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: 10693971
• 负责人: Angela Raquel Wahl
• 金额: $ 13.01万
• 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 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10693971
• 关键词: Affect; Animal Model; Autopsy; Binding; Brain; CD4 Positive T Lymphocytes; Cell division; Cells; Clonal Expansion; DNA; Development; Drug Kinetics; Goals; HIV; HIV Infections; Human; Individual; Infection; Interruption; Kinetics; Knowledge; Location; Macrophage; Microglia; Myeloid Cells; Neurocognitive; Pathology; Penetration; Performance; 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; mouse model; neuroAIDS; novel; prevent; reconstitution; self-renewal; 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毒感染的最重要的宿主 实施艾滋病毒治愈方案。然而，髓系细胞已被证明感染艾滋病毒/SIV和 建立动物模型1-4的潜伏期。因此，仅消除T细胞库不太可能导致 彻底根除病毒。我们的长期目标之一是帮助开发有效的艾滋病毒治疗方法 通过更好地了解拥有复制的细胞的类型和位置来制定策略 在抗逆转录病毒疗法抑制下的合格艾滋病毒。艾滋病毒相关的神经疾病或手部疾病影响高达50% HIV携带者(PLWH)5-7提示HIV感染细胞可能持续存在于ART抑制的大脑中 个人。在抗逆转录病毒药物抑制的PLWH患者的脑脊液中很容易检测到HIV-DNA。 在场与较差的神经认知表现有关。获取的脑组织的分析 PLWH的尸检结果表明，巨噬细胞和小胶质细胞是HIV感染的主要目标 脑9-11，并证明HIV-DNA+细胞存在于无菌个体10-12的脑组织中。 小胶质细胞是脑中髓系细胞的主要群体，与巨噬细胞相比，小胶质细胞较长。 由于这些原因，小胶质细胞被认为是一种关键的细胞 大脑中的艾滋病毒蓄水池11。虽然关于HIV的机制有大量的知识 静息的CD4+T细胞的潜伏期和持久性，对HIV持久性的了解明显较少 因此，有必要确定它们作为抗逆转录病毒治疗后HIV重新激活的可能来源的作用。 停产。具体地说，在大脑中，小胶质细胞的作用相对未知，部分原因是 在PLWH的这个隔间里采样细胞有困难。我们的假设是艾滋病毒保持了一种持久的 我们的目标是利用一种创新的人性化小鼠 用人脑小胶质细胞重组的模型，以增加对如何 通过分析1)人类抗逆转录病毒药物对HIV的抑制，小胶质细胞有助于HIV的持久性和病毒反弹 大脑中的小胶质细胞，2)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 在分析治疗中断后，人脑中的小胶质细胞反弹。获得的新知识 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的艾滋病毒治疗方法。