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Dr. Vanessa Rivera-Amill
Title: Influence of Cocaine on Immune Cells and HIV-1 Pathogenesis


Cocaine is one of the most widely abused drugs in the United States; it is also considered a cofactor in human immunodeficiency virus infection as a result of its frequent association with such high risk behaviors as sharing contaminated needles and practicing unsafe sex. Also recognized is the role of cocaine on the modulation of the immune response and its ability to potentiate HIV replication and disease progression. However, the mechanism by which cocaine mediates these effects remains ill-defined. HAART (highly active antiretroviral therapy) controls viral replication, significantly improving survival and quality of life. It is widely recognized that adherence to HAART is not easy. Recently it was recognized that P-glycoprotein (Pgp), which is encoded by the MDR1 gene (multi-drug resistance), acts as an efflux pump; one of its substrates is a protease inhibitor (PI), a component of HAART. Our preliminary data revealed that chronic cocaine users had increased levels of Pgp expression on CD4+ T cells, CD8+ T cells, and monocytes. In addition, CXCR4 (a major HIV-1 coreceptor) levels were also increased. These results suggest that cocaine may also play a role in the efficacy of HAART by reducing the bioavailability of the protease inhibitor and by promoting disease progression through the up-regulation of CXCR4. Our study hypothesis is that cocaine primarily alters cytokine/chemokine cascade function, consequently yielding up-regulation of Pgp and CXCR4, which in turn leads to both the decreased bioavailability of the PI and the promotion of HIV-1 replication, respectively. Our specific aims will address this hypothesis in an effort to clarify the relationship between cocaine use and the expression of Pgp and CXCR4. The in vitro effects of cocaine on immunological cell function and Pgp and CXCR4 expression will be examined in specific aim 1 through microarray analysis, flow cytometry, and Western blot analysis, among others. This will be followed by specific aim 2, in which we are going to determine the effects of PI and Pgp inhibitors on HIV-1 replication in cells previously exposed to cocaine. Finally, in specific aim 3, we will generate an MDR1 gene knockdown on T cells/monocytes and determine its effect on CXCR4 expression and HIV-1 replication in the presence of PIs. At the conclusion of this study, we will have significantly advanced our understanding of the effects of cocaine on HIV-1 pathogenesis. Our long term goal is to provide a better understanding of the effect of cocaine use on immunological cells and HAART efficacy for the possible inclusion of Pgp inhibitors in therapy regimens.
 


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