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.

项目概要/摘要 HIV 感染会导致中枢神经系统合并症，近 75% 的晚期 HIV 患者出现 神经系统表现。血脑屏障可防止抗逆转录病毒药物进入中枢神经系统，并且 从而形成水库。巨噬细胞和小胶质细胞至少仍处于潜伏感染状态，等待着攻击 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和 巨噬细胞。这些小胶质细胞被认为是从室下区重新增殖的，最初的细胞是 CD4-ve。这可以使这些细胞免受感染。此外，SIV感染使巨噬细胞 抗细胞凋亡：Pexidartinib 可恢复这种细胞凋亡敏感性。这可以提供一个途径来检查 中枢神经系统中潜伏感染细胞的消耗，有可能减少后来的神经系统疾病， 包括主要的中枢神经系统合并症：手部疾病。 有争议的是，潜伏感染的小胶质细胞和巨噬细胞可能是病毒反弹的来源。 周边。在病毒设定点后去除这些小胶质细胞，让猕猴接受稳定的 cART，并确定是否 中枢神经系统储库可以返回，可以回答这个问题。短暂耗尽小胶质细胞的影响 中枢神经系统（CNS），特别是在 SIV 感染的情况下，代表了我们知识上的重大差距。因此，有 迫切需要了解在 SIV 中暂时去除中枢神经系统中潜伏感染的小胶质细胞的影响 神经病理学。该 R21 应用旨在解决中枢神经系统中去除小胶质细胞的影响 在 SIV 感染的情况下，神经炎症有积极和消极的影响。