Myeloid cell signaling pathways in neuroHIV

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Project Summary Macrophages are central players in HIV-Associated Neurocognitive Disorders (HAND), where they are implicated in neuroinflammation, neurotoxicity, and at times in neuroprotection. Brain macrophages and microglia are sensitive to signals to micro- environmental signals and display a wide range of activation states resulting in their different functional roles. A critical barrier to harnessing macrophages for therapeutic benefit lies in our limited understanding of the signals that regulate their phenotype and function. We identified a unique subset of monocyte derived macrophages (MDMs) regulated by Wnt7A. Wnt7A is a secreted glycoprotein expressed by neurons and endothelial cells of the blood brain barrier, with central roles in BBB development, neurogenesis, and synaptogenesis, to a name a few. We reported that Wnt7A-MDMs are distinct from M-1 and M-2 like MDMs and exhibit an intermediate phenotype and functional capacity. We hypothesize that macrophages differentiated under the influence of Wnt7A are neuroprotective and will decrease CNS viral load. Using in vitro, humanized mice, and brain post-mortem clinical studies we will define the impact of Wnt7A-MDMs on HIV-associated neuropathogenesis (Aim 1) and determine the association between Wnt7A levels in the CNS and the pathologic and clinical manifestation of HIV (Aim 2). Together, these studies will define a unique pathway driving macrophage phenotype and function and its impact on HIV-mediated dysregulation in the CNS. This understanding can potentially be harnessed for cellular therapeutic neuroprotection in context of HIV and/or other neurodegenerative diseases.