Characterization of cocaine induced signaling pathways that enhances HIV transcription

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TITLE: Assessing the impact of cocaine and HIV in accelerating aging process Accelerated aging is a complication of HIV infection despite the effectiveness of highly active antiretroviral therapy (HAART or ART). This is due, in part, to HIV-associated neurological disorders (HAND) which are caused mainly by the ongoing immune activation and inflammation in the CNS. There is considerable evidence that suggests an additive or synergistic effect of cocaine on the persistence and severity of neurocognitive dysfunction in HIV- infected patients. Therefore, the relationship between drugs of abuse, such as cocaine, HIV infection, neurodegeneration and accelerated aging is of particular interest. Overall goal of the proposed investigation is to understand the underlying mechanisms through which cocaine use further accelerates the aging process in HIV infected individuals by enhancing immune activation and inflammation. Currant anti-HIV therapy is unable to restrict HIV protein production. Certain HIV proteins are toxic, especially to the CNS, as they stimulate pro-inflammatory cytokines and immune activation. Cocaine further enhance HIV protein production. The investigation proposed in this application will establish that cocaine accelerates the aging process by comparing cocaine treated and untreated HIV-infected both lymphoid and myeloid cells. Results will be confirmed in PBMCs of HIV-infected subjects with or without cocaine exposure. The following aims are proposed to confirm and quantify the impact of cocaine in promoting premature aging: Aim 1A: Analysis of cell surface markers of immune activation and inflammation, selectively triggered by cocaine Aim 1B: Investigate the potential impact of cocaine exposure on cell senescence Aim 1C: Determine the cocaine effect on cell exhaustion Aim 2: Define the plasma markers of immune activation and inflammation following cocaine use Aim 3: Examine the impact of cocaine on telomere length, telomerase transcript, protein and activity. The investigation proposed in this application will establish that cocaine accelerates the aging process by comparing cocaine-using HIV infected subjects with those not using cocaine.