An NF-kB site in the 5'-untraslated leader region of the Human Immunodeficiency virus type 1 enhances the viral expression in response to NF-kB-activating stimuli.

The 5'-untranslated leader region of human immunodeficiency virus, type 1 (HIV-1), includes a complex array of putative regulatory elements whose role in the viral expression is not completely understood. Here we demonstrate the presence of an NF-κB-responsive element in the trans- activation response (TAR) region of HIV-1 that confers the full induction of HIV-1 long terminal repeat (LTR) in response to NF-κB-activating stimuli, such as DNA alkylating agents, phorbol 12-myristate 13-acetate, and tumor necrosis factor-α. The TAR NF-κB site GGGAGCTCTC spans from positions +31 to +40 and cooperates with the NF-κB enhancer upstream of the TATA box in the NF-κB-mediated induction of HIV-1 LTR. The conclusion stems from the following observations: (i) deletion of the two NF-κB sites upstream of the TATA box reduces, but does not abolish, the HIV-1 LTR activation by NF-κB inducers; (ii) deletion or base pair substitutions of the TAR NF-κB site significantly reduce the HIV-1 LTR activation by NF-κB inducers; (iii) deletions of both the NF-κB sites upstream of the TATA box and the TAR NF- κB site abolish the activation of HIV-1 LTR in response to NF-κB inducers. Moreover, the p50·p65 NF-κB complex binds to the TAR NF-κB sequence and trans-activates the TAR NF-κB-directed expression. The identification of an additional NF-κB site in the HIV-1 LTR points to the relevance of NF-κB factors in the HIV-1 life cycle.