HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 VPR IS A POSITIVE REGULATOR OF VIRAL TRANSCRIPTION AND INFECTIVITY IN PRIMARY HUMAN MACROPHAGES

It is currently well established that HIV-1 Vpr augments viral replica tion in primary human macrophages. In its virion-associated form, Vpr has been suggested. to aid efficient translocation of the proviral DNA into the cell nucleus. Although Vpr growth-arrests dividing T cells, the relevance of this biological activity in nondividing macrophages i s unclear. Here we use Vpr-mutants to demonstrate that the molecular d eterminants involved in G2-arresting T cells are also involved in incr easing viral transcription in macrophages, even though these cells are refractive to the diploid DNA status typical of G2 phase. Our results suggest that the two phenotypes, namely the nuclear localization and the G2-arrest activity of the protein, segregate functionally among th e late and early functions of Vpr. The nuclear localization property o f Vpr correlates with its ability to effectively target the proviral D NA to the cell nucleus early in the infection, whereas the G2-arrest p henotype correlates with its ability to activate viral transcription a fter establishment of an infection. These two functions may render Vpr 's role essential and not accessory under infection conditions that cl osely mimic the in vivo situation, that is, primary cells being infect ed at low viral inputs.