During HIV/SIV infecfion there is chronic hyperactivation of the immune system, with circulating virus stimulating expression of type I IFNs. resulting in increased numbers of infected cells trafficking to the brain and the functional impairment of effector T cells by PDL-1 and PD-1 and IDO. In the brain, activation of microglia/macrophages and astrocytes by virus promotes the release of proinflammatory cytokines/chemokines and the induction of iNOS resulting in the production of neurotoxic reactive oxygen species (ROS). Viral and host inflammatory and neurodegenerative products alter the function of neurons, resulting in excitotoxicity and reduced expression of DA and serotonin. Our hypothesis is that the effects of continued peripheral immune system hyperactivation in HIV/SIVinfected individuals are only partly reversible and that early treatment with HAART provides a significant protective advantage to the periphery and the brain by preserving effector T cell function, reducing trafficking of acfivated/infected macrophages and T cells into the brain, stopping the inflammatory neurodegenerative process and preserving levels of DA and serotonin. We recently developed the first SIV/macaque model of highly active anti-retroviral therapy (HAART) in HIVinfected individuals. We use a therapeutic regimen that includes an RT inhibitor (Tenofovir), two protease inhibitors (Atazanavir and Saquinavir) and an integrase inhibitor (206DA - Merck). In this project we will use this model to first determine the effect of HAART administered during acute infecfion, just after acute infection or during eariy virus recrudescence on preservation of innate and adaptive immune responses in the periphery. We next will compare the ability of HAART administered at various stages of infecfion to stop the pro-inflammatory cytokine cycle in the brain, suppress virus replication, preserve immune function and prevent the development of CNS disease. Finally, we will determine the effect of HAART administered at various stages of infection on the depletion of the neurotransmitters DA and serotonin.
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