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: 10621797
• 负责人: MICHAEL Ilya BUKRINSKY
• 金额: $ 76.29万
• 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/10621797
• 关键词: AIDS dementia; ATP binding cassette transporter 1; Acceleration; 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; Learning; Life Cycle Stages; Life Expectancy; Macrophage; 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; brain cell; cholesterol transporters; comorbidity; effective therapy; executive function; exosome; extracellular vesicles; functional disability; in vitro testing; in vivo; inhibitor; innovation; 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 艾滋病毒感染的有效治疗减少了与HIV相关的神经认知障碍（手）的严重程度， 然而，CNS神经功能障碍的事件（〜50％的HIV患者）尚未减少 治疗。随着HIV感染患者的预期寿命延长，神经功能障碍可降低 通过影响学习和执行职能的生活质量，并使这些人处于发展的风险 重大健康问题。这种合并症的治疗选择受到对其的理解不佳的限制 病毒学抑制患者的致病机制。已经提出了一些假设，范围 从HIV感染引起的低年级慢性神经炎症到HIV相关因素的神经毒性，到HIV 加快已知神经退行性疾病的自然发展，例如阿尔茨海默氏病。 尽管这些假设与某些手相一致，但它们都没有解释完整 这种疾病的病理表现及其与HIV感染的独特关系。在此应用程序中，我们 提出测试新假设的建议，如果确认，将指出CNS发病机理的关键要素 由HIV感染引起的神经疾病，可能转化为新的治疗机会。我们 假设HIV相关的中枢神经系统疾病的中心机制是脂质的重组 由HIV NEF引起的筏。神经脂质筏的变化促进蛋白质折叠/聚集的蛋白质错误， 加剧炎症反应，并影响神经元通信导致功能 损害并最终遇到神经变性。脂质筏的功能障碍对于发病机理必不可少 在包括阿尔茨海默氏症在内的许多神经退行性疾病中，指出了我们假设的广泛相关性 人口老龄化的疾病。该假设基于我们发表的初步发现，即HIV蛋白 NEF重组巨噬细胞和神经元中的脂质筏。我们最近证明了对脂筏的变化 由NEF造成的与受prions感染的神经元中发现的相似。重要的是，最近的研究表明 暴露于含有NEF的外泌体的神经元，由HIV感染的脑巨噬细胞，小胶质细胞和 星形胶质细胞，采用功能活性的外源性NEF。包括大脑在内的病毒储层中的NEF生产， 在存在抗逆转录病毒疗法的情况下继续进行。将追求以下目标来测试这一创新性 假设。目标1：建立NEF对小鼠中与HIV相关的CNS神经功能障碍的贡献 模型；目标2：确定从HIV感染细胞释放NEF的机制会影响胆固醇 神经元的代谢，引起神经功能障碍；目标3：靶向脂质筏作为潜在的疗法 治疗与HIV相关的神经功能障碍的方法。这些相互联系但独立的目标将 提供与HIV相关的中枢神经系统疾病的可行模型。