CONSERVATION AND HOST-SPECIFICITY OF VPR-MEDIATED CELL-CYCLE ARREST SUGGEST A FUNDAMENTAL ROLE IN PRIMATE LENTIVIRUS EVOLUTION AND BIOLOGY

The human immunodeficiency virus type 1 (HIV-1) Vpr protein prevents i nfected cells from passing through mitosis by arresting them in the G( 2) phase of the cell cycle. Vpr is conserved among all primate lentivi ruses, suggesting an important role in the virus life cycle. Moreover, in this study we show that the ability to cause cell cycle arrest is also conserved in Vpr proteins from a wide variety of both tissue cult ure-passaged and uncultured human (HIV-1 and HIV-2), sooty mangabey (s imian immunodeficiency virus SIVSM), African green monkey (SIVAGM), an d Sykes' monkey (SIVSYK) isolates. However, this property is cell type specific and appears to depend on the particular primate species from which the cells are derived. SIVAGM and SIVSYK Vpr proteins are capab le of arresting African green monkey cells but are completely inactive in human cells. By contrast, HIV-1, HIV-2, and SIVSM Vpr proteins fun ction in both simian and human cell types, although SIVSM Vpr function s more efficiently in simian cells than it does in human cells. Neithe r differential protein stability nor subcellular localization explains the species-specific activities of these proteins. These results thus suggest that Vpr exerts its G(2) arrest function by interacting with cellular factors that have evolved differently among the various prima te species.