This is a revised application in which the Principal Investigator proposes to study SIV encephalitis using magnetic resonance spectroscopy (MRS). In the first specific aim, the Investigator and collaborators will quantify the dynamics of the brain injury mediated by SIV using MR spectroscopy with a 3 Tesla instrument. Macaques inoculated with a neurovirulent SIV strain will be studied with MRS at regular and frequent intervals, until death or euthanasia. The gray and white matter volumes will be measured and compared with those of age- and sex-matched macaque controls. MRS will be performed to quantify the N-acetylaspartate (NAA) levels and to obtain a rotation between the levels of NAA and creatinine. In addition to the radiological studies, viral isolations, antibody determinations, and quantification of viral antigen will be performed. In collaboration with M. Heyes NIMH, the levels of quinolinic acid will be measured as well. After necropsy, the CNS tissues will be examined quantitatively for neuropathological alterations, including neuronal and glial cell counts, and quantififcation of dendritic and synaptic areas. The relationship between NAA changes and other parameters of HIV infection will then be determined. In the second specific aim the researchers will develop a treatment protocol whereby the animals will be treated with AZT beginning one week prior to inoculation with neurovirulent virus. MRI and MRS will be obtained at regular intervals after inoculation. In addition, some animals will be given the NMDA antagonist memantine. In other experiments, the animals will be treated after infection. These studies have been simplified since the prior submission. They will begin on Year 02 of the grant.
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