The human immunodeficiency virus (HIV), the causative agent of AIDS, is complex retrovirus with levels of control imparted by regulatory and accessory proteins not found in simple retroviruses. It is important to continue to study these regulatory/accessory proteins because they offer a window into control of normal host cell processes. This grant focuses on the interaction of the cell cycle progression by causing cells to accumulate in the G2 phase of the cell cycle and to a subsequent block in mitosis. It has been unclear why this would be beneficial for the virus. In this proposal, we seek to understand the mechanism of action of Vpr and resolve the question of the selective advantage this confers on the virus. We will critically test the hypothesis that the selection for G2 arrest is due to increased virus production in the G2 phase of the cell cycle in cells with a short half-life. This will be done by setting up mixed infections between viruses that do or do not cause cell cycle arrest, and then measuring the relative fitness of the viruses under conditions where the life-span of the infected cells is experimentally manipulated. To understand the mechanism of Vpr-induced G2 arrest, we will determine if the interaction between Vpr and the cell cycle regulators, Cdc25, can explain the effects of Vr on cell cycle arrest. This will be done with biochemical and genetic experiments to define the nature and importance of inhibition of Cdc25 activity by Vpr. Finally, we will characterize the effect of Vpr on segregation of chromosomes in mitosis. It is anticipated that these results will allow us to more fully understand the interaction of the virus with its host.
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