The Role of Myeloid Cells in HIV Latency and Persistence in the Brain

骨髓细胞在艾滋病毒潜伏期和大脑持续存在中的作用

• 批准号: 10619981
• 负责人: Angela Raquel Wahl
• 金额: $ 70.52万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10619981
• 关键词: Affect; Animal Model; Animals; Autopsy; Brain; CD4 Positive T Lymphocytes; Cells; Clonal Expansion; DNA; Development; Drug Kinetics; Goals; HIV; HIV Infections; Human; Individual; Infection; Interruption; Kinetics; Knowledge; Location; Microglia; Myeloid Cells; Neurocognitive; Pathology; Penetration; Persons; Population; Regimen; Reporting; Rest; Role; SIV; Sampling; Source; T-Lymphocyte; Tissues; Viral reservoir; Virus; Virus Replication; brain cell; brain tissue; experimental study; humanized mouse; innovation; integration site; macrophage; mouse model; neuroAIDS; novel; prevent; reconstitution; viral rebound

Latently infected CD4+ T cells are considered to be the most important HIV reservoir preventing the implementation of an HIV cure. However, myeloid cells have been shown to be infected by HIV/SIV and to establish latency in animal models1-4. Therefore, elimination of the T cell reservoir alone is not likely to result in complete virus eradication. One of our long-term goals is to aid the development of effective HIV cure strategies by gaining a better understanding of the type and location of the cells that harbor replication competent HIV under ART suppression. HIV-associated neurological disorders or HAND affect up to 50% of people living with HIV (PLWH)5-7 suggesting that HIV-infected cells may persist in the brain of ART-suppressed individuals. HIV-DNA has been readily detected in the CSF of aviremic ART-suppressed PLWH and its presence is associated with poorer neurocognitive performance8. Analyses of brain tissue obtained postmortem from PLWH indicate that macrophages and microglia are major targets for HIV infection in the brain9-11 and demonstrate the presence of HIV-DNA+ cells in brain tissue from aviremic individuals10-12. Microglia are the predominant population of myeloid cells in the brain and in contrast to macrophages, are long lived and undergo cell division13,14. For these reasons, microglia are thought to represent a key cellular reservoir of HIV in the brain11. While there is a significant body of knowledge about the mechanisms of HIV latency and persistence in resting CD4+ T cells, there is significantly less known about HIV persistence in myeloid cells and therefore, a need to establish their possible role as a source of HIV reactivation after ART discontinuation. Specifically, in the brain the contribution of microglia is relatively unknown due in part to the difficulties in sampling cells in this compartment in PLWH. Our hypothesis is that HIV maintains a persistent reservoir in the brain under suppressive ART and our objective is to utilize an innovative humanized mouse model reconstituted with human brain microglia to increase the knowledge and understanding about how microglia contribute to HIV persistence and viral rebound by analyzing 1) HIV suppression by ART in human microglia in the brain, 2) the viral reservoir present in infected microglia, and 3) the development of HIV latency and rebound in human microglia in the brain after analytical therapy interruption. The new knowledge gained from the proposed experiments will contribute to a better understanding of HIV persistence in the brain, reactivation, and aid the development of novel HIV Cure approaches that target the CNS.

潜在感染的CD4+ T细胞被认为是最重要的HIV储存库 艾滋病毒治愈的实施。但是，已证明髓样细胞被HIV/SIV感染，至 在动物模型1-4中建立延迟。因此，消除T细胞储存库不太可能导致 完全消除病毒。我们的长期目标之一是帮助开发有效的艾滋病毒治疗 通过更好地理解具有复制的单元的类型和位置，可以采取策略 在艺术抑制下有能力的艾滋病毒。与HIV相关的神经系统疾病或手影响多达50％ 患有艾滋病毒（PLWH）5-7的人表明，感染艾滋病毒的细胞可能会持续存在于艺术抑制的大脑中 个人。 HIV-DNA很容易在Aviromemic Art抑制的PLWH的CSF中检测到 存在与较差的神经认知性能8。对获得的脑组织的分析 PLWH的验尸表明巨噬细胞和小胶质细胞是艾滋病毒感染的主要靶标 Brain9-11并证明了来自Aviromic个个体的脑组织中HIV-DNA+细胞的存在10-12。 小胶质细胞是大脑中髓样细胞的主要种群，与巨噬细胞相反，很长 生活并经历细胞部门13,14。由于这些原因，小胶质细胞被认为代表了钥匙细胞 大脑中的艾滋病毒储量11。虽然对艾滋病毒机制有大量知识 静止CD4+ T细胞的潜伏期和持久性，对HIV的持久性知之甚少 因此，需要确定其作为ART后HIV重新激活的来源的可能作用 中断。具体而言，在大脑中，小胶质细胞的贡献相对尚不清楚。 PLWH中此隔室中采样细胞的困难。我们的假设是艾滋病毒保持持久性 在抑制性艺术下，大脑中的水库和我们的目标是利用创新的人源化鼠标 模型与人脑小胶质细胞重构，以增加知识和理解 小胶质细胞通过分析1）人类中的ART抑制HIV抑制HIV的持久性和病毒反弹 大脑中的小胶质细胞，2）受感染的小胶质细胞中存在的病毒储层，3）艾滋病毒潜伏期的发展 分析疗法中断后，大脑中人类小胶质细胞反弹。获得的新知识获得了 从提出的实验中，将有助于更好地了解大脑中的HIV持久性， 重新激活，并有助于针对CNS的新型HIV治疗方法的发展。