AN AUTOCRINE LOOP OF HIV TYPE-1 TAT PROTEIN RESPONSIBLE FOR THE IMPROVED SURVIVAL PROLIFERATION CAPACITY OF PERMANENTLY TAT-TRANSFECTED CELLS AND REQUIRED FOR OPTIMAL HIV-1 LTR TRANSACTIVATING ACTIVITY

Human immunodeficiency virus type 1 (HIV-1) transactivating Tat protei n is pivotal to virus replication. Tat's potential effects on HIV-1 pa thogenesis, however, go well beyond its role in the virus's life cycle . Current data indicate that biologically active Tat is released from HIV-1-infected cells and readily endocytosed and targeted to the nucle us of nearby, or perhaps distant, cells, where it may exert a series o f pleiotropic effects. This paracrine action has been extensively inve stigated, and depending on the amounts of exogenously added Tat, its e ffects may extend from the suppression of immunocompetent cells to tra nsactivation of heterologous genes to the promotion of growth of Kapos i's sarcoma spindle cells. We have already observed that various cell lines, either permanently transfected with an expressive HIV-1 rat gen e construct or cultured in the presence of exogenously added Tat prote in, are protected from programed cell death after serum withdrawal or other apoptotic stimuli. The present article shows that various types (lymphoblastoid, epithelial, neuronal) of permanently tar-transfected cell lines actively release fully bioactive Tat protein. The addition of anti-Tat antibody to the culture medium completely abolishes their increased survival/proliferation capacity in serum-free culture. In th ese conditions, therefore, the enhanced survival/proliferation potenti al of permanently tat-transfected cells seems entirely dependent on a Tat-protein autocrine loop. The finding that anti-Tat antibody, added to culture medium, exerts a negative influence on the expression of a Tat-resp on sive HIV-1 long terminal repeat chloramphenicol-acetyltran sferase construct, transiently transfected into permanently tat-transf ected cells, suggests that the Tat autocrine loop may also be required of for optimal HIV-1 long terminal repeat transactivation.