Accelerated apoptosis in peripheral blood mononuclear cells (PBMCs) from human immunodeficiency virus type-1 infected patients and in CD4 cross-linked PBMCs from normal individuals

Abstract

This study investigates apoptosis as a mechanism for CD4+ T-cell depletion in human immunodeficiency virus type-1 (HIV-1) infection. Although several recent studies have shown that T cells of HIV-infected individuals show enhanced susceptibility to cell death by apoptosis, the mechanisms responsible for apoptosis are largely unknown. By using a flow cytometric technique and by morphology, we have quantitated the percentage of cells undergoing apoptosis in peripheral blood mononuclear cells (PBMCs) from HIV-seronegative donors and from HIV- infected asymptomatic patients. The PBMCs were cultured without any stimulus or with staphylococcus enterotoxin B, anti-T-cell receptor (TCR) alpha beta monoclonal antibody WT-31, or phytohemagglutinin for periods up to 6 days. In addition, we sought to determine whether cross- linking of CD4 followed by various modes of TCR stimulation in vitro could induce apoptosis in normal PBMCs. Here we show that (1) patient PMBCs undergo marked spontaneous apoptosis; (2) stimulation of T cells of patients as well as normal donors results in increased apoptosis; and (3) cross-linking of CD4 molecules is sufficient to induce apoptosis in CD4+ T cells if cross-linking is performed in unfractioned PBMCs, but not if CD4 molecules are cross-linked in purified T-cell preparations. These observations strongly suggest that accelerated cell death through apoptosis plays an important role in the pathogenesis of HIV-1 infection. At the same time, our observations implicate cross- linking of CD4 in vivo as a major contributor to this mechanism of accelerated cell death in HIV infection.

Selective CD4+ T cell deletion after specific activation in HIV-infected individuals; protection by anti-CD28 monoclonal antibodies

“…In contrast to our reports measuring cell death after specific activation, and to the recent analysis by Clerici et al (G. Shearer, personal communication) using recall antigens, these studies measured cell death in unstimulated culture [14,15] or in cryopreserved PBMC, after polyclonal stimulation [14,15,26]. However, this programmed cell death affects primarily CD8 T cells [13][14][15], and is not specific for AIDS [8,13,17,18], nor does it correlate with progression of disease [11,14,15]. As such, this may be of dubious relevance to disease pathogenesis.…”

“…This spontaneous cell death reflects in fact the continuous activation of the cells in vivo [11,12]. It affects primarily CD8 T cells [13][14][15], and has already been described for different acute or chronic viral pathologies like lymphocytic choriomeningitis virus infection in mice [16] or Epstein-Barr virus (EBV) infection in humans [17,18]. It does not correlate with the stage of the disease [11,12,14,15], nor is it specific for AIDS [8].…”

Cell death induced by the Fas/Fas ligand pathway and its role in pathology

“…It has also been suggested that the observed depletion of CD4 + cells during HIV infection involves AICD, following cross-linking of CD4 by gp120/anti-gp120 immune complexes and consequent cell death by a Fas-dependent pathway. 60 In addition, renal tubular epithelial cells are killed after HIV-1 infection, following Fas up-regulation in infected cells. 61 Levels of FasL are unaffected.…”

Expression of the fas antigen in patients infected with human immunodeficiency virus

“…Our laboratory has previously demonstrated that PBMC from HIV patients undergo accelerated apoptosis, and that crosslinking the CD4 molecule can induce apoptosis in human PBMC from normal controls (16). In addition, we have recently found that this crosslinking process upregulates the expression of Fas antigen in normal lymphocytes ( 17); others have shown that crosslinking human CD4 T cells with HIV gp120 followed by signalling through the TCR resulted in activation-dependent apoptosis (2).…”