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J. Biol. Chem., Vol. 280, Issue 9, 7413-7426, March 4, 2005

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CD4 Down-regulation by HIV-1 and Simian Immunodeficiency Virus (SIV) Nef Proteins Involves Both Internalization and Intracellular Retention Mechanisms^*

Jeremy J. Rose, Katy Janvier, Soundararajulu Chandrasekhar, Rafick P. Sekaly¶, Juan S. Bonifacino, and Sundararajan Venkatesan||

From the Laboratory of Molecular Microbiology, NIAID and Cell Biology and Metabolism Branch, NICHD, National Institutes of Health, Bethesda, Maryland 20892 and the ^¶Universite de Montreal, Montreal, Quebec H3C 3J7, Canada

Among the pleiotropic effects of Nef proteins of HIV and simian immunodeficiency virus (SIV), down-modulation of cell surface expression of CD4 is a prominent phenotype. It has been presumed that Nef proteins accelerate endocytosis of CD4 by linking the receptor to the AP-2 clathrin adaptor. However, the related AP-1 and AP-3 adaptors have also been shown to interact with Nef, hinting at role(s) for these complexes in the intracellular retention of CD4. By using genetic inhibitors of endocytosis and small interfering RNA-induced knockdown of AP-2, we show that accelerated CD4 endocytosis is not a dominant mechanism of HIV-1 (NL4-3 strain) Nef in epithelial cells, T lymphocyte cell lines, or peripheral blood lymphocytes. Furthermore, we show that both the CD4 recycling from the plasma membrane and the nascent CD4 in transit to the plasma membrane are susceptible to intracellular retention in HIV-1 Nef-expressing cells. In contrast, AP-2-mediated enhanced endocytosis constitutes the predominant mechanism for SIV (MAC-239 strain) Nef-induced down-regulation of human CD4 in human cells.

Received for publication, August 17, 2004 , and in revised form, December 16, 2004.

^* 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: Laboratory of Molecular Biology, Bldg. 10, Rm. 6A05, NIAID, National Institutes of Health, Bethesda, MD, 20892-1576. Tel.: 301-496-6359; Fax: 301-402-4122; E-mail: aradhana{at}helix.nih.gov or sv1s{at}nih.gov.

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