THE VPR PROTEIN OF HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 INFLUENCES NUCLEAR-LOCALIZATION OF VIRAL NUCLEIC-ACIDS IN NONDIVIDING HOST-CELLS

The replication of human immunodeficiency virus type 1 (HIV-1) in nond ividing host cells such as those of macrophage lineage is an important feature of AIDS pathogenesis. The pattern of HIV-1 replication is dic tated, in part, by the nucleophilic property of the viral gag matrix ( MA) protein, a component of the viral preintegration complex that faci litates nuclear localization of viral nucleic acids in the absence of mitosis. We now identify the accessory viral protein Vpr, as a second nucleophilic component that influences nuclear localization of viral n ucleic acids in nondividing cells. Reverse transcription and nuclear l ocalization of viral nucleic acids following infection of cells by vir uses lacking Vpr or viruses containing mutations in a gag MA nuclear l ocalization sequence were indistinguishable from the pattern observed in cells infected by wild-type HIV-1. These viruses retained the abili ty to replicate in both dividing and nondividing host cells including monocyte-derived macrophages. In contrast, introduction of both gag MA and Vpr mutations in HIV-1 attenuated nuclear localization of viral n ucleic acids in nondividing cells and virus replication in monocyte-de rived macrophages. These studies demonstrate redundant nucleophilic de terminants of HIV-1 that independently permit nuclear localization of viral nucleic acids and virus replication in nondividing cells such as monocyte-derived macrophages. In addition, these studies provide a de fined function for an accessory gene product of HIV-1.