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: 10613982
• 负责人: Santhi Gorantla
• 金额: $ 53.88万
• 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/10613982
• 关键词: Acceleration; Acute; Affect; Aging; Animal Model; Animals; Area; Astrocytes; Behavior; Behavioral; Binding; Blood; Blood Cells; Blood Vessels; Brain; Cells; Central Nervous System; 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; HIV/AIDS; Hematopoietic Stem Cell Transplantation; Homeostasis; Human; Human immunodeficiency virus test; Image; Immune; Immune system; Immunity; Impaired cognition; Incidence; Infection; Infiltration; Inflammation; Intervention; Invaded; Investigation; Kinetics; Link; Long-Term Potentiation; Macrophage; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Methods; Microglia; Modeling; Mus; Neuroglia; Neuronal Injury; Neurons; Neuropathogenesis; Opportunistic Infections; Outcome; Pathogenesis; Pathology; Peripheral; Predisposition; Prevalence; Productivity; 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; 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; transmission process; 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.

抽象的 自艾滋病毒/艾滋病流行病开始以来 并传播艾滋病毒以及更严重的后果。影响易感性和疾病的因素 进展仍然不清楚。病毒储层建立在急性艾滋病毒感染的早期发生，并达到一套 感染的前两个月内，这反过来决定了慢性储层的大小 阶段。艾滋病毒感染后立即进入大脑，并在巨噬细胞，小胶质细胞中复制 在星形胶质细胞中。增加药物使用的敏感性可能会影响中枢神经系统（CNS）的大小 储层，可能影响自发的病毒学缓解和病毒反弹动力学。中枢神经系统病毒库 大小还可能决定HIV相关的神经认知障碍（手）严重程度，病毒复发和 反弹。到目前为止，还没有手段研究病毒动力学，CNS病毒侵袭，对MP的敏感性 大脑中的感染以及HIV感染的储层，因此可以有效发展干预措施。一个 小型动物模型，例如人源化鼠标，由于使用的操纵而提供了很大的优势 宿主/人类细胞，以及通过HIV本身建立慢性感染的可能性。人性化 小胶质细胞（HMGL）小鼠模型与人类免疫系统和人神经胶质细胞重构 与周围HIV感染有关的中枢神经系统感染和疾病的自然发展。这里，我们 建议部署我们的HMGL小鼠，以阐明HIV-1侵入，持久性和 用于使用物质的神经病发生。我们的目标是定义CNS病毒储存库并研究变化 在脑病毒储层中，由于滥用物质具有消除病毒性的总体目标。 我们的目的是1。 人源化小胶质细胞中慢性感染期间的潜伏期，2。确定宿主遗传特征 加速中枢神经系统病毒储层并评估抗逆转录病毒疗法（ART）对神经胶质稳态的影响， 3。使用多模式方法研究HIV和SUD诱导的神经病理学。完整 在建立与人类疾病的联系中的这种人源化小鼠模型的表征，并证明 在购物车，艾滋病毒感染和吸毒期间对中枢神经系统水库进行全面评估将被证明是 神经hiv场的重要价值。

项目成果

Impaired extinction of cocaine seeking in HIV-infected mice is accompanied by peripheral and central immune dysregulation.

感染艾滋病毒的小鼠对可卡因的消退作用受损，并伴有外周和中枢免疫失调。

• DOI: 10.21203/rs.3.rs-3276379/v1
• 发表时间: 2023
• 期刊: Research square
• 作者: Barker,Jacqueline;Buck,Lauren;Xie,Qiaowei;Willis,Michelle;Side,Christine;Giacometti,Laura;Gaskill,Peter;Park,Kyewon;Shaheen,Farida;Guo,Lili;Gorantla,Santhi
• 通讯作者: Gorantla,Santhi