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 gene induces cell cycle arrest in the G(2) phase of the cell cycle and is characterized by an accumulation of the hyperphosphorylated form of cdc2 kinase. This phenotype is similar to the effect of DNA-damaging agents, which can also cause cells to arrest at G(2). We previously reported that Vpr mimicked some of the effects of a DNA alkylating agent known as nitrogen mustard (HN2). Here we extend these earlier observations by further comparing the activation state of cdc2 kinase, the kinetics of G(2) arrest, and the ability to reverse the arrest with chemical 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 methylxanthines at concentrations similar to those needed to reverse the 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 that are similar to those utilized by DNA-damaging agents.