HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 VPR GENE INDUCES PHENOTYPIC EFFECTS SIMILAR TO THOSE OF THE DNA ALKYLATING AGENT, NITROGEN-MUSTARD

The product of the human immunodeficiency virus type 1 (HIV-1) vpr gen e induces cell cycle arrest in the G(2) phase of the cell cycle and is characterized by an accumulation of the hyperphosphorylated form of c dc2 kinase. This phenotype is similar to the effect of DNA-damaging ag ents, which can also cause cells to arrest at G(2). We previously repo rted that Vpr mimicked some of the effects of a DNA alkylating agent k nown as nitrogen mustard (HN2). Here we extend these earlier observati ons by further comparing the activation state of cdc2 kinase, the kine tics of G(2) arrest, and the ability to reverse the arrest with chemic al compounds known as methylxanthines, Infection of cells synchronized in the G(1) phase of the cell cycle with a pseudotyped HIV-1 resulted in arrest at G(2) within 12 h postinfection, before the first mitosis , Similar to that induced by HN2, Vpr-induced arrest led to a decrease in cdc2 kinase activity. Vpr-mediated G(2) arrest was alleviated by m ethylxanthines at concentrations similar to those needed to reverse th e G(2) arrest induced by HN2, and cells proceeded apparently normally through at least one complete cell cycle, These results are consistent with the hypothesis that Vpr induces G(2) arrest through pathways tha t are similar to those utilized by DNA-damaging agents.