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Vicente Planelles

Associate Professor of Pathology

B.S. Universidad Complutense, Spain

Ph.D. University of California, Davis

Research

References

vicente.planelles@path.utah.edu

 

Research

The primary focus of our research is to understand how HIV-1 and related primate lentiviruses cause cell cycle dysregulation and apoptosis in infected CD4+ lymphocytes. Our investigations have revealed that a small protein encoded by HIV-1, the viral protein "R" (Vpr), is necessary and sufficient to induce both effects and, is therefore, a molecular determinant of AIDS pathogenesis. We have recently begun to understan the molecular mechanisms by which Vpr expression leads to deleterious effects in the host cell. Vpr is a 96-amino acid protein that specifically activates the ATM-and-Rad3-related protein kinase, ATR. The normal function of ATR is to sense DNA damage in the mammalian genome, and to induce checkpoint activation and apoptosis in response to such damage.   Vpr usurps ATR and the downstream pathways under its control, to increase the efficiency of viral replication, and to induce cytopathic effects. These cytopathic effects ultimately result in death of the infected lymphocytes, one of the hallmarks of development of AIDS.

A second aspect of our research relates to the effects of HIV infection on macrophages. Macrophages are also an important target for HIV. Infection of macrophages with HIV leads to relatively slow cytopathicity, and this allows macrophages to circulate, access various peripheral organs, and disseminate the virus. Thus, our laboratory has developed a strong interest in understanding the molecular basis for the different effects that HIV and, in particular, Vpr, exhibit when infecting T-cells and macrophages.

 

A. HIV-1 Vpr activates ATR, which in turn phosphorylates BRCA1, H2AX and Chk1, leading to the induction of various downstream effects. B. Expression of a Vpr-IRES-GFP bicistronic mRNA, but not GFP alone, leads to the formation of nuclear foci that contain RPA (also a target for ATR phosphorylation), indicative of a cellular condition known as "replicational stress". Hydroxyurea (HU) is the positive control. C. Vpr can be found in association with the chromatin. Orc2, positive control. The precise mechanism of activation of ATR by Vpr is currently under investigation. We hypothesize that the chromatin localization of Vpr is critical toward ATR activation.

References