Project #3:In the central nervous system, HIV-1 induced disorders are coupled with dysregulation of cytokines as aresult of their abnormal pattern of expression. Among these cytokines, Tumor Necrosis Factor a (TNFa),has captured much attention due to the positive feedback interplay between the HIV-1 regulatory protein,Tat, and the downstream executors of the TNFa signaling pathway, including NFKB transcription factors.Expression of TNFa can also be dysregulated by opiates suggesting that cooperativity between HIV-1 andopiates at the molecular level may influence the neuropathogenesis of AIDS in drug-addicted patients.However, the molecular mechanism involved in the activation of TNFa upon HIV-1 infection in the context ofdrugs of abuse such as morphine remains unknown. Our preliminary results support the possibleinvolvement of the p65 subunit of NFKB and p38 MARK signaling in this event. Activation of TNFa canpromote oxidative stress in cells which, in turn, initiates a positive feedback cascade of events that furtherenhances TNFa production. Morphine has been shown to induce oxidative stress via an unknown pathwayleading us to envision a role for TNFa in morphine-induced oxidative stress during the course of viralinfection. Together with activated TNFa, the HIV-1 regulatory protein (Tat) and the envelope protein(gp120) can exert a toxic effect on neurons causing neuronal injury and death and morphine can acceleratethis by affecting several key regulatory events that control neuronal cell survival. We plan to identify themechanism by which morphine and HIV-1 infection upregulate TNFa gene expression and to determine thesignaling events that are involved in Tat, gp120, and TNFa induced neuronal cell dysfunction. In thecontext of this program project, we will be able to develop and utilize, in parallel, cell culture models fromHIV-1 and SIV-1 infected macrophages from human and monkey to unravel the various regulatorypathways that are affected upon drug treatment and viral infection, and cross examine the biologicalrelevance of the in vitro cell culture findings to the results from the experimental SIV/macaque model that isthe central focus of this program. Through such an integrated synergism with the other participants of thisprogram, the outcome of these molecular studies will provide critical information that can be translatedtoward the development and use of therapeutic approaches in addicted AIDS patients.
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