Identification of a potential HIV-induced source of bystander-mediated apoptosis in T cells: Upregulation of TRAIL in primary human macrophages by HIV-1 Tat

The induction of apoptosis in T cells by bystander cells has been repeatedl y implicated as a mechanism contributing to the T cell depletion seen in HI V infection. It has been shown that apoptosis could be induced in T cells f rom asymptomatic HIV-infected individuals in a Fas-independent, TNF-related apoptosis-inducing ligand (TRAIL)-dependent manner if the cells were pretr eated with anti-CD3. it has also been shown that T cells from HIV-infected patients were even more sensitive to TRAIL induction of apoptosis than they were to Fas induction. Recently, it has been reported that in an HIV-1 SCI D-Hu model, the vast majority of the T cell apoptosis is not associated wit h p24 and is therefore produced by bystander effects. Furthermore, few apop totic cells were associated with neighboring cells which were positive for either Fas ligand or TNF. However, most of the apoptotic cells were associa ted with TRAIL-positive cells. The nature of these TRAIL-positive cells was undetermined. Here, we report that HIV infection of primary human macropha ges switches on abundant TRAIL production both at the RNA and protein level s. Furthermore, more macrophages produce TRAIL than are infected by HIV, in dicating that a bystander mechanism may, at least in part, upregulate TRAIL . Exogenously supplied HIV-1 Tat protein upregulates TRAIL production by pr imary human macrophages to an extent indistinguishable from infection. The results suggest a model in which HIV-1-infected cells produce extracellular Tat protein, which in turn upregulates TRAIL in macrophages which then can induce apoptosis in bystander T cells. Copyright (C) 2001 National Science Council. ROC and S. Karger AG, Basel.