IMPAIRED INDUCTION OF THE APOPTOSIS-PROTECTIVE PROTEIN BCL-X(L) IN ACTIVATED PBMC FROM ASYMPTOMATIC HIV-INFECTED INDIVIDUALS

Progression to AIDS in asymptomatic HIV-infected individuals is charac terized by a gradual but progressive loss of CD4(+) T cells. While the mechanisms underlying this decline are currently unknown, recent evid ence suggests that these cells are abnormally sensitive to apoptosis i n response to activation signals. Recent work has implicated downregul ation of Bcl-2 with the increased spontaneous apoptosis in lymphocytes from HIV-infected patients. We have evaluated the roles of the apopto sis-protective proteins Bcl-2 and Bcl-x in stimulated PBMC from asympt omatic HIV-infected and HIV-uninfected individuals. We found that Bcl- 2 was constitutively expressed in PBMC from both HIV-infected and unin fected samples. However, Bcl-x induction was delayed and responses wer e decreased in stimulated HN-infected samples. Additionally, single-ce ll intracellular staining of Bcl-x revealed a significant inverse corr elation between PWM-induced Bcl-x expression and apoptosis (r = -0.695 , P = 0.005). This was confirmed at the single-cell level in direct ex periments when stimulated cells were sorted based on Bcl-x induction a nd then measured for apoptosis. Furthermore, low Bcl-x expression was not due to reduced lymphocyte activation following PWM stimulation. Ou r data indicate that the induction of Bcl-x is markedly impaired in as ymptomatic HIV-infected patients and that stimuli which induce inadequ ate expression of Bcl-x are associated with increased levels of apopto sis in these cells.