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

基本信息

批准号：
10302787
负责人：
Santhi Gorantla
金额：
$ 53.7万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
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 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10302787
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 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 virology

项目摘要

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/艾滋病流行以来，人们认识到吸毒与感染艾滋病毒/艾滋病密切相关传播艾滋病毒，以及更严重的后果。影响易感性和疾病的因素进展仍不清楚。病毒库的建立发生在急性艾滋病毒感染的早期，并达到一定程度感染前两个月内的点，这反过来又决定了慢性病毒库的大小阶段。 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会影响中枢神经系统 (CNS) 的大小储存库，这可能会影响自发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 相关神经认知障碍 (HAND) 的严重程度、病毒复发和反弹。到目前为止，还没有手段研究病毒动力学、中枢神经系统病毒入侵、MP 易感性脑部感染和艾滋病毒感染库，以便有效制定干预措施。一个小动物模型，如人源化小鼠，由于使用的操作而提供了巨大的优势宿主/人类细胞，以及艾滋病毒本身造成慢性感染的可能性。人性化的小胶质细胞（hMGL）小鼠模型是用人类免疫系统和人类胶质细胞重建的，允许中枢神经系统感染和与外周艾滋病毒感染相关的疾病自然进展。在此，我们提议部署我们的 hMGL 小鼠来阐明 HIV-1 入侵、持续和传播的机制物质使用的神经发病机制。我们的目标是定义中枢神经系统病毒库并研究变化由于滥用药物而导致大脑病毒库中的病毒，其总体目标是根除病毒。我们的目标是，1. 研究可卡因对中枢神经系统病毒入侵、储存库建立和病毒传播的影响 2. 人源化小胶质细胞小鼠慢性感染期间的潜伏期，以确定宿主遗传特征加速中枢神经系统病毒储存并评估抗逆转录病毒治疗（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。完整的该人源化小鼠模型在建立与人类疾病的联系方面的表征，并证明在 cART、HIV 感染和药物滥用期间对中枢神经系统储库进行综合评估将被证明是一个对神经HIV领域具有重要价值。