A TAT-INDUCED AUTO-UP-REGULATORY LOOP FOR SUPERACTIVATION OF THE HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 PROMOTER

The virus-encoded Tat protein strongly activates transcription of huma n immunodeficiency virus (HIV). A well-recognized mechanism involves i nteraction of Tat with the nascent RNA transcript of the viral tar gen e; mutation of tar greatly decreases activation by Tat. However, Tat s till provides a low level of activation, demonstrating that it also ha s a tar-independent mode of action. We propose that this tar-independe nt mode of Tat action is through activation of gene transcription to p roduce tumor necrosis factor alpha. This cytokine and other compounds that activate NF-kappa B up-regulate the HIV promoter at a low level, similarly to the second Tat action. Through this mechanism, they also activate promoters of tumor necrosis factor alpha and other cytokines and thereby establish an auto-up-regulatory loop. Activated NF-kappa B motifs in the HIV promoter synergize with Tat/tar. Mutations of these motifs decrease activation by Tat to a few percent of the wild-type v alue. In cooperation, the two modes of activation by Tat (tar dependen t and cytokine based) set up positive up-regulatory loops which greatl y superactivate transcription of HIV. Agents that block these synergis tic pathways at three different steps and are more inhibitory in combi nation than is any one alone have been found. Thereby, multidrug modal ities for transcription of HIV are proposed for virus suppression.