Novel pathogenic mechanism of HIV-associated CNS neurological disorders

HIV相关中枢神经系统疾病的新致病机制

• 批准号: 10447749
• 负责人: MICHAEL Ilya BUKRINSKY
• 金额: $ 68.09万
• 依托单位: GEORGE WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-15 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10447749
• 关键词: AIDS dementia; ATP binding cassette transporter 1; Adverse effects; Affect; Age; Aging; Alzheimer' s Disease; Animal Model; Anti-Retroviral Agents; Apolipoprotein A-I; Apoptosis; Astrocytes; Automobile Driving; Behavioral; Binding Proteins; Brain; Cells; Central Nervous System Diseases; Cholesterol; Cholesterol Homeostasis; Chronic; Clinical; Communication; Development; Disease; Down-Regulation; Elements; Exposure to; Functional disorder; Genetic Transcription; HIV; HIV Infections; HIV-associated neurocognitive disorder; Health; Impaired cognition; Impairment; Incidence; Individual; Inflammation; Inflammatory Response; Lead; Learning; Life Cycle Stages; Life Expectancy; Mediating; Membrane Microdomains; Microglia; Modeling; Morphology; Mus; Nerve Degeneration; Neurocognitive Deficit; Neurodegenerative Disorders; Neurologic; Neurologic Dysfunctions; Neurologic Symptoms; Neurons; Pathogenesis; Pathogenicity; Pathologic; Pathology; Patients; Persons; Pharmaceutical Preparations; Physiological; Population; Prions; Production; Publishing; Quality of life; Risk; Severities; Testing; Therapeutic; Therapeutic Agents; Translating; Translations; Viral Proteins; Viral reservoir; aged; aging population; antiretroviral therapy; base; brain cell; cholesterol transporters; comorbidity; effective therapy; executive function; exosome; extracellular vesicles; functional disability; in vitro testing; in vivo; inhibitor; innovation; macrophage; mouse model; nef Protein; nervous system disorder; neuroAIDS; neurocognitive disorder; neuroinflammation; neurotoxicity; novel; novel strategies; prevent; protein aggregation; protein misfolding

Abstract Effective treatment of HIV infection has reduced the severity of HIV-associated neurocognitive disorder (HAND), however, the incidence of CNS neurological dysfunction (~50% of HIV patients) has not been diminished by the treatment. With dramatically extended life expectancy of HIV-infected patients, neurological dysfunction reduces the quality of life by affecting learning and executive functions, and puts these individuals at risk of developing significant health problem. The treatment options for this co-morbidity are limited by poor understanding of its pathogenic mechanisms in virologically suppressed patients. Several hypotheses have been suggested, ranging from low grade chronic neuroinflammation caused by HIV infection, to neurotoxicity of HIV-related factors, to HIV accelerating the natural development of known neurodegenerative diseases, such as Alzheimer’s disease. Although these hypotheses are consistent with some elements of HAND, none of them explains the full pathological manifestation of this disorder and its unique relationship with HIV infection. In this application, we propose to test a novel hypothesis that, if confirmed, will point to the key element of pathogenesis of CNS neurological disorder caused by HIV infection and may translate to novel treatment opportunities. We hypothesize that the central mechanism in HIV-associated CNS disorder is the reorganization of lipid rafts caused by HIV Nef. Changes in neuronal lipid rafts promote protein misfolding/aggregation, exacerbate inflammatory responses, and affect neuronal communications leading to functional impairment and eventually to neurodegeneration. Dysfunction of the lipid rafts is essential for pathogenesis of many neurodegenerative diseases, including Alzheimer’s, pointing to a broad relevance of our hypothesis to diseases of aging population. This hypothesis is based on our published and preliminary findings that HIV protein Nef reorganizes lipid rafts in macrophages and neurons. We recently demonstrated that changes to lipid rafts inflicted by Nef are similar to those found in neurons infected by prions. Importantly, recent studies have shown that neurons exposed to Nef-containing exosomes, released by HIV-infected brain macrophages, microglia and astrocytes, take up exogenous Nef, which is functionally active. Nef production in viral reservoirs, including brain, continues in the presence of antiretroviral therapy. The following aims will be pursued to test this innovative hypothesis. Aim 1: To establish the contribution of Nef to HIV-associated CNS neurological dysfunction in mouse models; Aim 2: To determine mechanisms by which Nef released from HIV-infected cells affects cholesterol metabolism in neurons, causing neurological dysfunction; Aim 3: To target lipid rafts as a potential therapeutic approach to treat HIV-associated neurological dysfunction. These interconnected but independent aims will provide an actionable model of HIV-associated CNS disorder.

摘要 艾滋病毒感染的有效治疗降低了艾滋病毒相关神经认知障碍(HAND)的严重程度， 然而，中枢神经系统功能障碍的发生率(约50%的艾滋病毒患者)并未因 治疗。随着艾滋病毒感染患者的预期寿命大幅延长，神经功能障碍减少 通过影响学习和执行功能来影响生活质量，并将这些人置于发展的风险中 严重的健康问题。这种并存疾病的治疗选择受到对其认识不足的限制。 病毒学抑制患者的致病机制。已经提出了几个假设，范围包括 从HIV感染引起的低度慢性神经炎，到HIV相关因子的神经毒性，再到HIV 加速阿尔茨海默病等已知神经退行性疾病的自然发展。 尽管这些假设与手部的某些要素是一致的，但它们都不能解释全部 这种疾病的病理表现及其与艾滋病毒感染的独特关系。在此应用程序中，我们 建议检验一个新的假说，如果得到证实，将指向中枢神经系统发病的关键因素 由艾滋病毒感染引起的神经系统疾病，并可能转化为新的治疗机会。我们 假设HIV相关中枢神经系统疾病的中心机制是脂质的重组 由HIV Nef引起的木筏。神经元脂筏的变化促进了蛋白质的错误折叠/聚集， 加剧炎症反应，影响神经元通讯，导致功能性 损伤，并最终导致神经退化。脂筏功能障碍是发病的基础 许多神经退行性疾病，包括阿尔茨海默氏症，表明我们的假设与 人口老龄化疾病。这一假设是基于我们已发表的和初步的发现，艾滋病毒蛋白 NEF重组巨噬细胞和神经元中的脂筏。我们最近证明了脂筏的变化 Nef的致病作用类似于在被Pron感染的神经元中发现的那些。重要的是，最近的研究表明 暴露于含有Nef的外切体的神经元，由感染HIV的脑巨噬细胞、小胶质细胞和 星形胶质细胞，吸收外源性Nef，这是功能活跃的。在病毒库中产生NEF，包括大脑， 在抗逆转录病毒治疗的情况下继续存在。将追求以下目标来测试这一创新 假设。目的1：探讨Nef在HIV相关中枢神经系统功能障碍中的作用 模型；目标2：确定HIV感染细胞释放的Nef影响胆固醇的机制 神经元的新陈代谢，导致神经功能障碍；目标3：靶向脂筏作为一种潜在的治疗方法 治疗艾滋病毒相关神经功能障碍的方法。这些相互关联但独立的目标将 为HIV相关中枢神经系统疾病提供可操作的模型。