HIV-1 TAT INDUCES THE EXPRESSION OF THE INTERLEUKIN-6 (IL6) GENE BY BINDING TO THE IL6 LEADER RNA AND BY INTERACTING WITH CAAT ENHANCER-BINDING PROTEIN-BETA (NF-IL6) TRANSCRIPTION FACTORS

Human immunodeficiency virus type 1 (HIV-1) infection is associated wi th severe psoriasis, B cell lymphoma, and Kaposi's sarcoma, A deregula ted production of interleukin-6 (IL6) has been implicated in the patho genesis of these diseases, The molecular mechanisms underlying the abn ormal IL6 secretion of HIV-1-infected cells may include transactivatio n of the IL6 gene by HIV-1. Here we report the molecular mechanisms of Tat activity on the expression of the IL6 gene. By using 5' deletion mutants of pIL6Pr-CAT and using IL6:HIV-1-LTR hybrid constructs where discrete regions of the IL6 promoter replaced the TAR sequence in HIV- 1 LTR, we identified a short sequence of the 5'-untranslated region of the IL6 mRNA that is required for Tat to trans-activate the IL6 promo ter, This sequence acquires a stem-loop structure and includes a UCU s equence that binds to Tat and is necessary for full trans-activation, In addition, we provide the evidence that Tat can function by enhancin g the CAAT enhancer-binding protein (C/EBP) DNA binding activity and i s able to complex with in vitro translated C/EBP beta, which is a majo r mediator of IL6 promoter function, By using the yeast two-hybrid sys tem and immunoprecipitation, we observed that the interaction of Tat w ith C/EBP proteins also occurred in vivo. The data are consistent with the possibility that Tat may function on heterologous genes by intera cting with RNA structures possibly present in a large number of cellul ar and viral genes. In addition, Tat may function by protein-protein i nteractions, leading to the generation of heterodimers with specific t ranscription factors.