SECRETION OF EXTRACELLULAR FACTOR(S) INDUCED BY X-IRRADIATION ACTIVATES THE HIV TYPE-1 LONG TERMINAL REPEAT THROUGH ITS KAPPA-B MOTIF

X-irradiation has been used in the treatment of several human diseases , including AIDS-related-malignancies. X-irradiation might induce the transcription and the replication of human immunodeficiency virus type 1 (HIV-1) and enhance nuclear factor kappa B (NF-kappa B), In the pre sent article we show that the activation of the HIV-1 long terminal re peat (LTR) by direct X-irradiation can be mimicked by coculture of tra nsfected cells with X-irradiated nontransfected (HIV-l-negative) cells , In the human colonic carcinoma cell line HT29, the activation seems to depend on an extracellular factor(s) released by a cell line treate d with X-rays, The HIV-1 LTR cis-acting element conferring X-indirect responsiveness was identified as the KB tandem motif, The two main nuc lear HIV-1 kappa B-binding complexes activated by X-direct and -indire ct irradiation were the NF-KB p50/p65 and c-Rel/p65 heterodimers, Nucl ear NF-kappa B activation was dependent on protein neosynthesis, It wa s partially inhibited by 100 mu M pyrrolidine dithiocarbamate, a poten t antioxidant drug, but was not correlated with a significant decrease in cellular I kappa B alpha, Furthermore, X-irradiation induces the e xpression of several cytokine genes generally associated with stress r esponse and antibodies against interleukin 6 and TNF-alpha partially i nhibited the X-indirect activation of the HIV-1 LTR, The use of protei n kinase C (PKC)-specific inhibitor and of forskolin, an adenylate cyc lase activator, suggests that a PKC-dependent pathway and the cAMP int racellular concentration could play a role in the X-indirect enhanceme nt of HIV-1 LTR transcription in the HT29 cell line, In addition, supe rnatants of an X-irradiated HT29 cell culture activated the HIV-1 stim ulation in infected peripheral blood monocytes.