Impact of drugs of abuse on HIV brain reservoirs and HAND in humanized microglia mice

滥用药物对人源化小胶质细胞小鼠的 HIV 脑库和 HAND 的影响

• 批准号: 10451682
• 负责人: Santhi Gorantla
• 金额: $ 53.85万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 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 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10451682
• 关键词: AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Acute; Affect; Aging; Animal Model; Animals; Area; Astrocytes; Behavior; Behavioral; Blood; Blood Cells; Brain; Cells; Central Nervous System Diseases; Central Nervous System Infections; Chimera organism; Chronic; Cocaine; Contracts; Development; Disease; Disease Progression; Disease remission; Drug abuse; Epidemic; Evaluation; Functional disorder; Goals; HIV; HIV Infections; HIV Seropositivity; HIV-associated neurocognitive disorder; Hematopoietic Stem Cell Transplantation; Homeostasis; Human; Human immunodeficiency virus test; Image; Immune; Immune system; Immunity; Impaired cognition; Incidence; Infection; Inflammation; Intervention; Investigation; Kinetics; Link; Long-Term Potentiation; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Methods; Microglia; Modeling; Mus; Neuraxis; Neuroglia; Neuronal Injury; Neurons; Neuropathogenesis; Opportunistic Infections; Outcome; Pathogenesis; Pathology; Peripheral; Predisposition; Prevalence; Recurrence; Reporter; Research; Research Personnel; Residual state; Rodent Model; Role; Severities; Substance Use Disorder; Substance abuse problem; Substance of Abuse; Synaptic plasticity; Therapeutic; Tissue-Specific Gene Expression; Viral; Viral reservoir; Virus; Virus Diseases; Virus Latency; Virus Replication; Work; abuse liability; acute infection; animal imaging; antiretroviral therapy; axon injury; cell behavior; chronic infection; detection assay; drug of abuse; experience; genetic signature; human disease; humanized mouse; imaging modality; insight; macrophage; mouse model; multimodality; nervous system disorder; neuroAIDS; neurocognitive disorder; neuropathology; neurophysiology; nucleic acid detection; reconstitution; serial imaging; single-cell RNA sequencing; skills; substance use; therapeutic development; therapeutic target; tool; viral rebound

ABSTRACT Since the start of the HIV/AIDS epidemic, it has been recognized that drug abuse is strongly linked to contracting and transmitting HIV, as well as more severe consequences. Factors influencing the susceptibility and disease progression are still unclear. Viral reservoir establishment occurs early in acute HIV infection and reaches a set point within the first two months of infection, which in turn determines the size of the reservoir in the chronic stage. HIV enters the brain right after infection and replicates in macrophages, microglia, and to a small extent in astrocytes. Increased susceptibility in substance use could affect the size of the central nervous system (CNS) reservoir, which may influence spontaneous virological remission and viral rebound kinetics. CNS viral reservoir size may also determine the HIV- associated neurocognitive disorder (HAND) severity, viral recurrence, and rebound. Until now, there was no means to study the viral dynamics, CNS viral invasion, susceptibility to MP infection in the brain, and the reservoirs of HIV infection so that interventions can be developed effectively. A small animal model, like the humanized mouse, provides great advantages due to manipulations using host/human cells, as well as the possibility of establishing chronic infection by HIV itself. The humanized microglial (hMGL) mouse model is reconstituted with the human immune system and human glial cells, which allows natural progression of CNS infection and disease in relation to peripheral HIV infection. Herein, we propose to deploy our hMGL mouse to elucidate the mechanisms of HIV-1 invasion, persistence, and neuropathogenesis for substance use. Our objective is to define the CNS viral reservoir and investigate changes in the brain viral reservoir as a consequence of substances of abuse with an overarching goal of viral eradication. Our aims are, 1. to investigate the effect of cocaine on the CNS viral invasion, reservoir establishment, and viral latency during chronic infection in humanized microglial mice, 2. to determine the host genetic signatures that accelerate the CNS viral reservoir and assess the influence of antiretroviral therapy (ART) on glial homeostasis, and 3. to study HIV and SUD-induced neuropathology using a multimodal approach. The complete characterization of this humanized mouse model in establishing linkages to human disease, and demonstrating a comprehensive evaluation of the CNS reservoir during cART, HIV infection, and drug abuse will prove to be a significant value to the neuroHIV field.

摘要 自艾滋病毒/艾滋病开始流行以来，人们认识到药物滥用与感染艾滋病毒/艾滋病密切相关， 和传播艾滋病病毒，以及更严重的后果。影响易感性和疾病的因素 进展尚不清楚。病毒储库建立发生在急性HIV感染的早期， 在感染的头两个月内，这反过来又决定了慢性感染中水库的大小。 阶段HIV感染后立即进入大脑，并在巨噬细胞、小胶质细胞和小范围内复制。 在星形胶质细胞中。物质使用敏感性增加可能影响中枢神经系统（CNS）的大小 水库，这可能会影响自发病毒缓解和病毒反弹动力学。中枢神经系统病毒储库 大小也可能决定HIV相关神经认知障碍（HAND）的严重程度、病毒复发和 反弹迄今为止，还没有研究病毒动力学、中枢神经系统病毒侵袭、对MP的敏感性的手段 因此，我们必须加强对大脑中的艾滋病毒感染和艾滋病毒感染宿主的研究，以便能够有效地制定干预措施。一 小动物模型，如人源化小鼠，由于使用 宿主/人类细胞，以及通过HIV本身建立慢性感染的可能性。人源化 用人免疫系统和人神经胶质细胞重建小胶质细胞（hMGL）小鼠模型， 允许CNS感染和与外周HIV感染相关的疾病的自然进展。在此我们 我们建议使用我们的hMGL小鼠来阐明HIV-1侵袭、持久性和 神经病理学我们的目标是确定中枢神经系统病毒储库和调查变化 在大脑中的病毒库作为滥用物质的结果，其总体目标是根除病毒。 我们的目标是，1。研究可卡因对CNS病毒侵袭、储库建立和病毒感染的影响。 人源化小胶质细胞小鼠慢性感染期间的潜伏期，2.以确定宿主的遗传特征， 加速CNS病毒库，并评估抗逆转录病毒治疗（ART）对神经胶质稳态的影响， 和3.使用多模式方法研究HIV和SUD诱导的神经病理学。完整的 在建立与人类疾病的联系方面，对这种人源化小鼠模型进行了表征， 在cART、HIV感染和药物滥用期间对CNS储库的综合评价将被证明是一个 对神经艾滋病领域有重要价值。