While highly active antiretroviral therapy (HAART) has dramatically improved the quality of life for HIV-infected individuals, there has been an increase in the prevalence of HIV-associated neurological diseases. In fact, there is ongoing inflammation in the brains of HAART patients. Chronic HIV infection leads to the expression of a key enzyme in tryptophan metabolism, IDO (Indolamine 2, 3, Di-Oxygenase), which is upregulated during SIV/HIV infection. This enzyme dampens cell-mediated immune responses by diverting tryptophan to kynurenine (Kyn) metabolism. Activation of the normally silent Kyn pathway results in draining of tryptophan reserves. Tryptophan is essential for the production of neuroprotective serotonin, activation of effector T cells, and general protein synthesis throughout the body. The Kyn metabolite quinolinic acid leads to neurodegeneration by promoting NMDA (N-methyl-D-aspartic acid) receptor-mediated excitotoxicity. Other kynurenine metabolites, combined with the depletion of tryptophan, inhibit effector T-cell function, thus permitting more HIV replication in both the CNS and periphery. The net effect is more virus replication, greater CNS inflammation and upregulation of IFN3, which in turn further upregulates IDO, setting up a positive feedback loop that eventually leads to neuronal damage manifested as motor and cognitive dysfunction. In this application we will investigate the hypothesis that IDO is a central mechanism for the development of HIV-associated neurological disease, determine the extent and timing of IDO expression in brain and the periphery of SIV-infected animals, quantitate inducers of IDO expression (IFN3 and virus), identify IDO expressing cells in the CNS and periphery and define the consequences of IDO expression by quantitating tryptophan, kynurenine, kynurenine metabolites, inflammatory and neurodegeneration markers and viral load. We next will dissect the specific effects of IDO activation and inhibition on individual cell types from the brain and periphery in vitro. Finally we will investigate the consequences of IDO expression and inhibition in SIV-infected animals on serotonin levels in the brain and on effector T cell function in a prospective study.
Chronic activation of the immune regulatory enzyme IDO (Indolamine 2, 3, Di-Oxygenase) in the brains of HIV-infected individuals results in suppression of immune responses and increases in the number of infected and inflammatory cells in the brain. IDO consumes tryptophan (Trp) when active. Trp is required for synthesis of serotonin, a neurotransmitter that is critical for numerous brain functions including sleep, memory and learning, temperature regulation, mood, behavior, as well as systemic cardiovascular function, muscle contraction, and endocrine regulation. We propose that IDO is responsible for HIV neurological disease and the depletion of serotonin. We will study this using a well-characterized SIV model of HIV infection.
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