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J. Biol. Chem., Vol. 279, Issue 30, 31398-31408, July 23, 2004

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The Effects of HIV-1 Nef on CD4 Surface Expression and Viral Infectivity in Lymphoid Cells Are Independent of Rafts^*

Nathalie Sol-Foulon, Cécile Esnault, Yann Percherancier¶, Françoise Porrot, Patricia Metais-Cunha, Françoise Bachelerie¶, and Olivier Schwartz||

From the Virus and Immunity Group, URA CNRS 1930, and the ^¶Unité d'Immunologie Virale, Institut Pasteur, 28 rue du Dr Roux, 75724 Paris Cedex 15, France

The HIV-1 Nef protein is a critical virulence factor that exerts multiple effects during viral replication. Nef modulates surface expression of various cellular proteins including CD4 and MHC-I, enhances viral infectivity, and affects signal transduction pathways. Nef has been shown to partially associate with rafts, where it can prime T cells for activation. The contribution of rafts during Nef-induced CD4 down-regulation and enhancement of viral replication remains poorly understood. We show here that Nef does not modify the palmitoylation state of CD4 or its partition within rafts. Moreover, CD4 mutants lacking palmitoylation or unable to associate with rafts are efficiently down-regulated by Nef. In HIV-infected cells, viral assembly and budding occurs from rafts, and Nef has been suggested to increase this process. However, using T cells acutely infected with wild-type or nef-deleted HIV, we did not observe any impact of Nef on raft segregation of viral structural proteins. We have also designed a palmitoylated mutant of Nef (NefG3C), which significantly accumulates in rafts. Interestingly, the efficiency of NefG3C to down-regulate CD4 and MHC-I, and to promote viral replication was not increased when compared with the wild-type protein. Altogether, these results strongly suggest that rafts are not a key element involved in the effects of Nef on trafficking of cellular proteins and on viral replication.

Received for publication, February 13, 2004 , and in revised form, April 29, 2004.

^* This work was supported by grants from the Agence Nationale de Recherche sur le SIDA (ANRS), SIDACTION, the European Community (QLK2-CT 2000-01630), and the Institut Pasteur. 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.

Both authors contributed equally to this work.

^|| To whom correspondence should be addressed. Tel.: 33-1-45-68-83-53; Fax: 33-1-40-61-34-65; E-mail: schwartz{at}pasteur.fr.

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