Imaging immune signaling in virally-suppressed HIV

项目摘要 该项目将通过病毒感染的方式， 人类免疫缺陷病毒（VS+PWH）。这项拟议的工作建立在我们先前的基础上。 支持特定领域认知障碍和局部小胶质细胞激活之间联系的数据， VS+PWH。为了对活体大脑中的小胶质细胞进行特异性成像，我们开发了一种放射性示踪剂[11 C]CPPC。 靶向小胶质细胞表达殖民地刺激因子1受体（CSF 1 R）。脑内CSF 1 R水平高， 在包括VS+PWH的人类死后神经变性病例中报告。CSF 1 R也很高。 在一只感染艾滋病病毒的猕猴模型的额叶皮层中发现， 抗逆转录病毒治疗后抑制的病例。此外，它在增强神经毒性细胞增殖中的作用也被证实。 小胶质细胞反应使CSF 1 R成为治疗性消耗小胶质细胞的有吸引力的靶点， 神经退行性疾病在人体中使用[11 C]CPPC和正电子发射断层扫描（PET）是很好的 耐受性，并允许我们定位和估计在人脑中的小胶质细胞密度在体内。基于已发表 证据和我们的初步数据，我们假设更高的CSF 1 R，与活化的 小胶质细胞，在VS+PWH的大脑相比，匹配的，未感染的控制（HIV-CON）。在VS+PWH中，我们 假设较高的区域CSF 1 R将与较低的认知表现相关，受影响的 认知领域由高CSF 1 R的区域模式形成。因此，我们建议使用[11 C]CPPC VS+PWH和HIV-CON的PET横断面，以评估CSF 1 R的组间差异， 小胶质细胞活化和增殖。我们还将评估区域CSF 1 R和认知功能之间的关系。 性能总之，与神经心理学相关的病理性小胶质细胞活动的早期检测， 损伤仍然是一个未满足的医疗需求，CSF 1 R是一个引人注目的小胶质细胞成像和靶向治疗的目标。 疗法我们的研究将为设计更大规模的提案提供初步数据，以进一步研究 CSF 1 R信号在VS+PWH认知障碍中的作用。此外，它可能会建立CPPC PET， 这是一种很有前途的研究工具，旨在监测VS+PWH随年龄增长的局部小胶质细胞反应， 对神经免疫疗法的反应。

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.