Crosslinking CD4 by human immunodeficiency virus gp120 primes T cells for activation-induced apoptosis.

Abstract

Summ~aryDuring human immunodeficiency virus (HIV) infection there is a profound and selective decrease in the CD4 + population of T lymphocytes. The mechanism of this depletion is not understood, as only a small fraction of all CD4 + cells appear to be productively infected with HIV-1 in seropositive individuals. In the present study, crosslinking of bound gp120 on human CD4 + T cells followed by signaling through the T cell receptor for antigen was found to result in activation-dependent cell death by a form of cell suicide termed apoptosis, or programmed cell death. The data indicate that even picomolar concentrations of gp120 prime T cells for activationinduced cell death, suggesting a mechanism for CD4 + T cell depletion in acquired immune deficiency syndrome (AIDS), particularly in the face of concurrent infection and antigenic challenge with other organisms. These results also provide an explanation for the enhancement of infection by certain antibodies against HIV, and for the paradox that HIV appears to cause AIDS after the onset of antiviral immunity.T he immunodeficiency that defines AIDS is due primarily to a progressive decline in the number and function of CD4 + T cells. The mechanism of this decline is debated, though lyric infection of cells targeted by interaction of CD4 with the envelope glycoprotein of the HIV virion, gp120, is an obvious model (1-4), and recent data suggest an apoptotic mechanism of cell death after HIV infection (5). However, previous studies have found that only 1 in 1-10 x 104 PBMC actively express HIV-1 in patients with AIDS (6-10), and immune dysfunction is seen early in infection, before a significant proportion of CD4 + cells has been eliminated (11-15). Thus, it is likely that mechanisms other than direct viral destruction contribute to CD4 + T cell loss and to the anergy associated with CD4 + T cell-dependent immune responses.Mouse splenic T cells pretreated with anti-CD4 antibodies die by apoptosis when stimulated through the oL/~ TCR (16). Apoptosis is an active form of physiologic cell death, requiring RNA and protein synthesis, which is characterized by the activation of endogenous endonucleases that cleave chromatin DNA between nucleosomes (17, 18). Here we report that crosslinking of gp120 on human CD4 + T cells followed by signaling through the TCR results in activation-induced cell death. This cell death has the characteristic features of apoptosis, including the histologic changes of nuclear and cytoplasmic condensation and DNA fragmentation into nucleosome-sized multimers of 200 bp. Our data provide a mechanism for the recent observation that CD4 + T cells from HIV-infected individuals are primed in vivo for suicide by apoptosis, upon TCR activation by both superantigen and MHC class II-restricted antigens (19). Materials and Methodslsola~'on ofCD4 + T Cells. Human T ceils were separated from Ficoll-Hypaque-isolated PBMC by rosetting with 2-aminoethylisothio-uronium bromide hydrobromide (AET)-treated SRBC, as described (20). CD4 + calls were isolated by incu...

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.…”

“…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. Preincubation of X4-tropic HIV1 with high concentrations of sCD4 blocks Env binding to both CD4 and CXCR4 cell-surface receptors, but preincubation with suboptimal sCD4 concentrations induces Env conformational changes that allow it to directly engage CXCR4, 39,40 thus bypassing the prior requirements to bind the CD4 cell-surface receptor.…”

“…3 Because most of the viral particles produced during HIV1 infection are replication-defective, 6 but can still bind to-, and enter into-CD4 þ T cells, viral proteins present at the surface or inside the viral particles have been proposed as candidates for the killing of noncycling CD4 þ T cells in the absence of productive infection of these cells. 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.…”

CD95/phosphorylated ezrin association underlies HIV-1 GP120/IL-2-induced susceptibility to CD95(APO-1/Fas)-mediated apoptosis of human resting CD4+T lymphocytes

“…The gp120/CD4 interaction may lead both to sensitization of T cells to CD95-mediated apoptosis 55 and activation induced T-cell death. 56 Moreover, gp120 protein shed from both infected cells and HIV-1 virions may bind to uninfected CD4 þ T cells and gp120 can by itself transduce intracellular signals. 57 These signals are thought to be receptor.…”

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

“…48,49 This activation can then contribute to the elimination of CD4 þ T cells by AICD. 50,51 CD95/Fas-induced apoptosis may also play an important role in CD4 þ T-cell depletion. 26,27,52 Thus, apoptosis may be an important contributor if not the major one for the loss of CD4 þ T cells.…”