Targeting of SIV Macrophage Reservoirs in the CNS by CSF1R Inhibition

通过 CSF1R 抑制靶向 CNS 中的 SIV 巨噬细胞库

基本信息

批准号：
10162662
负责人：
Woong-Ki Kim
金额：
$ 67.9万
依托单位：
EASTERN VIRGINIA MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-15 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10162662
关键词：
AIDS/HIV problem Ablation Acquired Immunodeficiency Syndrome Acute Address Anti-Retroviral Agents Applications Grants Astrocytes Blood - brain barrier anatomy Brain CD4 Positive T Lymphocytes CSF1 gene Central Nervous System Infections Cerebrospinal Fluid Collaborations Colony Stimulating Factor Activation DNA Development Encephalitis Funding Opportunities Goals HIV HIV Infections HIV-1 HIV-associated neurocognitive disorder Highly Active Antiretroviral Therapy Human In Vitro Individual Infection Interruption Lead Lesion Link Macaca Macrophage Colony-Stimulating Factor Receptor Microglia Modeling Myelogenous Myeloid Cells Neuraxis Outcome Patients Peripheral Pharmacology Phase Public Health Receptor Inhibition Receptor Signaling Recovery Research Research Priority Residual state Rhesus SIV SIV encephalitis Signal Transduction Site Source Supporting Cell Testing Therapeutic Time Tissues United States National Institutes of Health Viral Viral Load result Viral reservoir Viremia Virus Virus Diseases Virus Replication Withdrawal Work acute infection antiretroviral therapy cell type chronic infection design in vivo inhibitor/antagonist innovation kinase inhibitor macrophage monocyte neuroinflammation novel novel therapeutic intervention overexpression simian human immunodeficiency virus small molecule small molecule inhibitor therapeutic development therapeutic target viral rebound

项目摘要

Project Summary Despite the advent of highly active antiretroviral therapy (HAART), HIV-associated neurocognitive disorders remain surprisingly common. HIV and the closely-related simian immunodeficiency virus (SIV) may persist in the brain ‘sanctuary’, where access of otherwise potent antiretrovirals is limited. It is now becoming clear that myeloid cells support HIV/SIV infection independently of CD4 T cells and can be the source of rebound virus in tissues including brain upon cessation of suppressive antiretroviral therapy (ART). To date, however, therapeutic strategies for targeting HIV in the myeloid cells and in the central nervous system (CNS) have not yet been developed. The overall goal of this proposal is to lead collaborations to exploit the known pharmacological colony-stimulating factor 1 receptor (CSF1R) inhibition for macrophage targeting to target long-lived infected CSF1Rhigh myeloid cells in the CNS. Recently, we found, for the first time, overexpression and activation of the CSF1R in CNS myeloid cells including perivascular macrophages (PVM) and activated microglia in SIV-infected macaques with encephalitis, as well as in the brain of virally suppressed HIV patients. We also found that CSF1R blockade in vitro selectively ablated rhesus monocyte-derived CSF1Rhigh macrophages. Our central hypothesis is that resident CSF1Rhigh myeloid cells in the brain contribute to persistent HIV brain infection and neuroinflammation despite HAART. Consequently, selective targeting of infected myeloid cells by CSF1R signaling blockade will eliminate the persistent viral reservoir from the CNS. The first aim will determine whether ablation of CSF1Rhigh myeloid cells in the CNS in during acute infection will decrease DNA proviral load in the brain. The second aim will focus on ablating the CSF1Rhigh brain myeloid cells in the setting of ART-treated chronic infection. The research proposed in this application is innovative because it represents an entirely novel departure from the current approach to maintaining viral suppression in HIV-infected patients. Our contribution here will be significant because it is a first step toward the development of therapeutic strategies for targeting virus-infected CNS myeloid cells or inhibiting viral infection of myeloid cells in the CNS. Once such strategies become available, there is promise that persistent myeloid HIV reservoirs could be eradicated from brain and other tissues.

项目摘要尽管高度活跃的抗逆转录病毒疗法（HAART）冒险，但与HIV相关的神经认知障碍仍然很普遍。艾滋病毒和与密切相关的猿猴免疫缺陷病毒（SIV）可能持续存在大脑“庇护所”，在该大脑中，其他潜在的抗逆转录病毒的机会受到限制。现在很清楚髓样细胞独立于CD4 T细胞支持HIV/SIV感染，并且可以成为反弹病毒的来源组织包括抑制性抗逆转录病毒疗法（ART）后的大脑。但是，迄今为止针对髓样细胞和中枢神经系统（CNS）靶向HIV的治疗策略尚未尚未开发。该提案的总体目标是领导合作来利用已知的药理学菌落刺激因子1受体（CSF1R）抑制巨噬细胞靶向靶标中枢神经系统中的长寿命感染的CSF1RHIGH髓样细胞。最近，我们第一次发现了过表达 CNS髓样细胞中CSF1R的激活，包括血管周围巨噬细胞（PVM）并激活 SIV感染的猕猴的小胶质细胞以及病毒抑制的HIV患者的大脑中的小胶质细胞。我们还发现，CSF1R blocade在体外有选择地消融单核细胞衍生的CSF1RHIGH 巨噬细胞。我们的中心假设是，大脑中的居民CSF1RHIGH髓样细胞有助于持续的HIV脑感染和神经炎症目的地HAART。因此，选择性定位 CSF1R信号阻塞感染的髓样细胞将消除CNS的持续病毒储存剂。第一个目的将决定急性感染中CNS中CSF1RHIGH髓样细胞的消融是否会减少大脑中的DNA临时负荷。第二个目标将集中于烧毁CSF1RHIGH脑髓样在艺术治疗的慢性感染的情况下。本应用程序中提出的研究是创新的因为它代表了与当前的方法完全新颖的偏离，以维持病毒抑制 HIV感染患者。我们在这里的贡献将是重要的，因为这是迈向发展的第一步靶向病毒感染的CNS髓样细胞或抑制髓样病毒感染的理论策略中枢神经系统中的细胞。一旦这种策略可用，就有保证持续的髓样艾滋病毒储层可以从大脑和其他组织中放大。