Glucocorticoids suppress human immunodeficiency virus type-1 long terminalrepeat 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 gl ucocorticoid-responsive element (GRE)-like sequences that could mediate a p ositive effect of glucocorticoids on HIV-1. In addition, we recently demons trated 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 luci ferase activities in a cell-type specific, dose-dependent. and glucocortico id receptor-mediated fashion. This effect of dexamethasone was not potentia ted by Vpr, was antagonized by the glucocorticoid receptor antagonist RU 48 6 and required the DNA-binding domain of the receptor. These data suggest t hat the inhibitory effect of glucocorticoids on the HIV-1-LTR may be exerte d via non-GRE-dependent inhibition of the strongly positive host transcript ion factor NF-kappaB, which interacts with the DNA- and ligand-binding doma ins 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 con clude that glucocorticoids suppress, rather than stimulate, the HIV-1 promo ter, thus acting, protectively for the host. Their apparent negative clinic al association with AIDS is most likely due to immunosuppression of the hos t. Published by Elsevier Science Ltd.