Immune Mechanisms Underlying Age-Related Neurodegeneration in HIV Infection

HIV 感染中与年龄相关的神经变性的免疫机制

• 批准号: 10094931
• 负责人: Swaminathan Smita Iyer
• 金额: $ 39.17万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10094931
• 关键词: AIDS dementia; Acute; Age; Aging; Alzheimer' s Disease; American; Amyloid; Animals; Behavioral Research; Biological Assay; Blood - brain barrier anatomy; Brain; CD4 Positive T Lymphocytes; California; Cells; Cerebrospinal Fluid; Clinical; Cognitive; Data; Dementia; Developed Countries; Disease; Disease Marker; Foundations; Functional disorder; Gold; HIV; HIV Infections; HIV-associated neurocognitive disorder; Health; Healthcare; Helper-Inducer T-Lymphocyte; Human; Immune; Immunologics; Immunology; Impaired cognition; Impairment; Incidence; Infection; Infiltration; Inflammation; Inflammatory; Interferons; Interleukin-17; Interruption; Intervention; Link; Macaca; Macaca mulatta; Measures; Metabolism; Microscopic; Modeling; Nerve Degeneration; Neurobiology; Neurocognitive; Neurocognitive Deficit; Neurons; Outcome; Pathogenesis; Pathologic; Pathology; Patients; Population; Primates; Research; Research Personnel; Research Project Grants; Rhesus; Risk; Role; SIV; Schedule; Standard Model; Synapses; Syndrome; T-Lymphocyte Subsets; Technology; Testing; Therapeutic; Time; United Nations; United States National Institutes of Health; Viral; Virus; age group; age related; age related neurodegeneration; aged; antiretroviral therapy; disability; effective intervention; evidence base; global health; high risk; monocyte; neurocognitive disorder; neuroinflammation; neuron loss; nonhuman primate; novel; preclinical study; predictive marker; prevent; recruit; tau Proteins; tau aggregation; tau-1; therapy design; therapy development; virology

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.

项目摘要 作为与年龄相关的残疾的主要原因，神经认知疾病如阿尔茨海默病（AD）和 其他痴呆症也将对全球医疗保健产生重大影响，因为60岁以上的人口， 在接下来的三十年里，老年人几乎翻了一番。一组年龄相关的 神经退行性疾病是HIV感染（HIV+）患者。据估计，50%的艾滋病毒+患者 抗逆转录病毒疗法（ART）随着年龄的增长而发展出轻度至重度的脑功能损伤。艾滋病病毒- 相关的神经认知障碍（HAND），这种综合征预计将在未来急剧增加， 十年来，超过70%的美国艾滋病毒感染者年满50岁，ART在美国变得更加广泛。 发展中国家的团结合作HAND即将产生的全球影响强调了迫切需要了解 抗逆转录病毒治疗的HIV+患者神经退行性变的机制基础，并制定有效的干预措施。 这项建议的重点是了解免疫机制的基础年龄相关的神经退行性变 在HIV感染后，使用一个强大的恒河猴模型，该模型概括了HIV病理生理学的突出方面， 在人类身上。在本研究项目的目标1中，我们将建立单核细胞在神经退行性变中的作用; 特别是促炎单核细胞。在目标2中，我们将确定Th 1和Th 17 CD 4 T细胞亚群的作用， 神经退化考虑到艾滋病毒和艾滋病毒相关的神经炎症干扰淀粉样蛋白， 在目的3中，我们将研究病理性AD标志物是否在HIV相关的tau代谢过程中被诱导。 神经炎症调查人员和合作者在解决 申请中提出的科学问题将有助于深入了解免疫和突触 神经退行性变的潜在机制这些临床前研究将建立机制， 实验基础，以确定预测生物标志物的手，并随后使机会， 相关和易于处理的模型，用于测试新的靶向干预措施作为ART的后续治疗。 在猕猴中SIV诱导的HAND后遗症的定量测量可以评估干预参数 在人类研究之前进行疗效评估。