Examining HIV-mediated disruption of CNS immune homeostasis using a triple humanized mouse

摘要 目前，缺乏足够的动物模型来复制人类感染艾滋病毒-1的事件 提出了研究中枢神经系统(CNS)艾滋病毒病理学的关键障碍。根除HIV-1感染 已经成为当务之急。当代高效的抗逆转录病毒疗法(ART)显著延长了 它可以改善感染者的生命，但并未解决与艾滋病毒相关的神经认知障碍(手)的发病率。 艾滋病毒持续存在于人类的血液淋巴室和中枢神经系统(CNS)。持久化 艾滋病毒在外周和中枢神经系统的储存都会导致慢性炎症和终末器官疾病。临床 观察表明，病毒存在于中枢神经系统驻留的免疫细胞和中枢神经系统的非免疫细胞中， 比如星形胶质细胞。中枢神经系统病毒库是终生的。尽管如此，关于持续性中枢神经系统病毒性质的知识 水库及其对神经免疫动态平衡的影响有限，因为现有的小 动物模型。我们的目标是建立一种新的三重人源化小鼠模型 人血/血淋巴系统、小胶质细胞和星形胶质细胞相互作用的研究 人脑胶质细胞在中枢神经系统免疫和神经元发育过程中的感染和免疫激活 功能障碍。同时拥有外周血液/免疫细胞和人脑细胞的小鼠(Hubb小鼠)是 有望为神经艾滋病的研究提供一个全面的模型。该模型最适合于研究 属于当前RFA范围内的研究领域。利用新的Hubb-小鼠，我们的目标是研究：1)。艾滋病病毒 ART抑制过程中的神经胶质库与单细胞神经免疫稳态失调 转录分析，以及2)。神经元完整性和功能的改变是调控失调的结果 神经免疫动态平衡。经ART治疗的动物抑制所有组织和细胞中的外周病毒复制 包括星形胶质细胞和小胶质细胞在内的多种类型，有助于病毒学、免疫学和神经病理学评估。 这项拟议的工作有望为新的Hubb-MICE奠定基础，为未来对多个 在慢性感染/免疫激活背景下的手部病理学方面，持续的艾滋病毒宿主 中枢神经系统和神经炎症。小鼠模型将是开发治疗方法的重要工具 并用于设计从中枢神经系统储藏室根除艾滋病毒的战略。

ABSTRACT Currently, the lack of adequate animal models to replicate the events of HIV-1 infection in humans presents a critical barrier to study HIV pathology of the central nervous system (CNS). Eradicating HIV-1 infection has become a priority. Contemporary, highly active antiretroviral therapy (ART) has significantly prolonged the lives of those infected, but it has not resolved the incidence of HIV-associated neurocognitive disorders (HAND). HIV persists in the human hemato-lymphoid compartments and in the central nervous system (CNS). Persistent HIV reservoirs both in the periphery and CNS result in chronic inflammation and end-organ diseases. Clinical observations reveal that the virus is present in CNS-resident immune cells and in non-immune cells of the CNS, such as astrocytes. The CNS viral reservoir is life-long. Still, knowledge on the nature of persistent CNS viral reservoirs and their influence on neuroimmune homeostasis is limited because of deficiencies in existing small animal models. We aim to establish a new TRIPLE humanized mouse model reconstituted with autologous human blood/ hematolymphoid system, microglia, and astrocytes to study the interaction of peripheral HIV- infection and immune activation with human brain glial cells in developing CNS immune and neuronal dysfunction. Mice that possess both peripheral blood/immune cells and human brain cells (HuBB-mice) are expected to provide a comprehensive model to study NeuroAIDS. The model is best suitable to study the research areas that fall within the scope of the current RFA. Using the new HuBB-mice, we aim to study: 1). HIV glial reservoirs during suppressive ART and the dysregulation of neuroimmune homeostasis using single-cell transcriptomic analysis, and 2). the altered neuronal integrity and function as a consequence of dysregulated neuroimmune homeostasis. Animals treated with ART suppress peripheral viral replication in all tissues and cell types, including astrocytes and microglia, facilitating virologic, immunologic, and neuropathologic assessments. The proposed work is expected to lay the groundwork on the new HuBB-mice for future evaluations of multiple aspects of HAND pathology in the context of chronic infection/ immune activation, persistent HIV reservoirs in CNS, and neuroinflammation. The mouse model will be an important tool to develop therapeutics to alleviate HAND and for designing HIV eradication strategies from CNS reservoirs.