Vpr and Signaling Events
HIV-1 encodes four accessory proteins, Vif, Vpr, Vpu, and Nef. These are small proteins with multiple functions and regulate various aspects of the virus-host cell relationship. My laboratory has primarily focused on Vpr. Vpr induces cell cycle arrest in the G2 phase. The immediate consequence of this activity of Vpr is that infected cells do not enter mitosis and, therefore, do not divide. A later consequence of the cell cycle disturbance is that the infected cell commits to apoptosis or programmed cell death. We hypothesize that this chain of events explains, at least in part, the severe depletion in CD4-positive lymphocytes observed during the acquired immunodeficiency syndrome.
A major research objective of my laboratory is to understand, at a molecular level, the succession of signaling events that ultimately lead to the induction of apoptosis. We have found that Vpr interferes with the normal DNA replication of dividing cells. This interference, in turn activates a cellular system that monitors the integrity of DNA as well as the processivity of DNA replication. This system is known as the ATR serine-threonine kinase.
Through activation of the ATR kinase, Vpr accomplishes the activation of two different, but interdependent signaling cascades, leading to cell cycle disruption and apoptosis.