Activation of NF-kappa B and p38 MAP kinase is not sufficient for triggering efficient HIV gene expression in response to stress

Recent studies have established an essential role for p38 MAP kinase in UV activation of human immunodeficiency virus (HIV) gene expression. However, p38 MAP kinase is not involved in activation of NF-kappa B, a key transcrip tional activator of HIV gene expression, in response to UV, suggesting that NF-kappa B acts independently of p38 MAP kinase. In this study, we have in vestigated whether activation of HIV gene expression occurs when p38 MAP ki nase and NF-kappa B are activated by separate stress-causing treatments, ea ch relatively specific for activating only one of the factors. Treatment of cells with sorbitol (hyperosmotic shock) strongly activates p38 MAP kinase , whereas the cytokine TNF-alpha is a poor activator of p38 MAP kinase. On the other hand, TNF-alpha is a strong activator of NF-kappa B whereas sorbi tol is not. Sorbitol, however, activates AP-1 DNA binding activity in a man ner similar to that of UV. Most importantly, both sorbitol and TNF-alpha ar e poor activators of HIV gene expression in HeLa cells stably transfected w ith an HIVcat reporter gene, whereas UV elicits a strong response. The comb ined treatment with UV and hyperosmotic shock produces an additive effect o n HIV gene expression, suggesting that these agents activate at least in pa rt by different mechanisms. The combined treatment with sorbitol and TNF-al pha activates p38 and NF-kappa B to levels similar to those with UV, yet on ly results in 25-30% of the CAT levels elicited by UV. Inhibition of NF-kap pa B activation by the protease inhibitor N-alpha-tosyl-L-phenylalanine chl oromethyl ketone (TPCK) prevents UV activation of HIV gene expression, but does not inhibit p38 MAP kinase activation. We conclude that whereas both p 38 MAP kinase and NF-kappa B are important for UV activation of HIV gene ex pression they act independently from each other and activation of both fact ors is not sufficient for triggering a full HIV gene expression response. A ctivation of HIV gene expression by UV must therefore involve additional ce llular processes, such as those triggered by DNA damage, for generation of a full gene expression response.