This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Our focus is to identify specific monocyte subsets that correlate with and are predictive of neuronal injury during neuroAIDS. We hypothesize that specific subsets of monocytes expand with and drive central nervous system disease, and these subsets decrease with immune modulators directly targeting monocytes or monocyte traffic. This study using rhesus macaques has the direct relevance to the studies of human neuroAIDS. Their use permits controlled exploration of the neuropathogenesis of disease that have pathological hallmarks of HIV and neuroinflammation. During SIV and HIV infection, the vast majority of cells demonstrated to be productively infected in the CNS are cells of the monocyte/macrophage lineage. With infection, there is an accumulation of perivascular macrophages with CD14 and CD16 expression, some of which are productively infected and also express PCNA a marker of infected cells in the bone marrow, blood and brain. The accumulation of these cells can be found early, days-to-weeks post infection, and with terminal AIDS. There is good reason to believe that populations of monocytes in the bone marrow and blood could be a source of perivascular macrophages and indeed cells that accumulate with virus, the so-called Trojan Horse cells. This study will directly assess the significance of continued monocyte traffic on neuronal injury during AIDS, using a CD8 depletion and SIVmac251 infection model of rapid, consistent CNS disease resulting in neuronal injury as assessed by MRS and neuropathological examination. We will identify specific monocyte subsets, immunophenotypically and functionally, that correlate with and are predictive of neuronal injury.
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