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

Abstract

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. The depletion of CD4ϩ T lymphocytes is a central pathogenic feature of human immunodeficiency virus type 1 (HIV-1) 2 infection and is largely responsible for the profound immunodeficiency characteristic of the late stages of HIV disease (1). Multiple mechanisms have been shown to contribute to the HIV-1-associated loss of CD4 ϩ T cells in HIV-1-infected individuals, among which the HIV-1-induced apoptosis of bystander uninfected cells is considered to be the most important (2-5). Several virally encoded proteins, including the envelope protein gp120, Tat, and Vpr, have been implicated in this process (3,6,7). Cumulative data demonstrate a major role for the HIV envelope glycoprotein in the death of uninfected lymphocytes (8, 9). The presence of measurable amounts of circulating soluble gp120 in HIV-infected subjects and the accumulation of a high concentration of envelope glycoproteins in lymphoid tissues underscore the potential for the envelope to contribute to T cell dysfunction (10, 11). A number of studies have indicated that HIV-1 gp120-induced apoptosis could represent an exacerbation of activation-induced cell death (12, 13). In fact, circulating T lymphocytes in HIV-1-infected patients are characterized by a high degree of immune activation (14, 15). Although immune activation may modulate HIV-mediated apoptosis, the molecular mechanisms involving the cross-talk between the T cell receptor (TCR) pathway and HIV-1 gp120 and leading to T cell loss are still unclear. Because the proteintyrosine phosphatase CD45 plays an essential role in TCR signaling (16 -18), it seemed reasonable to speculate that it may play a key role in HIV envelope-mediated apoptosis. CD45 is a transmembrane protein-tyrosine phosphatas...

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“…2D), implying that direct cell-to-cell communication between pDCs and mB cells is required for mB cell apoptosis. HIV gp120 contains binding regions for CD4 and the HIV coreceptor and has been shown to induce significant FasL expression via cellular receptors (48). Consistent with this information, gp120 induced more FasL expression in pDCs than HIV (Fig.…”

Glycoprotein 120 Binding to CXCR4 Causes p38-Dependent Primary T Cell Death That Is Facilitated by, but Does Not Require Cell-Associated CD4

“…In this study, we demonstrate that gp120 binding to either CD4 or CXCR4 each fails to activate Akt in primary human CD4 T cells, similar to the previous reports that gp120 does not activate Akt in cell lines (29,61). Recent studies indicate that the phosphorylation of BH 3 -only proteins by Akt or by p38/JNK results in divergent effects on proapoptotic activity of these proteins.…”

Protein Tyrosine Phosphatases: Emerging Regulators of Apoptosis

“…Importantly, both the extra-cellular domain and the catalytic activity of CD45 were observed to be necessary for GP120-promoted cell death. 81 Molecular analysis of this pathway revealed that GP120 enhances the phosphatase activity of CD45, which translates to the dephosphorylation of Lck. 81 CD45 was also observed to enhance the induction of FasL expression in cells treated with GP120; nonetheless, it did not promote Fas-mediated cell death.…”

“…81 CD45 was also observed to enhance the induction of FasL expression in cells treated with GP120; nonetheless, it did not promote Fas-mediated cell death. 78,81 Interestingly, CD45 is required for GP120 initiated inactivation of AKT and caspase-3 processing. 81 The impact of other PTPs involved in the regulation of AKT in HIV-infection associated cell death has yet to be investigated.…”