EXTRACELLULAR VPR PROTEIN INCREASES CELLULAR PERMISSIVENESS TO HUMAN-IMMUNODEFICIENCY-VIRUS REPLICATION AND REACTIVATES VIRUS FROM LATENCY

The vpr gene product of human immunodeficiency virus (HIV and simian i mmunodeficiency virus is a virion-associated regulatory protein that h as been shown using vpr mutant viruses to increase virus replication, particularly in monocytes/macrophages. We have previously shown that v pr can directly inhibit cell proliferation and induce cell differentia tion, events linked to the control of HIV replication, and also that t he replication of a vpr mutant but not that of wild-type HIV type 1 (H IV-1) was compatible with cellular proliferation to. N. Levy, L. S. Fe rnandes, W. V. Williams, and D. B. Weiner, Cell 72:541-550, 1993). Her e we show that purified recombinant Vpr protein, in concentrations of <100 pg/ml to 100 ng/ml, increases wild-type HIV-1 replication in newl y infected transformed cell lines via a long-lasting increase in cellu lar permissiveness to HIV replication. The activity of extracellular V pr protein could be completely inhibited by anti-Vpr antibodies. Extra cellular Vpr also induced efficient HIV-1 replication in newly infecte d resting peripheral blood mononuclear cells. Extracellular Vpr transc omplemented a vpr mutant virus which was deficient in replication in p romonocytic cells, restoring full replication competence. In addition, extracellular Vpr reactivated HIV-1 expression in five latently infec ted cell lines of T-cell, B-cell, and promonocytic origin which normal ly express very low levels of HIV RNA and protein, indicating an activ ation of translational or pretranslational events in the virus life cy cle, Together, these results describe a novel pathway governing HIV re plication and a potential target for the development of anti-HIV thera peutics.