%0 Generic
%9 Doctoral Dissertation
%A Venkatachari, Narasimhan Jayanth
%D 2009
%F pittir:6861
%K Vpr; dissemination; HIV-1; virus; immune function; replication
%T EFFECT OF HIV-1 VIRAL PROTEIN R (VPR) ON T CELL TARGETS: CONSEQUENCES IN IMMUNOSUPPRESSION AND VIRAL DISSEMINATION
%U http://d-scholarship-dev.library.pitt.edu/6861/
%X CD4+T-cells have a central role in induction and homeostasis of the immune response, and are also the major target cells for HIV. HIV has devised mechanisms to subvert the immune system and further its cause of survival and dissemination. vpr is one of the accessory genes, which is essential for the virus survival in vivo. Being a soluble protein with an ability to transduce across cell membranes, Vpr can potentially affect bystander cells. We hypothesize that HIV-1 Vpr alters the functions of both infected and bystander T lymphocytes, utilizing direct and indirect mechanisms, and these Vpr-mediated effects contribute in part to the immune dysregulation, and aid in viral dissemination. The Specific Aims of this proposal are to: (1) Assess the immune modulatory effects of Vpr in infected and bystander T-lymphocytes; (2) Understand the role of Vpr in T lymphocytes, natural killer (NK) cells and dendritic cells (DC) interactions; and (3) Analyze the structure-function role of Vpr in immunopathogenesis. We utilized HIV-1wt and HIV-1ΔVpr viruses and compared the difference in the effects of these viruses under controlled simulated invitro conditions. The differences observed in the effect of these two viruses can be attributed to Vpr provided that the infections in both the experimental sets are similar. In some studies, to clearly identify infected cells, we employed EGFP reporter viruses. The effects in infected cells and bystander cells were evaluated. Results indicate that HIV-1 Vpr has a role in dysregulation of immune cells during HIV infection. Vpr differentially regulates the surface expression of T cell costimulatory molecules, CD28 and CTLA-4, and inhibits IFN-γ production in infected T cells. Vpr also inhibits NK cell function by augmenting TGF-β production and inducing altered expression of NK receptor ligands. Further, oligomerization of Vpr has a role in gag incorporation of Vpr and in viral pathogenesis. The findings presented in this study are significant for public health because mechanistic understanding of the pathogenesis will aid in development of novel anti-viral therapeutics.