Dioxin activates HIV-1 gene expression by an oxidative stress pathway requiring a functional cytochrome P450 CYP1A1 enzyme.
We have studied the effect of several environmental chemicals on the transient expression of a chloramphenicol acetyltransferase (cat) reporter gene linked to the promoter sequences in the long terminal repeat (LTR) of the human immunodeficiency virus type 1 (HIV-1). Aflatoxin B1, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD; dioxin) and benzo[a]pyrene cause a significant increases in CAT expression in mouse hepatoma Hepa-1 cells. The induction of CAT after TCDD treatment is abolished by administration of N-acetyl-L-cysteine or 2-mercaptoethanol and does not take place in a mutant cell line that lacks CYP1A1 enzymatic activity. Linker-scanning mutational analysis of transcription factor binding sites in the promoter revealed that both the NF kappa B and an adjacent aromatic hydrocarbon response element (AhRE) are required for TCDD-dependent CAT expression. In addition, mutation of the NFAT/AP-1 binding sites in the negative regulatory region of the promoter increases the magnitude of the TCDD effect. We conclude that induction of a functional CYP1A1 monooxygenase by TCDD stimulates a pathway that generates thiol-sensitive reactive oxygen intermediates which, in turn, are responsible for the TCDD-dependent activation of genes linked to the LTR. These data might provide an explanation for findings that TCDD increases infectious HIV-1 titers in experimental systems and for epidemiologic reports suggesting that exposure to aromatic hydrocarbons, such as found in cigarette smoke, is associated with an acceleration in AIDS progression.
Yao
Y
Y
Center for Environmental Genetics, University of Cincinnati Medical Center, OH 45267-0056, USA.
Hoffer
A
A
Chang
C Y
CY
Puga
A
A
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D015500:Chloramphenicol O-Acetyltransferase / Q000235:genetics*; D003001:Cloning, Molecular; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects*; D015967:Gene Expression Regulation, Viral / Q000187:drug effects*; D017930:Genes, Reporter / Q000187:drug effects*; D015497:HIV-1 / Q000235:genetics*; D051379:Mice; D008969:Molecular Sequence Data; D018384:Oxidative Stress; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D012091:Repetitive Sequences, Nucleic Acid; D014407:Tumor Cells, Cultured
D000072317:Polychlorinated Dibenzodioxins; D003577:Cytochrome P-450 Enzyme System; D015500:Chloramphenicol O-Acetyltransferase