Imaging immune signaling in virally-suppressed HIV

点击翻译按钮获取中文摘要

PROJECT SUMMARY This project will image the proliferation of activated microglia, resident immune cells in the brain, in virally suppressed people with human immunodeficiency virus (VS+PWH). The proposed work builds on our prior data that support a link between domain-specific cognitive impairment and localized, microglial activation in VS+PWH. In order to specifically image microglia in the living brain, we developed a radiotracer, [11C]CPPC that targets the colony stimulating factor 1 receptor (CSF1R) expressed by microglia. High CSF1R in brain has been reported in human postmortem cases of neurodegeneration including VS+PWH. High CSF1R was also found in frontal cortex of a simian immunodeficiency virus-infected macaque model of HIV, including virally suppressed cases after antiretroviral therapy. Furthermore, its role in potentiating proliferation of neurotoxic microglial response makes CSF1R an attractive target for therapeutic depletion of microglia in neurodegenerative disease. Use of [11C]CPPC with positron emission tomography (PET) in humans is well tolerated and allows us to localize and estimate microglial density in human brain in vivo. Based on published evidence and our preliminary data, we hypothesize higher CSF1R, consistent with proliferation of activated microglia, in the brains of VS+PWH compared to matched, uninfected controls (HIV-CON). Within VS+PWH, we hypothesize that higher regional CSF1R will be associated with lower cognitive performance, with the affected cognitive domains shaped by the regional pattern of high CSF1R. We therefore propose to use [11C]CPPC PET cross-sectionally in VS+PWH and HIV-CON to assess group differences in the CSF1R that marks microglial activation and proliferation. We will also assess relationships between regional CSF1R and cognitive performance. In summary, early detection of pathological microglial activity that is linked to neuropsychological impairment remains an unmet medical need, and CSF1R is a compelling microglial target for both imaging and therapy. Our study will provide preliminary data toward design of a larger scale proposal to study further the role of CSF1R signaling in cognitive impairment within VS+PWH. Furthermore, it may establish CPPC PET as a promising tool for studies aimed at monitoring localized microglial response in VS+PWH over aging and in response to neuroimmune therapy.