The HIV-1 gene product is a 96 amino acid protein, which is important for viral replication and likely to be critical for HIV-1 pathogenesis. Vpr is expressed following infection of cells and is also found packaged in virions. In 1995, the PI was among the first to describe a novel phenotype of the Vpr protein whereby cells infected by HIV-1 expressing Vpr undergo arrest at the G2 phase of the cell cycle. They subsequently published that cell cycle arrest induced by Vpr is followed by apoptosis of the arrested cells. Recently, they found that not only does de novo expression of Vpr induce cell cycle arrest, but Vpr packaged into virions is capable of inducing cell cycle arrest when introduced into cells following infection. Vpr has been shown to augment virus production and one potential function of Vpr is to prevent T-cell clonal expansion in response to antigens thus suppressing an early step in establishing an effective immune response. Therefore, Vpr may be a critical determinant for pathogenic features of HIV-1 disease and further understanding of Vpr mechanisms of action may facilitate the development of therapeutic agents directed against Vpr. Damage to cell DNA by irradiation or chemical modification can lead to arrest at multiple points in the cell cycle including the so-called G2 checkpoint. Failure to repair the damage can lead to apoptosis. According to the PI, Vpr is the only gene product known to induce such an efficient cell cycle arrest in mammalian cells at G2. Thus, an understanding of the mechanism of action of Vpr will also be important in understanding the signal transduction pathways which lead to arrest at the G2 checkpoint in mammalian cells. Previously, the PI generated a considerable amount of preliminary data about Vpr action, developed a number of unique assays for assessment of Vpr function and developed reagents which will allow him to effectively carry forward further studies on the mechanism of Vpr action.
The specific aims are:
Aim 1. To further characterize cell cycle arrest by HIV-1 Vpr.
Aim 2. To further characterize Vpr mediated apoptosis Aim 3. To identify cellular factors involved in Vpr-mediated cell cycle arrest and apoptosis.
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