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

基本信息

批准号：
10452642
负责人：
ANDREW G MACLEAN
金额：
$ 25.5万
依托单位：
TULANE UNIVERSITY OF LOUISIANA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10452642
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 antagonist 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

项目摘要

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。