MYCOBACTERIUM-TUBERCULOSIS MANNOSE-CAPPED LIPOARABINOMANNAN CAN INDUCE NF-KAPPA-B-DEPENDENT ACTIVATION OF HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 LONG TERMINAL REPEAT IN T-CELLS

Tuberculosis has emerged as an epidemic, extended by the large number of individuals infected with human immunodeficiency virus type 1 (HIV- 1), The major goal of this study was to determine whether the mycobact erial cell wall component mannose-capped lipoarabinomannan (ManLAM) of Mycobacterium tuberculosis (M. tuberculosis) could activate transcrip tion of HIV-1 in T cells with the use of an in vitro cell culture syst em, These experiments are of prime importance considering that CD4-exp ressing T lymphocytes represent the major virus reservoir in the perip heral blood of infected individuals. Using the 1G5 cell line harbourin g the luciferase reporter gene under the control of the HIV-1 LTR, it was first found that culture protein filtrates (CFP) from M. tuberculo sis or purified ManLAM could activate HIV-1 LTR-dependent gene express ion unlike similarly prepared CFP extracts devoid of ManLAM. The impli cation of protein tyrosine kinase(s), protein kinase A and/or protein kinase C was highlighted by the abrogation of the ManLAM-mediated acti vation of HIV-1 LTR-driven gene expression using herbimycin A and H7, It was also determined, using electrophoresis mobility shift assays, t hat M. tuberculosis ManLAM led to the nuclear translocation of the tra nscription factor NF-kappa B, M. tuberculosis ManLAM resulted in clear induction of the luciferase gene placed under the control of the wild -type, but not the KB-mutated, HIV-1 LTR region, Finally, the ManLAM-m ediated activation of HIV-1 LTR transcription was found to be independ ent of the autocrine or paracrine action of endogenous TNF-alpha. The results suggest that M. tuberculosis can upregulate HIV-1 expression i n T cells and could thus have the potential to influence the pathogene sis of HIV-1 infection.