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.

抽象的 HIV感染的有效治疗降低了HIV相关神经认知障碍（HAND）的严重程度， 然而，中枢神经系统神经功能障碍的发生率（约 50% 的 HIV 患者）并没有因 治疗。随着艾滋病毒感染者的预期寿命显着延长，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，并使这些人面临发展的风险 严重的健康问题。这种共病的治疗选择因对其缺乏了解而受到限制 病毒学抑制患者的致病机制。人们提出了几种假设，范围 从 HIV 感染引起的低度慢性神经炎症，到 HIV 相关因素的神经毒性，再到 HIV 加速已知神经退行性疾病的自然发展，例如阿尔茨海默病。 尽管这些假设与 HAND 的某些要素一致，但它们都没有解释完整的内容。 这种疾病的病理表现及其与 HIV 感染的独特关系。在这个应用程序中，我们 提议测试一个新的假设，如果得到证实，将指出中枢神经系统发病机制的关键要素 HIV 感染引起的神经系统疾病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核心机制是脂质的重组 HIV Nef 引起的筏。神经元脂筏的变化促进蛋白质错误折叠/聚集， 加剧炎症反应，影响神经元通讯，从而导致功能障碍 损伤并最终导致神经退行性变。脂筏功能障碍对于发病机制至关重要 许多神经退行性疾病，包括阿尔茨海默病，表明我们的假设与 人口老龄化带来的疾病。这一假设是基于我们已发表的初步发现，即 HIV 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 造成的损伤类似于在受朊病毒感染的神经元中发现的损伤。重要的是，最近的研究表明 神经元暴露于含有 Nef 的外泌体，这些外泌体是由 HIV 感染的大脑巨噬细胞、小胶质细胞和 星形胶质细胞吸收具有功能活性的外源性 Nef。病毒库中的 Nef 产生，包括大脑， 在抗逆转录病毒治疗的情况下继续进行。将追求以下目标来测试这一创新 假设。目标 1：确定 Nef 对小鼠 HIV 相关 CNS 神经功能障碍的影响 模型；目标 2：确定 HIV 感染细胞释放的 Nef 影响胆固醇的机制 神经元代谢，引起神经功能障碍；目标 3：将脂筏作为潜在的治疗方法 治疗 HIV 相关神经功能障碍的方法。这些相互关联但独立的目标将 提供了 HIV 相关中枢神经系统疾病的可行模型。