Activation of transcription factor NF-kappa B by the tat protein of human immunodeficiency virus type 1

A recombinant Tar protein was used to investigate the molecular mechanisms of transcriptional activation of the human immunodeficiency virus type 1 long terminal repeat (LTR). Liposome-mediated delivery of this protein to responsive cells results in dose-dependent LTR activation. As evaluated by mRNA quantitation with competitive PCR, the activation response is rapid and transient, peaking at 5 h after the beginning of Tat treatment. In vivo footprinting experiments at the LTR shelved that transcriptional activation is concomitant with a modification of the protein-DNA interaction pattern at the downstream kappa B Site of the enhancer and at the adjacent Spl boxes. The effects of Tar on the enhancer are mediated by Tat-induced nuclear translocation of NF-kappa B, which parallels the kinetics of transcriptional activation. This induction results from degradation of the inhibitor I kappa B-alpha, is blocked under antioxidant conditions and by a protease inhibitor, and occurs as a rapid response in different cell types. The functional response to Tat is impaired upon cell treatment with a kappa B site decoy or with sodium salicylate, an inhibitor of NF-kappa B activation, These results show that NF-kappa B activation by Tat is important for LTR transcriptional activation. Furthermore, they suggest that some of the pleiotropic effects of Tat on cellular functions can be mediated by induction of NF-kappa B.