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Ramu A. Subbramanian^*, Allegria Kessous-Elbaz, Robert Lodge^*, Janique Forget^*, Xiao-Jian Yao^*, Dominique Bergeron^*, and Eric A. Cohen^*

From the ^* Laboratory of Human Retrovirology, Department of Microbiology and Immunology, and the Department of Pathology, Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada H3C3J7

It is currently well established that HIV-1 Vpr augments viral replication 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 is unclear. Here we use Vpr-mutants to demonstrate that the molecular determinants involved in G2-arresting T cells are also involved in increasing 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 the late and early functions of Vpr. The nuclear localization property of Vpr correlates with its ability to effectively target the proviral DNA to the cell nucleus early in the infection, whereas the G2-arrest phenotype correlates with its ability to activate viral transcription after establishment of an infection. These two functions may render Vpr's role essential and not accessory under infection conditions that closely mimic the in vivo situation, that is, primary cells being infected at low viral inputs.

¹Abbreviations used in this paper: β2-AR, β2-adrenergic receptor; SIV, simian immunodeficiency virus.

E.A. Cohen is a recipient of a National Health Scientist award from the National Health Research and Development Program (NHRDP) of Canada. This work was supported by grants from the Medical Research Council and Fonds pour La Formation de Chercheurs et L'Aide à La Recherche (FCAR) to E.A. Cohen.

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