Brain macrophages are targets of HIV/SIV infection in the CNS. We have shown that perivascular brain macrophages are a major target of SIV infection in animals with SIV encephalitis (SIVE). The perivascular macrophage population has a similar immunophenotype to circulating PBMC's observed in the blood of HIV infected humans with dementia (CD14/CD16/CD69 positive). Using a model of CD8 depletion with SIV infection that results in a high incidence of SIVE, we observe significant perivascular macrophage accumulation. We hypothesize that a distinct, identifiable population of infected blood monocyte/macrophages similar to perivascular cell in the brain traffics to the CNS and that this population is held in check by CD8+ lymphocytes. To test this hypothesis we will: Examine the CNS of SIV infected animals with and without CD8 depletion to analyze the phenotype, relative cell numbers, and level of infection of subpopulations of brain macrophages at peak viremia and in animals with SIVE. This will be achieved by using immunohistochemistry, double and triple label immunoflourescence with confocal microscopy and quantitative image analysis to examine the expression of CD14/CD16/CD69 and gp120 by perivascular brain macrophages. 2. Identify populations of monocyte/macrophages in the blood of SIV infected macaques that correspond immunophenotypically to perivascular brain macrophages. We propose to examine populations of peripheral blood monocyte/macrophages (CD14+) for a) the number of CD14/CD69+ and CD14/CD16+ cells in the blood and brain during disease development b) the level of SIV infection, and c) env and nef sequences of peripheral blood monocyte/macrophage subpopulations in comparison to brain and other tissue macrophages. 3. Determine the ability of CD8+ lymphocytes to control the number and level of viral infection of blood and brain monocyte/macrophages. Based on the observation of the rapid accumulation of perivascular macrophages in CD8 depleted animals we will study the ability of CD8+ lymphocytes to keep infected blood monocyte/macrophages in check by combinations of : a) direct lysis b) indirect inhibition of viral replication, and c) inhibition of blood monocyte/macrophage traffic through an in vitro BBB model.
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