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 human immunodeficiency virus (HIV). A well-recognized mechanism involves interaction of Tat with the nascent RNA transcript of the viral tar gene; mutation of tar greatly decreases activation by Tat. However, Tat still provides a low level of activation, demonstrating that it also has a tar-independent mode of action. We propose that this tar-independent mode of Tat action is through activation of gene transcription to produce 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 value. In cooperation, the two modes of activation by Tat (tar dependent and cytokine based) set up positive up-regulatory loops which greatly superactivate transcription of HIV. Agents that block these synergistic pathways at three different steps and are more inhibitory in combination than is any one alone have been found. Thereby, multidrug modalities for transcription of HIV are proposed for virus suppression.