Glucocorticoids suppress human immunodeficiency virus type-1 long terminal repeat activity in a cell type-specific, glucocorticoid receptor-mediated fashion: direct protective effects at variance with clinical phenomenology.
Glucocorticoid administration and/or excess secretion have been associated with increased Human Immunodeficiency Virus Type-1 (HIV-1) replication and AIDS progression. The HIV-1 long terminal repeat (LTR) promoter contains glucocorticoid-responsive element (GRE)-like sequences that could mediate a positive effect of glucocorticoids on HIV-1. In addition, we recently demonstrated that the HIV-1 accessory protein Vpr is a potent coactivator of the glucocorticoid receptor, which, like the host coactivator p300, potentiates the effect of glucocorticoids on GRE-containing, glucocorticoid-responsive genes. Such an effect may increase the sensitivity of several host target tissues to glucocorticoids by several fold, and may, thus, contribute to a positive effect of glucocorticoids on the HIV-1-LTR in infected host cells. In this study, we determined the direct effect of glucocorticoids on HIV-1-LTR by examining the ability of dexamethasone to modulate the activity of this promoter coupled to the luciferase reporter gene in human cell lines. Dexamethasone markedly inhibited Tat-stimulated, p300- or Vpr-enhanced luciferase activities in a cell-type specific, dose-dependent, and glucocorticoid receptor-mediated fashion. This effect of dexamethasone was not potentiated by Vpr, was antagonized by the glucocorticoid receptor antagonist RU 486 and required the DNA-binding domain of the receptor. These data suggest that the inhibitory effect of glucocorticoids on the HIV-1-LTR may be exerted via non-GRE-dependent inhibition of the strongly positive host transcription factor NF-kappaB, which interacts with the DNA- and ligand-binding domains of the receptor. Alternatively, it is also possible that dexamethasone-activated glucocorticoid receptor competes with other transcription factors for their binding sites on the promoter region or squelches transcription factors shared by HIV-1-LTR and glucocorticoid-responsive promoters. We conclude that glucocorticoids suppress, rather than stimulate, the HIV-1 promoter, thus acting, protectively for the host. Their apparent negative clinical association with AIDS is most likely due to immunosuppression of the host.
Pediatric and Reproductive Endocrinology Branch, National Institute of Child Health and Human Development, Building 10, Room 9D42, National Institutes of Health, 10 Center Drive MSC 1583, Bethesda, MD 20892, USA. kinot@mail.nih.gov
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D000818:Animals; D002460:Cell Line; D002522:Chlorocebus aethiops; D003907:Dexamethasone / Q000494:pharmacology*; D015696:Gene Products, tat / Q000494:pharmacology; D016336:Gene Products, vpr / Q000494:pharmacology; D005938:Glucocorticoids / Q000494:pharmacology*; D016325:HIV Long Terminal Repeat / Q000187:drug effects*; D006801:Humans; D019169:Jurkat Cells; D008156:Luciferases / Q000235:genetics; D008324:Mammary Tumor Virus, Mouse / Q000235:genetics; D009154:Mutation; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism*; D020079:Terminal Repeat Sequences; D014162:Transfection; D020298:U937 Cells
D015696:Gene Products, tat; D016336:Gene Products, vpr; D005938:Glucocorticoids; D011965:Receptors, Glucocorticoid; D003907:Dexamethasone; D008156:Luciferases