Activation-induced CD4⁺ T cell death in HIV-positive individuals correlates with Fas susceptibility, CD4⁺ T cell count, and HIV plasma viral copy number

The relevance of activation-induced cell death (AICD) of CD4⁺ T cells to AIDS pathogenesis is unknown. The present study investigates the relationship of AICD to a defined molecular mechanism regulating peripheral T cell homeostasis, Fas-mediated apoptosis, and clinical correlates of the pathogenesis of AIDS. Increased pokeweed mitogen (PWM)-induced AICD (22.8 versus 4.4%,p = 0.006) and Fas-mediated apoptosis (27.7 versus 12.0%, p = 0.002) of CD4⁺ T cells were observed in HIV⁺ versus HIV^- individuals. Similarly, increased PWM-mediated AICD (16.2 versus 2.2%,p < 0.001) and Fas- mediated apoptosis (25.8 versus 7.6%,p = 0.005) were noted in CD8⁺ T cells from HIV⁺ versus HIV^- individuals. PWM-induced AICD of CD4⁺ T cells was blocked (83% median specific inhibition) by Fas-blocking antibodies, whereas PWM-induced AICD of CD8⁺ T cells was Fas independent. Comparison between PWM- and anti-CD3-mediated AICD of CD4⁺ T cells indicated that PWM- and not CD3-induced AICD is Fas dependent. HIV⁺ individuals with an HIV RNA copy number of <30,000 copies/ml had lower PWM-induced AICD of CD4⁺ T cells than did those with an HIV RNA copy number of >30,000 copies/ml (5.7 versus 22.1%, p = 0.034), and PWM-induced AICD inversely correlated with CD4⁺ T cell count (R = -0.567, p = 0.043). Initiation of HAART decreased PWM-induced CD4⁺ T cell AICD from 24.4 to 9.4% posttreatment (p = 0.035). These results demonstrate that PWM-induced AICD of CD4⁺ T cells from HIV⁺ individuals is mediated by Fas/FasL, parallels the in vivo susceptibility of the CD4⁺ T cell to Fas-mediated apoptosis, and correlates with clinical markers of AIDS pathogenesis and response to HAART.