DIFFERENTIAL-EFFECTS OF I-KAPPA-B MOLECULES ON TAT-MEDIATED TRANSACTIVATION OF HIV-1 LTR

The tat gene product of the human immunodeficiency virus type 1 (HIV-1 ) strongly induces the transcription directed by the viral long termin al repeat (LTR). Tat acts by interacting with a target RNA element loc ated immediately downstream of the initiation site. In addition, the a ction of Tat appears to be assisted by the upstream DNA enhancer eleme nts, including the binding sites for the NF-kappa B/Rel family of host transcription factors. In the present study, we demonstrate that Tat transactivation of the HIV-1 LTR is markedly inhibited by several cyto plasmic inhibitors of NF-kappa B/Rel, suggesting the critical involvem ent of these host transcription factors in the function of the viral T at protein. Furthermore, the various NF-kappa B inhibitors appear to h ave differential effects on Tat. While I kappa B alpha, I kappa B beta , and p100 potently inhibit Tat-mediated transactivation, p105 fails t o inhibit, but even moderately synergizes, the action of Tat. We furth er demonstrate that the action of these NF-kappa B/Rel inhibitors on T at correlates with their inhibitory activities on the RelA subunit of NF-kappa B. Finally, we show that a degradation-resistant I kappa B al pha mutant is able to potently inhibit Tat-mediated activation of the HIV-1 LTR in both untreated and tumor necrosis factor alpha-stimulated T cells, thus suggesting that such an I kappa B alpha mutant may serv e as a constitutive repressor of HIV-1 LTR. (C) 1996 Academic Press, I nc.