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

基本信息

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
项目类别：
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&apos 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

项目摘要

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）并没有因随着艾滋病毒感染者预期寿命的显着延长，神经功能障碍也随之减少。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由于对这种共病的了解不足，治疗方案受到限制。已经提出了多种病毒学抑制患者的致病机制。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。在本申请中，我们研究了这种疾病的病理表现及其与 HIV 感染的独特关系。测试一个新的假设，如果提出，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。 HIV相关中枢神经系统疾病的核心机制是脂质的重组 HIV Nef 引起的筏状结构导致神经元脂质的变化促进蛋白质错误折叠/聚集，加剧炎症反应，影响神经通讯，导致功能障碍脂筏损伤并最终导致神经变性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，表明我们的假设与该假设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 造成的损伤与感染朊病毒的神经元造成的损伤相似，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外源性 Nef，该病毒在病毒库（包括大脑）中具有功能活性。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 1：确定 Nef 对小鼠 HIV 相关中枢神经系统功能障碍的影响。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，导致神经功能障碍；目标 3：靶向脂筏作为潜在的治疗方法这些相互关联但独立的目标将是治疗艾滋病毒相关神经功能障碍的方法。提供了 HIV 相关中枢神经系统疾病的可行模型。