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

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密切相关。 和传播艾滋病毒，以及更严重的后果。影响易感性和疾病的因素 进展仍不明朗。病毒库的建立发生在急性HIV感染的早期，并达到一组 在感染的前两个月内的时间点，这反过来又决定了慢性病患者的储蓄者的大小 舞台。HIV在感染后立即进入大脑，并在巨噬细胞、小胶质细胞中复制，并在很小程度上 在星形胶质细胞中。物质使用的易感性增加可能会影响中枢神经系统(CNS)的大小 这可能会影响病毒的自发缓解和病毒反弹动力学。中枢神经系统病毒库 大小也可能决定HIV相关神经认知障碍(手)的严重程度、病毒复发和 抢篮板球。到目前为止，还没有研究MP的病毒动力学、中枢神经系统病毒侵袭、MP易感性的手段 脑内感染，以及艾滋病毒感染的蓄水池，使干预措施得以有效开展。一个 小动物模型，如人性化的小鼠，由于使用 宿主/人类细胞，以及确定艾滋病毒本身慢性感染的可能性。人性化的 小胶质细胞(HMGL)小鼠模型是由人免疫系统和人神经胶质细胞重组而成的。 允许中枢神经系统感染和疾病与外周艾滋病毒感染相关的自然进展。在此，我们 建议利用我们的hMGL小鼠来阐明HIV-1的侵袭、持续和 物质使用的神经发病机制。我们的目标是确定CNS病毒库并调查变化 在大脑病毒储存库，作为滥用物质的结果，首要目标是根除病毒。 我们的目标是：1.研究可卡因对中枢神经系统病毒入侵、病毒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的潜伏期，2.确定宿主的遗传特征 加速中枢神经系统病毒库，评估抗逆转录病毒疗法(ART)对神经胶质细胞稳态的影响。 3.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表征这种人源化的小鼠模型，并展示 在CART、HIV感染和药物滥用期间对CNS宿主的全面评估将被证明是一种 对神经艾滋病毒领域具有重大价值。

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.