Imaging immune signaling in virally-suppressed HIV

病毒抑制的艾滋病毒中的免疫信号成像

• 批准号: 10118621
• 负责人: Jennifer Marie Coughlin
• 金额: $ 24.86万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-10 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10118621
• 关键词: AIDS dementia; Affect; Aging; Astrocytes; Autopsy; Autoradiography; Binding; Blood; Brain; Brain Injuries; Brain imaging; Cells; Cerebrospinal Fluid; Clinical; Clinical Research; Clinical Trials; Cognition; Cognitive; Data; Data Collection; Disease; Drug Kinetics; Early Diagnosis; HIV; Heterogeneity; High Prevalence; Hippocampus (Brain); Human; Image; Immune; Immune signaling; Immunotherapy; Impaired cognition; Impairment; Individual; Infection; Intervention; Interview; Learning; Link; Lipopolysaccharides; Macaca; Macaca mulatta; Macaca nemestrina; Macrophage Colony-Stimulating Factor Receptor; Measures; Medical; Memory; Methods; Microglia; Modeling; Monitor; Mus; Myeloid Cells; Nature; Nerve Degeneration; Neurodegenerative Disorders; Neuroimmune; Neuropsychological Tests; Neuropsychology; Pathologic; Pattern; Performance; Peripheral; Phenotype; Population; Positron-Emission Tomography; Property; Proteins; Publishing; Receptor Signaling; Reporting; Role; SIV; Sampling; Shapes; Short-Term Memory; Signal Transduction; Specificity; Techniques; Time; Tissues; Validation; Vascular Endothelium; Viral; Viral Load result; Work; antiretroviral therapy; base; cell type; cognitive function; cognitive performance; density; design; executive function; experience; frontal lobe; gray matter; imaging agent; imaging biomarker; in vivo; injury and repair; insight; nerve injury; neural circuit; neuroimaging; neuroinflammation; neuropsychiatric symptom; neurotoxic; nonhuman primate; radiotracer; receptor binding; response; targeted imaging; targeted treatment; tool; uptake

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.

项目总结 这个项目将在病毒中成像激活的小胶质细胞的增殖，这是大脑中的常驻免疫细胞。 抑制人类免疫缺陷病毒(VS+PWH)感染者。拟议的工作建立在我们先前工作的基础上 支持特定领域认知障碍和局部的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[11C]CPPC 靶向小胶质细胞表达的集落刺激因子1受体(CSF1R)。大脑中CSF1R的高水平 在包括VS+PWH在内的人类死后神经变性病例中已有报道。高CSF1R也是 在猴免疫缺陷病毒感染的猕猴模型的额叶皮质中发现艾滋病毒，包括病毒 抗逆转录病毒治疗后被抑制的病例。此外，其在促进神经毒物增殖方面的作用 小胶质细胞反应使CSF1R成为治疗耗竭小胶质细胞的有吸引力的靶点 神经退行性疾病。[11C]CPPC结合正电子发射断层扫描(PET)在人体中的应用效果良好 耐受性，并使我们能够在活体内定位和估计人脑中的小胶质细胞密度。基于已发布的 证据和我们的初步数据，我们假设较高的CSF1R，与激活的增殖一致 与匹配的未感染对照组(HIV-CON)相比，VS+PWH患者大脑中的小胶质细胞。在VS+PWH内，我们 假设较高的地区性CSF1R将与较低的认知表现相关，受影响的 高CSF1R区域模式塑造的认知域。因此，我们建议使用[11C]CPPC 在VS+PWH和HIV-CON中横断面评估两组在CSF1R中的差异 小胶质细胞活化和增殖。我们还将评估区域CSF1R和认知之间的关系 性能。综上所述，早期发现病理性小胶质细胞活动与神经心理学有关 损害仍然是一个未得到满足的医疗需求，CSF1R是一个引人注目的小胶质细胞靶点，无论是成像还是 心理治疗。我们的研究将为设计更大规模的方案提供初步数据，以进一步研究 CSF1R信号在VS+PWH认知损害中的作用此外，它还可以将CPPC PET确立为 一种有希望的研究工具，旨在监测VS+PWH随年龄和年龄增加而出现的局部小胶质细胞反应 对神经免疫治疗的反应。