Increased sensitivity of T lymphocytes to tumor necrosis factor receptor 1 (TNFR1)– and TNFR2-mediated apoptosis in HIV infection: relation to expression of Bcl-2 and active caspase-8 and caspase-3

Abstract

The destruction of CD4 T cells in human immunodeficiency virus (HIV) infection is associated with activation of apoptotic programs, partly mediated by death receptors. The role of CD95L/CD95 in depletion of patients' CD4 T cells is well documented, but the possible contribution of the tumor necrosis factor/tumor necrosis factor receptor (TNF/TNFR) pathway has not been examined. In this study, we found that both TNFR1 and TNFR2 induced marked apoptosis in peripheral T cells from HIV-infected persons, involving both CD4 and CD8 T cells. Longitudinal follow-up of HIV ؉ patients suggests an association between the in vivo evolution of CD4 T-cell numbers and variations in susceptibility to TNFR-induced apoptosis. Analysis of molecular mechanisms involved showed that it was not related to altered ex vivo expression of TNFR1-associated death domain, receptor interacting protein, or TNFR-associated factor 2. Susceptibility to TNFR-mediated apoptosis was rather related to Bcl-2 expression, because patients' T cells expressing high levels of Bcl-2 were completely protected from TNFR1-and TNFR2-induced cell death, whereas T cells expressing normal levels of Bcl-2 were not protected in patients in contrast to controls. Early recruitment of caspase-8 and caspase-3 is needed to transduce the apoptotic signals, and expression of both caspases in

Apoptosis in SIV infection

“…[48][49][50][86][87][88][89][90][91][92][93][94] Other members of the TNF-receptor ligand family (TRAIL, TNF-a) have also been implicated in the increased T-cell apoptosis seen in HIV-1-infected individuals. [95][96][97][98][99][100] Similarly, T cells from macaques infected with a pathogenic strain (SIVmac251) are more prone to undergo apoptosis following ligation of CD95/Fas than the other death receptors. 101 Moreover, in HIV-infected individuals and SIV-infected macaques, increased CD95/Fas sensitivity of CD8 þ T cells did not correlate with plasma viral load.…”

To kill or be killed: how HIV exhausts the immune system

“…96 The molecular mechanisms involved in the susceptibility of T cells from HIV-infected individuals to AICD have not been clearly identified yet. However, T-cell priming for apoptosis is associated with the in vivo expression in both CD4 þ and CD8 þ T cells of the active forms of caspase-8 and caspase-3, 109 which can be induced in vitro by a number of HIV proteins, such as Tat, Env, Nef or Vpr. 62,49,71,63 Since T-cell activation is downmodulating the level of the apoptosis inhibitory protein FLIP (FLICE-like inhibitory protein), it was hypothesized that susceptibility of patients' T cells to AICD was associated with decreased c-FLIP expression.…”

“…110 The TNF/TNF receptors death pathway is also activated in HIV þ individuals, and both CD4 þ and CD8 þ T cells are susceptible to TNFR1-and TNFR2-induced apoptosis. 109 Susceptibility of patients' T cells to TNFR-induced apoptosis is associated with the downregulation of Bcl-2 protein, while there is no increased expression of the two TNFRs on the surface of T cells, and TNFR1-associated death domain (TRADD), receptor interacting protein (RIP) or TNF receptorassociated factor 2 (TRAF-2) expression is not altered by HIVinfection. 109 The ligand for TNFRs, TNF-a, is detected at increased levels in the serum of symptomatic individuals and elevated levels of soluble TNFR2 were found to be predictive of HIV disease progression.…”

“…109 Susceptibility of patients' T cells to TNFR-induced apoptosis is associated with the downregulation of Bcl-2 protein, while there is no increased expression of the two TNFRs on the surface of T cells, and TNFR1-associated death domain (TRADD), receptor interacting protein (RIP) or TNF receptorassociated factor 2 (TRAF-2) expression is not altered by HIVinfection. 109 The ligand for TNFRs, TNF-a, is detected at increased levels in the serum of symptomatic individuals and elevated levels of soluble TNFR2 were found to be predictive of HIV disease progression. 111 The TNFR pathway may be involved in the destruction of CD8 T cells since it has been shown that ligation of the CXCR4 coreceptor by HIV gp120 upregulates the expression of TNF-RII on CD8 þ T cells, which become susceptible to apoptosis induced by membrane TNF expressed on macrophages.…”

Apoptosis of HIV-specific CD8+ T cells: an HIV evasion strategy

“…26,27,30,31 The involvement of TNFR1 and TNFR2 in apoptosis of CD8 þ T cells from HIVinfected individuals was shown recently. 60 Furthermore, TNFrelated apoptosis-inducing ligand (TRAIL) can mediate in part AICD of CD4 þ and CD8 þ T cells. 33 It is apparent that multiple mechanisms that can potentially crosstalk are involved in general CD8 þ T-cell apoptosis in HIV infection.…”