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.

摘要