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J. Biol. Chem., Vol. 280, Issue 6, 5032-5044, February 11, 2005

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Nef-induced Alteration of the Early/Recycling Endosomal Compartment Correlates with Enhancement of HIV-1 Infectivity^*

Ricardo Madrid, Katy Janvier¶, Douglas Hitchin||, John Day||, Scott Coleman||, Colleen Noviello||, Jerome Bouchet, Alexandre Benmerah, John Guatelli||**, and Serge Benichou

From the Institut Cochin, Department of Infectious Diseases, INSERM U567, CNRS UMR8104, Université Paris 5, 75014 Paris, France, the ^||San Diego Veterans Affairs Healthcare System, San Diego, California 92121, and the ^**Department of Medicine, University of California at San Diego, La Jolla, California 92093-0679

human immunodeficiency virus type 1 (HIV-1) Nef interacts with the clathrin-associated AP-1 and AP-3 adaptor complexes, stabilizing their association with endosomal membranes. These findings led us to hypothesize a general impact of this viral protein on the endosomal system. Here, we have shown that Nef specifically disturbs the morphology of the early/recycling compartment, inducing a redistribution of early endosomal markers and a shortening of the tubular recycling endosomal structures. Furthermore, Nef modulates the trafficking of the transferrin receptor (TfR), the prototypical recycling surface protein, indicating that it also disturbs the function of this compartment. Nef reduces the rate of recycling of TfR to the plasma membrane, causing TfR to accumulate in early endosomes and reducing its expression at the cell surface. These effects depend on the leucine-based motif of Nef, which is required for the membrane stabilization of AP-1 and AP-3 complexes. Since we show that this motif is also required for the full infectivity of HIV-1 virions, these results indicate that the positive influence of Nef on viral infectivity may be related to its general effects on early/recycling endosomal compartments.

Received for publication, February 3, 2004 , and in revised form, October 26, 2004.

^* This work was supported by grants from the National Institutes of Health (NIH AI38201), the University-wide AIDS Research Program of the University of California (RD98-SD-051), the University of California, San Diego (UCSD) Center for AIDS Research (NIH AI36214), the Research Center of AIDS and HIV Infection of the San Diego Veterans Affairs Medical Center, the National Center for Microscopy and Imaging Resource at UCSD (NIH RR04050), and the Agence Nationale de Recherche sur le SIDA and SIDACTION-ECS. 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.

These authors contributed equally to this work.

^¶ Present address: Cell Biology and Metabolism Branch, NICHD, National Institutes of Health, Bethesda, MD 20892.

To whom correspondence should be addressed: Institut Cochin, INSERM U567, CNRS UMR8104, Université Paris 5, 27 Rue du Faubourg Saint-Jacques, 75014 Paris, France. Tel.: 33-1-40516578; Fax: 33-1-40516570; E-mail: benichou{at}cochin.inserm.fr.

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