MR Spectroscopy of SIV Brain Injury

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DESCRIPTION (PROVIDED BY APPLICANT): A leading theory for the pathogenesis of neuroAIDS is that a specific bone marrow derived blood monocyte is virally infected and activated, then traffics into the CNS where it becomes a perivascular macrophage and sets off a cascade of events that result in neuronal injury. In light of experiments performed in our laboratory, we extend this theory and propose that accumulation of neuronal injury in neuroAIDS requires continuous trafficking of infected/activated CD 14/16 monocytic phagocytes (MPs) into the CNS to surmount turnover of these cells and endogenous neuronal recovery mechanisms. We seek to understand the dynamics of MP trafficking, MP turnover in the CNS and neuronal recovery through an experimental design that tests a series of specific hypotheses derived from the central theory. We will use 1H magnetic resonance spectroscopy (MRS) at high field (7T) in an accelerated simian immunodeficiency virus (SIV) macaque model of neuroAIDS that reliably produces SIV encephalitis and neuronal injury within weeks. Moreover, we will use HAART to experimentally manipulate CNS trafficking of activated blood monocytes, and modulate neuronal injury. Simultaneously with imaging, we will quantify levels of activated (CD14+/CD16+) monocytes, their SPV DNA and RNA levels, and virus in blood. We will complete this study with detailed immunological, virological, neuropathologic and MRS studies of the brains of the same animals. Our specific aims are: Specific Aim 1. Determine the amount of virally infected/activated CD14/16 MPs in blood, and at the same time determine regional neuronal injury in SIV infected/CD8 depleted macaques and similar animals undergoing HAART. Specific Aim 2. Determine the severity of CNS injury by in vivo & ex vivo MRS and immunohistochemistry in different brain regions, and determine the levels of perivascular MPs in those regions.