Immune Mechanisms Underlying Age-Related Neurodegeneration in HIV Infection

项目摘要 作为与年龄相关的残疾的主要原因，阿尔茨海默病(AD)和 其他痴呆症将显著影响全球医疗保健，因为60岁和60岁以上的人口 在接下来的30年里，老年人的数量几乎翻了一番。与年龄相关的风险显著增加的一组 神经退行性疾病是指感染艾滋病毒(HIV+)的患者。据估计，50%的HIV+患者正在接受 随着年龄的增长，抗逆转录病毒疗法(ART)会出现轻微到严重的脑功能损害。被指定为HIV- 相关神经认知障碍(HAND)，这种综合征预计在下一年将急剧增加 十年来，超过70%的美国艾滋病毒携带者年满50岁，抗逆转录病毒治疗在 发展中世界。Hand的全球影响迫在眉睫，突显出迫切需要了解 抗逆转录病毒治疗HIV阳性患者神经变性的机制基础及设计有效的干预措施。 这项建议的重点是了解年龄相关神经退行性变的免疫机制。 在HIV感染后使用一个健壮的恒河猴模型，该模型概括了HIV病理生理学的显著方面 在人类身上。在本研究项目的目标1中，我们将确定单核细胞在神经退行性变中的作用； 具体地说，就是促炎症单核细胞。在目标2中，我们将确定Th1和Th17 CD4T细胞亚群的作用 神经退行性变。考虑到HIV和HIV相关的神经炎症干扰淀粉样蛋白和 Tau代谢，在目标3中，我们将调查在HIV相关的过程中是否诱导了病理性AD标记物 神经炎。调查人员和合作者在处理 在应用中提出的科学问题将有助于深入了解免疫和突触 神经退化的潜在机制。这些临床前研究将建立机制和 识别手部预测生物标记物的实验基础，随后在 相关和易处理的模型，用于测试作为ART辅助治疗的新的、有针对性的干预措施。仅限于 SIV对猕猴手部后遗症的量化措施可评估干预参数 用于人体研究之前的疗效。

Project Summary As the leading cause of age-related disabilities, neurocognitive diseases such as Alzheimer’s disease (AD) and other dementias are poised to significantly impact global health care as the population of people aged 60 and older nearly doubles in the next three decades. One group at a significantly greater risk of age-related neurodegenerative diseases are HIV-infected (HIV+) patients. An estimated 50% of HIV+ patients on antiretroviral therapy (ART) develop mild to severe impairments in brain function with age. Designated as HIV- associated neurocognitive disorders (HAND), this syndrome is expected to increase dramatically in the next decade as more than 70% of Americans with HIV turn 50 and older, and ART becomes more widely available in the developing world. The imminent global impact of HAND underscores the urgent need to understand the mechanistic basis of neurodegeneration in HIV+ patients on ART and devise effective interventions. This proposal is focused on understanding the immune mechanisms underlying age-related neurodegeneration following HIV infection using a robust rhesus model which recapitulates salient aspects of HIV pathophysiology in humans. In Aim 1 of this research project, we will establish the role of monocytes in neurodegeneration; specifically, pro-inflammatory monocytes. In Aim 2, we will determine the role of Th1, and Th17 CD4 T cell subsets in neurodegeneration. Considering that HIV and HIV-associated neuroinflammation interfere with amyloid and tau metabolism, in Aim 3 we will investigate whether pathological AD markers are induced during HIV-associated neuroinflammation. The collective complementary expertise of the investigators and collaborators in tackling the scientific questions posed in the application will facilitate an in-depth understanding of the immune and synaptic mechanisms underlying neurodegeneration. These preclinical studies will establish the mechanistic and experimental foundations to identify predictive biomarkers of HAND and subsequently enable opportunities in a relevant and tractable model for testing novel, targeted interventions as adjunctive therapy to ART. Only by quantifying measures of SIV-induced HAND sequelae in macaques can parameters of intervention be evaluated for efficacy prior to human studies.