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J. Biol. Chem., Vol. 281, Issue 18, 12289-12299, May 5, 2006

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HIV-1 gp120-mediated Apoptosis of T Cells Is Regulated by the Membrane Tyrosine Phosphatase CD45^*

From the Division of Experimental Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02115

The molecular mechanism of the human immunodeficiency virus type 1 (HIV-1) gp120-induced apoptosis of bystander T cells is not well defined. Here, we demonstrate that CD45, a key component of the T cell receptor pathway, plays a crucial role in apoptosis induced by HIV-1 gp120. We observed that HIV-1 gp120-induced apoptosis was significantly reduced in a CD45-deficient cell line and that reconstitution of CD45 in these cells restored gp120-induced apoptosis. However, expression of a chimeric protein containing only the intracellular phosphatase domain was not able to restore the apoptotic function in the CD45-negative clone, indicating an important role for the extracellular domain of CD45 in this function. The role of CD45 in gp120-induced apoptosis was further confirmed in T cell lines and peripheral blood mononuclear cells using a selective CD45 inhibitor as well as CD45-specific small interfering RNA. We also observed that gp120 treatment induced CD45 association with the HIV coreceptor CXCR4. Further elucidation of downstream signaling events revealed that CD45 modulates HIV-1 gp120-induced apoptosis by regulating Fas ligand induction and activation of the phosphoinositide 3-kinase/Akt pathway. These results suggest a novel CD45-mediated mechanism for the HIV envelope-induced apoptosis of T cells.

Received for publication, November 1, 2005 , and in revised form, March 6, 2006.

^* This work was supported in part by National Institutes of Health Grant AI49140 and by a grant from the American Foundation for AIDS Research (to R. K. G.). 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.

¹ To whom correspondence should be addressed: Div. of Experimental Medicine, Beth Israel Deaconess Medical Center, Harvard Institutes of Medicine Bldg., Rm. 343, 4 Blackfan Circle, Boston, MA 02115. Tel.: 617-667-0060; Fax: 617-975-5243; E-mail: rganju{at}bidmc.harvard.edu.

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