ACTIVATION OF THE HIV-1 LONG TERMINAL REPEAT BY CYTOKINES AND ENVIRONMENTAL-STRESS REQUIRES AN ACTIVE CSBP P38 MAP KINASE/

The human immunodeficiency virus, type 1 (HIV-1) promoter is known to be activated by proinflammatory cytokines and UV light, These stimuli also activate various members of the mitogen-activated protein kinase family, including JNK/SAPK and CSBP/p38. In HeLa cells containing an i ntegrated HIV-1 long terminal repeat (LTR)-driven reporter, we now sho w that the specific p38 inhibitor, SB203580, inhibits activation of th e HIV-1 LTR by interleukin-1, tumor necrosis factor, UV light, and osm otic stress, Inhibition was 70-90% in all but the case of tumor necros is factor stimulation, where inhibition was 50%. Each of these stimuli activated p38, which was inhibited by SB203580 in vitro and in vivo w ith an IC50 (between 0.1 and 1 mu M) similar to that required to inhib it transcription. In contrast, SB203580 had no effect on JNK, which wa s also activated by these stimuli, The NF kappa B sites in the HIV-1 L TR were required for a response to cytokines but not to UV, and SB2035 80 remained capable of inhibiting UV activation in the absence of the NF kappa B sites, Studies in which SB203580 was added at different tim es relative to UV stimulation suggested that the critical p38-mediated phosphorylation event occurred between 2 and 4 h after UV treatment. These data indicate that p38 is required for HIV-1 LTR activation but that the action of p38 is delayed, presumably due to substrate unavail ability or inaccessibility.