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

使用三重人源化小鼠检查 HIV 介导的中枢神经系统免疫稳态破坏

• 批准号: 10705753
• 负责人: Santhi Gorantla
• 金额: $ 19.19万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-16 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10705753
• 关键词: AIDS dementia; Animal Model; Animals; Anti-Retroviral Agents; Architecture; Area; Astrocytes; Autologous; Autopsy; Axon; B-Lymphocytes; Blood; Blood - brain barrier anatomy; Blood Vessels; Brain; Cell Culture Techniques; Cell Separation; Cells; Central Nervous System; Chronic; Clinical; DNA; Development; Diffusion Magnetic Resonance Imaging; Disease; Evaluation; Event; Frequencies; Functional disorder; Future; General Population; Generations; HIV; HIV Infections; HIV-1; HIV-associated neurocognitive disorder; Hematopoietic; Hematopoietic stem cells; Highly Active Antiretroviral Therapy; Homeostasis; Human; Human immunodeficiency virus test; Immune; Immune System Diseases; Immune system; Immunologics; Impaired cognition; Impairment; Incidence; Infection; Infiltration; Inflammation; Knowledge; Life Expectancy; Macrophage; Magnetic Resonance Imaging; Measures; Mediating; Microglia; Modeling; Mus; Myelogenous; Nature; Nervous System; Neuroglia; Neuroimmune; Neuronal Dysfunction; Neurons; Oligodendroglia; Oral; Organ; Pathology; Pathway interactions; Penetration; Peripheral; Persons; Pharmaceutical Preparations; Phase; Population; Process; Risk; SIV; Scheme; System; Therapeutic; Tissues; Transplantation; Viral; Viral reservoir; Virus; Virus Latency; Virus Replication; Work; antiretroviral therapy; brain cell; brain tissue; cell type; chronic infection; design; digital; falls; hematopoietic engraftment; hematopoietic transplantation; human RNA sequencing; human pathogen; humanized mouse; imaging modality; immune activation; mouse model; nerve stem cell; nervous system disorder; neuroAIDS; neuroinflammation; neuropathology; nonhuman primate; peripheral blood; permissiveness; preclinical efficacy; preclinical safety; progenitor; reconstitution; research study; single-cell RNA sequencing; stem cells; therapeutic target; tool; transcriptomics; transmission process; viral DNA; viral RNA

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.

抽象的 目前，缺乏足够的动物模型来复制人类HIV-1感染事件 提出了研究中枢神经系统（CNS）的HIV病理学的关键障碍。消除HIV-1感染 已成为优先事项。当代高度活性的抗逆转录病毒疗法（ART）已显着延长 感染者的生活，但并未解决与艾滋病毒相关的神经认知疾病的发生（手）。 HIV一直存在于人类血淋巴结室和中枢神经系统（CNS）中。执着的 周围和中枢神经系统中的HIV储藏剂会导致慢性炎症和末期疾病。临床 观察结果表明，该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， 例如星形胶质细胞。中枢神经系统病毒储层是终生的。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稳态的影响受到限制，因为现有小的不足 动物模型。我们旨在建立一个新的三重人源化鼠标模型，以自体重构 人血/血词系统，小胶质细胞和星形胶质细胞研究周围HIV-的相互作用 在发育中CNS免疫和神经元中，人脑神经胶质细胞感染和免疫激活 功能障碍。具有外周血/免疫细胞和人脑细胞（HUBB--鼠）的小鼠是 预计将提供一个研究神经助剂的综合模型。该模型最适合研究 属于当前RFA范围内的研究区域。使用新的Hubb-s，我们的目标是研究：1）。艾滋病病毒 抑制艺术期间的神经胶质储层和使用单细胞的神经免疫稳态失调 转录组分析和2）。神经元的完整性改变和功能，导致失调 神经免疫稳态。用ART抑制所有组织和细胞中外周病毒复制的动物 类型，包括星形胶质细胞和小胶质细胞，促进病毒学，免疫学和神经病理学评估。 预计拟议的工作将在新的Hubb-s上奠定基础，以进行多重评估 在慢性感染/免疫激活的背景下，手病理学的各个方面，持续的HIV水库 中枢神经系统和神经炎症。鼠标模型将是开发治疗剂以减轻的重要工具 手和设计来自中枢神经系统水库的消除艾滋病毒策略。