THE HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 (HIV-1) TAT PROTEIN AND BCL-2GENE-EXPRESSION

Tat protein of human immunodeficiency virus type-1 (HIV-1) plays a cen tral role in viral replication and shows pleiotropic effects on the su rvival and growth of different cell types. Remarkably, Tat represents the first example of a viral protein, that can also be actively secret ed by infected cells and shows a cytokine-like activity on both HIV-1 infected and uninfected cells. We previously reported that the stable expression of tat cDNA rescues Jurkat cell Lines from apoptosis induce d by a variety of stimuli, such as serum withdrawal, engagement of fas antigen or even a productive infection with HIV-1. These findings sug gested that Tat was able to modulate the expression of one or more gen e(s) relevant for the control of cell survival/death. Consistently, Ju rkat cells stably transfected with tat show an upregulated expression of bcl-2. It is still unsettled whether Tat affects cell survival and bcl-2 expression directly or indirectly, modulating the expression of other cellular genes involved in the control of cell survival or encod ing for cytokines. Blocking experiments performed with anti-Tat neutra lizing antibodies revealed that Tat increases bcl-2 expression and pre vent lymphoid T cells from apoptosis by acting, at least in part, thro ugh an autocrine/paracrine loop. While high (nM-mu M) concentrations o f extracellular Tat display a cytotoxic activity on the antigen-mediat ed induction of T cell proliferation, low (pM) concentrations of Tat w ere able to protect both Jurkat cells and primary peripheral blood mon onuclear cells from apoptosis. Significantly, pM concentrations of Tat were detected in the sera of some HIV-1 infected individuals as well as in the culture supernatant of HIV-1 infected cells, raising the pos sibility that these levels of Tat protein may be present physiological ly in vivo. The potential relevance of Tat-mediated upregulation of bc l-2 for the pathogenesis of HIV-1 disease is discussed.