Background: Stimulation of the CD4 and CXCR4 receptors by the HIV-1 envelope glycoprotein gp120 or specific antibodies has been previously shown to induce a novel type of apoptosis in T-cells. This was induced via both the CD4 and CXCR4 receptors and was CD95 (Apo-1/Fas) and caspase independent. In this study, we investigated the role of CD4- and CXCR4-mediated apoptosis as a potential indirect mechanism of T-cell depletion during HIV-1 infection. The relative contribution of the "classical" or "novel" apoptotic pathways engaged by these receptors was investigated in the in vivo situation.

Methods: Peripheral blood lymphocytes (PBLs) from 157 HIV-1 seropositive individuals and 78 healthy control subjects were tested for their sensitivity to CD4 and CXCR4-induced apoptosis. This was determined by morphological criteria and flow cytometry. Apoptosis was also assayed in the presence or absence of inhibitors specific for caspases and the CD95-, TNF- and TRAIL-death systems. A linear regression analysis was performed in order to evaluate the effect of CD4 counts, viral load, and treatment on CD4 and CXCR4-induced apoptosis.

Results: We report that PBLs from HIV-1-infected individuals show higher sensitivity to CD4- and CXCR4-mediated apoptosis compared to PBLs from non-infected controls. Apoptosis sensitivity was confined to the CD4⁺ lymphocytes. In therapy, naive patients (n = 52) higher sensitivity to CD4/CXCR4-mediated apoptosis correlated with high viral load. Sensitivity was reduced after initiation of successful antiretroviral therapy. Apoptosis was independent of the CD95- and TNF-death systems. However, it was partially dependent on the TRAIL-system and caspases showing that both caspase-dependent and -independent pathways can be engaged by these receptors.

Conclusions: We conclude that increased sensitivity of PBLs from HIV-1 infected individuals to CD4/CXCR4-mediated apoptosis may play an important role in CD4⁺ lymphocyte depletion during HIV-1 infection. Moreover, multiple mechanisms of CD4- and CXCR4-induced apoptosis are operative in PBLs from HIV-1 infected individuals. These findings may have important implications for novel therapeutic approaches.