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.

潜伏感染的 CD4+ T 细胞被认为是预防艾滋病病毒感染的最重要的病毒库。 实施艾滋病毒治疗。然而，骨髓细胞已被证明会被 HIV/SIV 感染并 在动物模型中建立潜伏期1-4。因此，仅消除 T 细胞储库不太可能导致 彻底消灭病毒。我们的长期目标之一是帮助开发有效的艾滋病毒治疗方法 通过更好地了解进行复制的细胞的类型和位置来制定策略 ART抑制下的HIV感染能力。 HIV 相关神经系统疾病或 HAND 影响高达 50% HIV 感染者 (PLWH)5-7 表明 HIV 感染细胞可能持续存在于 ART 抑制的大脑中 个人。在无病毒血症的 ART 抑制的 PLWH 及其患者的 CSF 中很容易检测到 HIV-DNA 存在与较差的神经认知表现相关8。对获得的脑组织进行分析 PLWH 的尸检表明巨噬细胞和小胶质细胞是艾滋病毒感染的主要目标 脑 9-11 并证明无病毒血症个体的脑组织中存在 HIV-DNA+ 细胞 10-12。 小胶质细胞是大脑中髓样细胞的主要群体，与巨噬细胞相比，它的长度很长 生存并进行细胞分裂13,14。由于这些原因，小胶质细胞被认为代表了关键的细胞 大脑中的艾滋病毒储存库11。虽然人们对艾滋病毒的机制有大量的了解 静息 CD4+ T 细胞的潜伏期和持久性，对于 HIV 的持久性知之甚少。 骨髓细胞，因此需要确定它们作为 ART 后 HIV 再激活来源的可能作用 停产。具体来说，在大脑中小胶质细胞的贡献相对未知，部分原因是 在 PLWH 的该隔室中进行细胞取样存在困难。我们的假设是 HIV 持续存在 在抑制性 ART 下大脑中的储存库，我们的目标是利用创新的人源化小鼠 用人脑小胶质细胞重建模型，以增加关于如何进行的知识和理解 通过分析 1) 人类通过 ART 抑制 HIV，小胶质细胞有助于 HIV 持续存在和病毒反弹 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库，以及 3) HIV 潜伏期的发展 分析治疗中断后大脑中人类小胶质细胞的反弹。获得的新知识 拟议的实验将有助于更好地了解艾滋病毒在大脑中的持久性， 重新激活，并帮助开发针对中枢神经系统的新型艾滋病毒治疗方法。