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.
|Drewes, Julia L; Meulendyke, Kelly A; Liao, Zhaohao et al. (2015) Quinolinic acid/tryptophan ratios predict neurological disease in SIV-infected macaques and remain elevated in the brain under cART. J Neurovirol 21:449-63|
|Tharakan, Ravi; Tao, Dingyin; Ubaida-Mohien, Ceereena et al. (2015) Integrated microfluidic chip and online SCX separation allows untargeted nanoscale metabolomic and peptidomic profiling. J Proteome Res 14:1621-6|
|Royle, Caroline M; Tsai, Ming-Han; Tabarrini, Oriana et al. (2014) Modulation of HIV-1-induced activation of plasmacytoid dendritic cells by 6-desfluoroquinolones. AIDS Res Hum Retroviruses 30:345-54|
|Meulendyke, Kelly A; Queen, Suzanne E; Engle, Elizabeth L et al. (2014) Combination fluconazole/paroxetine treatment is neuroprotective despite ongoing neuroinflammation and viral replication in an SIV model of HIV neurological disease. J Neurovirol 20:591-602|
|Drewes, Julia L; Szeto, Gregory L; Engle, Elizabeth L et al. (2014) Attenuation of pathogenic immune responses during infection with human and simian immunodeficiency virus (HIV/SIV) by the tetracycline derivative minocycline. PLoS One 9:e94375|
|Meulendyke, Kelly A; Ubaida-Mohien, Ceereena; Drewes, Julia L et al. (2014) Elevated brain monoamine oxidase activity in SIV- and HIV-associated neurological disease. J Infect Dis 210:904-12|
|Meulendyke, Kelly A; Croteau, Joshua D; Zink, M Christine (2014) HIV life cycle, innate immunity and autophagy in the central nervous system. Curr Opin HIV AIDS 9:565-71|
|Nzowa, L K; Teponno, R B; Tapondjou, L A et al. (2013) Two new tryptophan derivatives from the seed kernels of Entada rheedei: effects on cell viability and HIV infectivity. Fitoterapia 87:37-42|
|Notarangelo, Francesca M; Wu, Hui-Qiu; Macherone, Anthony et al. (2012) Gas chromatography/tandem mass spectrometry detection of extracellular kynurenine and related metabolites in normal and lesioned rat brain. Anal Biochem 421:573-81|
|Meulendyke, Kelly A; Pletnikov, Mikhail V; Engle, Elizabeth L et al. (2012) Early minocycline treatment prevents a decrease in striatal dopamine in an SIV model of HIV-associated neurological disease. J Neuroimmune Pharmacol 7:454-64|
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