Mechanism of apoptosis in peripheral blood mononuclear cells of HIV-infected patients.

Lymphocytes from patients with HIV-infection have been shown to undergo accelerated spontaneous apoptosis. Binding of CD4 molecules by HIV envelope protein gp120 and anti-gp120 antibodies can lead to crosslinking of CD4 molecules (CD4XL) in vitro and conceivably in vivo. We have recently shown that CD4XL in vitro, when performed in unfractioned peripheral blood mononuclear cells (PBMC) on normal HIV seronegative donors, is by itself sufficient to induce T cell apoptosis (Blood 82:3392, 1993). To further examine the mechanisms involved in apoptosis, we have examined the expression of Fas antigen (Fas) using 3 color flow cytometry. Fas is a cell surface molecule known to mediate apoptosis-triggering signals. We induced CD4XL in PBMC obtained from normal donors, either by anti-CD4 mAb Leu3a or by HIV-1 envelope protein gp160. PBMC subpopulations were examined for Fas Ag expression and for apoptosis induction by flow cytometry. CD4XL was found to result in increased Fas expression as well as Fas mRNA in lymphocytes and the up-regulated Fas Ag was closely correlated with apoptotic cell death. CD4XL in PBMC also resulted in induction of the cytokines INF-tau and TNF-alpha in the absence of IL-2 and IL-4 secretion. Both these cytokins contributed to Fas Ag up-regulation and antibodies to TNF-alpha and INF-tau abrogated CD4XL-induced Fas up-regulation and T-cell apoptosis. These findings suggest that CD4XL occurring in vivo might play an important role in inducing an abberant cytokine profile (which has been observed in HIV infected individuals) and also in triggering of T-cell apoptosis.