Reducing the CNS reservoir through myeloid cell depletion

通过耗竭骨髓细胞减少中枢神经系统储库

• 批准号: 10254688
• 负责人: ANDREW G MACLEAN
• 金额: $ 21.25万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10254688
• 关键词: Acute; Address; Animals; Anti-Retroviral Agents; Apoptosis; Apoptotic; Astrocytes; Biological; Biological Assay; Blood - brain barrier anatomy; Brain region; CSF1R gene; Cell physiology; Cells; Central Nervous System Diseases; Central Nervous System Infections; Data; Development; Disease; FDA approved; Germ Cells; HIV; HIV Infections; Immunohistochemistry; In Situ Hybridization; In Vitro; Infection; Intervention; Knowledge; Laboratories; Long-Term Effects; Longitudinal Studies; Macaca; Measures; Methods; Microglia; Modeling; Myeloid Cells; National Institute of Mental Health; Neurologic Dysfunctions; Neurologic Symptoms; Patients; Pharmaceutical Preparations; Primates; Research; Research Project Grants; Resistance; Role; SIV; Severities; Site; Source; System; Systemic disease; Testing; Time; Tissues; United States National Institutes of Health; Viral; Viral Load result; Viral reservoir; Virus Diseases; Virus Replication; Work; blood-brain barrier disruption; comorbidity; experience; glial activation; in vivo; insight; macrophage; migration; nervous system disorder; neuroinflammation; neuropathology; nonhuman primate; novel; peripheral blood; prevent; subventricular zone; tool; trafficking; tumor; viral rebound

PROJECT SUMMARY/ABSTRACT HIV infection results in CNS comorbidities, with nearly 75% of patients with advanced HIV disease showing neurological manifestations. The blood-brain barrier prevents antiretroviral drugs from entering the CNS, and thus a reservoir occurs. Macrophage and microglia remain at least latently infected, awaiting an insult to reawaken. A recently FDA-approved drug, Pexidartinib, has been used to safely deplete microglia and macrophages. These microglia are believed to repopulate from the subventricular zone, with initial cells being CD4-ve. This could render these cells impervious to infection. Further, SIV infection makes macrophages resistant to apoptosis: Pexidartinib restores this apoptotic sensitivity. This could provide an avenue to examining the depletion of latently infected cells from the CNS, with the potential for diminishing later neurological disorders, including the major CNS comorbidity: HAND. There is debate that latently-infected microglia and macrophages can be a source of viral rebound to the periphery. Removing those microglia after viral setpoint, with macaques on stable cART, and determining if the CNS reservoir can return, could answer this very question. The effects of transiently depleting microglia from the CNS, especially in the context of SIV infection, represent a significant gap in our knowledge. Therefore, there is a critical need to understand the effects of transiently removing latently-infected microglia from the CNS in SIV neuropathology. This R21 application seeks to address how removing microglia from the CNS influences neuroinflammation both positively and negatively in the context of SIV infection.

项目总结/摘要 HIV感染导致CNS合并症，近75%的晚期HIV患者表现出 神经学表现血脑屏障阻止抗逆转录病毒药物进入CNS， 从而形成储层。巨噬细胞和小胶质细胞至少保持潜伏感染，等待对 重新醒来最近FDA批准的药物Pexidartinib已被用于安全地消耗小胶质细胞， 巨噬细胞这些小胶质细胞被认为是从脑室下区重新增殖的，初始细胞是 CD4-ve。这可以使这些细胞不受感染。此外，SIV感染使巨噬细胞 抗凋亡：Pexidartinib可恢复这种凋亡敏感性。这可以提供一种途径， 从中枢神经系统中清除潜伏感染细胞，具有减少后期神经系统疾病的潜力， 包括主要的CNS合并症：手。 有争议的是，潜在感染的小胶质细胞和巨噬细胞可能是病毒反弹到 外围。在病毒设定点后去除那些小胶质细胞，猕猴进行稳定的cART，并确定是否存在病毒。 中枢神经系统的储库可以恢复，可以回答这个问题。短暂消耗小胶质细胞的影响， 中枢神经系统，特别是在SIV感染的情况下，代表了我们知识的一个重大空白。因此有 迫切需要了解从SIV的CNS中暂时去除潜伏感染的小胶质细胞的效果 神经病理学这项R21申请旨在解决从CNS中去除小胶质细胞如何影响 SIV感染的背景下，神经炎症的积极和消极。