REPRESSION OF TUMOR NECROSIS FACTOR-BETA EXPRESSION BY THE HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 TAT PROTEIN IN CENTRAL NERVOUS SYSTEM-DERIVED GLIAL-CELLS

HIV-1 Tat is a potent transactivator that stimulates expression from t he HIV-1 LTR, from certain cellular gene promoters and from several he terologous viral promoters. Previous reports show that HIV-1 Tat trans activates tumor necrosis factor-beta (TNF-beta) promoter-directed gene expression in lymphocytic and monocytic cell lines and further demons trate that a 'TAR-like structure' downstream of the TNF-beta promoter is essential for Tat activity. The ability of Tat to activate TNF-beta may have profound effects as TNF has been shown to be a potent activa tor of HIV-I gene expression and an important immunomodulatory and gro wth regulatory factor. The studies presented herein demonstrate a nove l finding where HIV-1 Tat specifically represses (> 10-fold) TNF-beta promoter-directed gene expression in central nervous system-derived gl ial cells. Amino acid residues 2 to 36 of HIV-1 Tat are required for T NF-beta repression. Tat repression of TNF-beta, a factor which upregul ates HIV-1 gene expression, suggests a novel mechanism whereby HIV-1 i s able to establish latent infection of glial cells that present no de tectable virions and/or viral antigens. (C) 1997 Elsevier Science B.V.