}pasteur.fr.

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