The HIV-1 virion-associated protein Vpr is a coactivator of the human glucocorticoid receptor

The HIV-1 virion-associated accessor)I protein Vpr affects both viral repli cation and cellular transcription, proliferation, and differentiation. We r eport that Vpr enhances the activity of glucocorticoids in lymphoid and mus cle-derive cell Lines by interacting directly with the glucocorticoid recep tor and general transcription factors, acting as a coactivator. Vpr contain s the signature motif LXXLL also present in cellular nuclear receptor coact ivators, such as steroid receptor coactivator 1 and p300/CREB-binding prote in, which mediates their interaction with the glucocorticoid and other nucl ear hormone receptors. A mutant Vpr molecule with disruption of this coacti vator signature motif lost its ability to influence transcription of glucoc orticoid-responsive genes and became a dominant-negative inhibitor of Vpr, possibly by retaining its general transcription factor-binding activities. The glucocorticoid coactivator activity of Vpr may contribute to increased tissue glucocorticoid sensitivity in the absence of hypercortisolism and to the pathogenesis of AIDS.