Independent functions of Vpr protein in transcriptional coactivation and cell cycle arrest

Vpr is an accessory HIV protein that is incorporated into the virion via interaction with Gag. It has been proposed to have many functions during HIV life cycle. As a virion protein, Vpr acts early after infection and has been proposed to be important for the translocation of the viral DNA to the nucleus. Vpr also arrests cells at the G2 stage of the cell cycle and is a transactivator of several viral and cellular promoters. The functions of Vpr relevant to facilitating efficient propagation of HIV in primary cells remain to be elucidated. In addition to its other functions, we showed that Vpr is a coactivator of the glucocorticoid receptor. Mutational analysis indicates that transcriptional coactivation and cell cycle arrest are distinct Vpr functions and map on different parts of the molecule. We showed that Vpr strongly stimulates glucocorticoid response in some cell lines and it interacts with glucocorticoid receptor (GR) in vitro in the presence of the receptor agonist as well as in extracts of Vpr-expressing, glucocorticoid-treated cells. Vpr contains the signature motif LXXLL also present in cellular nuclear receptor coactivators, such as SRC-1 and p300/CBP, which mediates their interaction with the glucocorticoid and other nuclear hormone receptors. A mutant Vpr molecule with disruption of this motif lost its ability to influence transcription of glucocorticoid-responsive genes and to interact with GR. GR coactivation and cell cycle arrest are independent functions of Vpr, since we have identified mutants lacking either the cell cycle arrest or the coactivator activities. These results suggest that at least some Vpr effects on transcription are not associated with cell cycle arrest. Vpr also may contribute to the development of symptoms such as muscle wasting in patients with AIDS, in the absence of increased glucocorticoid levels.

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