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 terminal repeat (LTR). Tat acts by interacting with a target RNA element located immediately downstream of the initiation site. In addition, the action of Tat appears to be assisted by the upstream DNA enhancer elements, 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 cytoplasmic inhibitors of NF-kappa B/Rel, suggesting the critical involvement of these host transcription factors in the function of the viral Tat protein. Furthermore, the various NF-kappa B inhibitors appear to have differential effects on Tat. While I kappa B alpha, I kappa B beta, and p100 potently inhibit Tat-mediated transactivation, p105 fails to inhibit, but even moderately synergizes, the action of Tat. We further demonstrate that the action of these NF-kappa B/Rel inhibitors on Tat correlates with their inhibitory activities on the RelA subunit of NF-kappa B. Finally, we show that a degradation-resistant I kappa B alpha 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 serve as a constitutive repressor of HIV-1 LTR.
Harhaj
E
E
Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey Medical Center 17033, USA.
Blaney
J
J
Millhouse
S
S
Sun
S C
SC
D002460:Cell Line; D015696:Gene Products, tat / Q000378:metabolism*; D016325:HIV Long Terminal Repeat / Q000235:genetics*; D015497:HIV-1 / Q000235:genetics*; D006801:Humans; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051841:Transcription Factor RelB; D014157:Transcription Factors; D015533:Transcriptional Activation; D054322:tat Gene Products, Human Immunodeficiency Virus
D015696:Gene Products, tat; D016328:NF-kappa B; D011518:Proto-Oncogene Proteins; C497593:RELB protein, human; D014157:Transcription Factors; D054322:tat Gene Products, Human Immunodeficiency Virus; D051841:Transcription Factor RelB