CXCR4 and CD4 mediate a rapid CD95-independent cell death in CD4⁺T cells

Abstract

AIDS is characterized by a progressive decrease of CD4 ؉ helper T lymphocytes. Destruction of these cells may involve programmed cell death, apoptosis. It has previously been reported that apoptosis can be induced even in noninfected cells by HIV-1 gp120 and anti-gp120 antibodies. HIV-1 gp120 binds to T cells via CD4 and the chemokine coreceptor CXCR4 (fusin͞LESTR). Therefore, we investigated whether CD4 and CXCR4 mediate gp120-induced apoptosis. We used human peripheral blood lymphocytes, malignant T cells, and CD4͞CXCR4 transfectants, and found cell death induced by both cell surface receptors, CD4 and CXCR4. The induced cell death was rapid, independent of known caspases, and lacking oligonucleosomal DNA fragmentation. In addition, the death signals were not propagated via p56 lck and G i ␣. However, the cells showed chromatin condensation, morphological shrinkage, membrane inversion, and reduced mitochondrial transmembrane potential indicative of apoptosis. Significantly, apoptosis was exclusively observed in CD4 ؉ but not in CD8 ؉ T cells, and apoptosis triggered via CXCR4 was inhibited by stromal cell-derived factor-1, the natural CXCR4 ligand. Thus, this mechanism of apoptosis might contribute to T cell depletion in AIDS and might have major implications for therapeutic intervention.

A novel mechanism for HIV1-mediated bystander CD4+ T-cell death: neighboring dying cells drive the capacity of HIV1 to kill noncycling primary CD4+ T cells

“…[20][21][22][24][25][26] While our results confirm previous findings indicating that antibody-mediated engagement of CD4 or CXCR4 can indeed induce CD4 þ T-cell death, [27][28][29][30] they also indicate that the interactions of the HIV1 Env protein with CD4 and/or CXCR4 are not responsible for the killing by HIV1 particles of unstimulated, noncycling primary CD4 þ T cells. Rather, in the presence of cellular factors released by dying cells, CD4 þ T-cell killing required the presence of the Env protein on the viral particle simply because of a requirement for HIV1 postbinding fusion or entry into the CD4 þ T cells.…”

“…This suggested, as previously proposed, 25,26 that HIV1-mediated cell death might be due to post-CD4 binding events, such as HIV1 env engagement of its CXCR4 receptor. Consistent with a previous report, 30 plate-immobilized CXCR4-specific antibodies also induced CD4 þ T-cell death (Figure 2b), although to a lesser extent than the virus. However, because the CXCR4-specific antibodies caused CD4 þ T-cell death both when plate-immobilized or when added in solution (data not shown), we could not use these antibodies to assess whether blocking HIV1 Env interactions with CXCR4 might prevent or reduce HIV1-mediated CD4 þ T-cell death.…”

“…38 Both treatments prevented the capacity of HIV1 to induce CD4 þ T-cell death (Figure 1a), indicating that an interaction of the HIV1 Env with the CD4 cell-surface receptors was one of the events required for the induction of CD4 þ T-cell death. While the Leu3a antibody added in solution did not by itself affect CD4 þ T-cell survival (Figure 1a), CD4 receptor engagement by plateimmobilized Leu3a induced death in the same proportion of CD4 þ T cells as HIV1 (Figure 1a), consistent with previous reports, [27][28][29][30] and with the suggestion that HIV1 Env-mediated engagement of its CD4 cell-surface receptor may by itself cause CD4 þ T-cell death. [20][21][22]24 However, because CD4-specific antibodies may induce different cell signaling than HIV1 viral particles, we investigated whether HIV1-mediated CD4 þ T-cell death might rather be due to post-CD4-binding events.…”

“…In vitro findings have suggested that among such viral proteins, the HIV1 surface envelope (Env) constitutes a major potential candidate for the HIV1-mediated killing of CD4 þ T cells in the absence of productive infection, 16,[20][21][22][23][24][25][26] through death signaling caused by engagement of either its cell-surface receptor, CD4 [27][28][29] or, for the Env of X4-tropic HIV1 strains, of its CXCR4 coreceptor. 25,26,30,31 Incubation of noncycling, primary CD4 þ T cells with X4-tropic HIV1 viral particles has been previously reported to cause CD4 þ T-cell death, after a delay of 3-4 days. 32,33 The aims of our study were first to confirm this latter finding, and then to investigate the mechanisms involved.…”

Mechanisms of apoptosis induction by the HIV-1 envelope

“…Antibody-mediated crosslinking of CD4 (or CXCR4) in the absence of CD3 stimulation can sensitize T lymphocytes to apoptosis induction, 32 and similar findings have been reported for the gp120-mediated activation of T cells. 33 Stimuli converging on CD4 may activate the CD95/CD95L-dependent death receptor pathway or, alternatively, activate the Bax-dependent mitochondrial pathway to apoptosis.…”