DIOXIN ACTIVATES HIV-1 GENE-EXPRESSION BY AN OXIDATIVE STRESS PATHWAYREQUIRING A FUNCTIONAL CYTOCHROME-P450 CYP1A1 ENZYME

We have studied the effect of several environmental chemicals on the t ransient expression of a chloramphenicol acetyltransferase (cat) repor ter gene linked to the promoter sequences in the long terminal repeat (LTR) of the human immunodeficiency virus type 1 (HIV-1). Aflatoxin B- 1,2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD; dioxin) and benzo[a]pyren e cause a significant increases in CAT expression in mouse hepatoma He pa-1 cells. The induction of CAT after TCDD treatment is abolished by administration of N-acetyl-L-cysteine or 2-mercaptoethanol and does no t take place in a mutant cell line that lacks CYP1A1 enzymatic activit y, Linker-scanning mutational analysis of transcription factor binding sires in the promoter revealed that both the NP kappa B and an adjace nt aromatic hydrocarbon response element (AhRE) are required for TCDD- dependent CAT expression. In addition, mutation of the NFAT/AP-1 bindi ng sites in the negative regulatory region of the promoter increases t he magnitude of the TCDD effect. We conclude that induction of a funct ional CYP1A1 monooxygenase by TCDD stimulates a pathway that generates thiol-sensitive reactive oxygen intermediates which, in turn, are res ponsible for the TCDD-dependent activation of genes linked to the LTR. These data might provide an explanation for findings that TCDD increa ses infectious HIV-1 titers in experimental systems and for epidemiolo gic reports suggesting that exposure to aromatic hydrocarbons, such as found in cigarette smoke, is associated with an acceleration in AIDS progression.