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：
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
项目类别：
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

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.

项目摘要/摘要 HIV感染导致中枢神经系统合并症，近75％的晚期HIV疾病患者显示神经表现形式。血脑屏障可防止抗逆转录病毒药物进入中枢神经系统，并且因此发生了一个储层。巨噬细胞和小胶质细胞至少仍然受到潜在感染，等待侮辱恢复。最近通过FDA批准的药物Pexidartinib已被用来安全耗尽小胶质细胞和巨噬细胞。这些小胶质细胞被认为是从脑室下区域重新填充的，初始细胞为 CD4-VE。这可能会使这些细胞不受感染。此外，SIV感染使巨噬细胞成为巨噬细胞抗凋亡：pexidartinib恢复了这种凋亡敏感性。这可以为检查提供途径来自中枢神经系统的潜在感染细胞的耗竭，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。有辩论是，潜在感染的小胶质细胞和巨噬细胞可以成为病毒反弹的来源周边。在病毒设定点后去除那些小胶质细胞，并在稳定的购物车上猕猴，并确定是否是否 CNS水库可以返回，可以回答这个问题。瞬时耗尽小胶质细胞的影响中枢神经系统，尤其是在SIV感染的背景下，在我们的知识上代表了一个很大的差距。因此，有迫切需要了解SIV中CNS的瞬时去除潜在感染的小胶质细胞的影响神经病理学。该R21应用程序旨在解决如何从中枢神经系统中删除小胶质细胞在SIV感染的背景下，神经炎症均积极和负面。