Human immunodeficiency virus type 1 vpr induces apoptosis following cell cycle arrest

The human immunodeficiency virus type 1 (HIV-1) vpr gene encodes a protein which induces arrest of cells in the G(2) phase of the cell cycle. Here, we demonstrate that following the arrest of cells in G(2), Vpr induces apoptosis in human fibroblasts, T cells, and primary peripheral blood lymphocytes. Analysis of various mutations in the vpr gene revealed that the extent of Vpr-induced G(2) arrest correlated with the levels of apoptosis. However, the alleviation of Vpr-induced G(2) arrest by treatment with the drug pentoxifylline did not abrogate apoptosis. Together these studies indicate that induction of G(2) arrest, but not necessarily continued arrest in G(2), was required for Vpr induced apoptosis to occur, Finally, Vpr induced G(2) arrest has previously been correlated with inactivation of the Cdc2 kinase. Some models of apoptosis have demonstrated a requirement for active CdcZ kinase for apoptosis to occur. Here we show that accumulation of the hypophosphorylated or active form of the CdcZ kinase is not required for Vpr-induced apoptosis. These studies indicate that Vpr is capable of inducing apoptosis, and we propose that both the initial arrest of cells and subsequent apoptosis may contribute to CD4 cell depletion in HIV-1 disease.