No abstract

We have proposed that inappropriate induction of progrmmed cell death (PCD) or apoptosis, a physiological cell-suicide process, may play a role in the pathonesis of AIDS. This model has been supported by several reports of abnormal levels of PCD in vitro in both CD4+ and CD8+ T cells from human immuno iency virus type 1 (HlV-1)-infected persons. To further assess the nce of such a process In

SummaryHuman immunodeficiency virus (HIV) infection leads to a progressive loss of CD4+ T helper (Th) type 1 cell-mediated immunity that is associated with defective in vitro CD4 + T cell proliferation and abnormal T cell death by apoptosis in response to T cell receptor (TCR) stimulation. Quantification of interleukin (IL)-2, interferon y, IL-4, IL-5, and IL-10 secretion by immunoassays, and of interferon y, IL-4 and IL-10 messenger RNA expression by competitive reverse transcriptase polymerase chain reaction after in vitro stimulation of the TCR revealed a similar Th1 cytokine profile in T cells from HIV-infected persons and from controls. These data indicated that the loss ofCD4 + Thl cell function in HIV-infected persons is not related to a Thl to Th2 cytokine switch as previously proposed, but to a process of activation-induced death of CD4 + Thl cells . Despite the absence ofelevated levels of Th2 cytokines, apoptosis of CD4+ T cells, but not of CD8+ T cells, was prevented in vitro by antibodies to IL-10 or IL-4, two Th2 cytokines that downregulate Thl cell responses, or by the addition of recombinant IL-12, a cytokine that upregulates Thl functions . TCR-induced apoptosis of T cell hybridomas and preactivated T cells has been shown to involve the CD95 (Fas/Apo-1) molecule. CD4+ and CD8+ T cells from HIV-infected persons expressed high levels of the CD95 molecule, and, in contrast to T cells from controls, were highly sensitive to antibody-mediated CD95 ligation, which induced apoptosis in a percentage of T cells similar to that induced by TCR stimulation . As TCR-induced apoptosis, CD95-mediated apoptosis of CD4+ T cells, but not ofCD8 + T cells, was prevented by the addition of recombinant IL-12 . Together, these findings suggest that apoptosis ofCD4+ T cells from HIV-infected persons involves an abnormal sensitivity to CD95 ligation, and to TCR stimulation in the presence of normal levels of Th2 cytokines. The preventive effect ofIL-12 on both mechanisms has potential implications for the design ofimmunotherapy strategies aimed at the upregulation ofCD4+ Thl cell functions in AIDS.