THE TAT PROTEIN OF HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 IS A SUBSTRATEAND INHIBITOR OF THE INTERFERON-INDUCED, VIRALLY ACTIVATED PROTEIN-KINASE, PKR

We demonstrate that the interferon-induced, double-stranded (ds) RNA-a ctivated kinase, PKR, is able to bind to and phosphorylate the human i mmunodeficiency virus type 1 (HIV-1) trans-activating protein, Tat. Fu rthermore, Tat can inhibit the activation and activity of the kinase, Phosphorylation of Tat by PKR is dependent on the prior activation of PKR by dsRNA and occurs on serine and threonine residues adjacent to t he basic region important for TAR RNA binding and Tat function, Activa ted PKR efficiently phosphorylates both the two-exon form of Tat (Tat- 86) and the single exon form (Tat-72). Mutagenesis indicates that the interaction between PKR and Tat requires the RNA-binding region of Tat , Tat competes with eukaryotic initiation factor 2, a well-characteriz ed substrate of PKR, for phosphorylation by activated PKR. Tat also in hibits the autophosphorylation of PKR by dsRNA, This biochemical evide nce of an intimate relationship between Tat, an important regulator of HIV transcription, and PKR, a pleiotropic cellular regulator, may pro vide insights into HIV-1 pathogenesis and, more generally, virus/host interactions.