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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.

项目摘要尽管出现了高效抗逆转录病毒治疗（HAART），但HIV相关的神经认知障碍仍然非常普遍艾滋病毒和密切相关的猿免疫缺陷病毒（SIV）可能会持续存在，大脑的“避难所”，在那里，其他有效的抗逆转录病毒药物的使用是有限的。现在很明显，骨髓细胞支持HIV/SIV感染，不依赖于CD 4 T细胞，并且可以是HIV/SIV感染后反弹病毒的来源。在停止抑制性抗逆转录病毒疗法（ART）后，包括脑在内的组织中的细胞毒性降低。然而，迄今为止，在骨髓细胞和中枢神经系统（CNS）中靶向HIV的治疗策略还没有尚未开发。该提案的总体目标是领导合作以利用已知的药理学集落刺激因子1受体（CSF 1 R）抑制巨噬细胞靶向靶点 CNS中的长寿命感染的CSF 1 R高骨髓细胞。最近，我们首次发现，和CNS髓样细胞包括血管周围巨噬细胞（PVM）中CSF 1 R的活化，在SIV感染的患有脑炎的猕猴中，以及在病毒抑制的HIV患者的大脑中，我们还发现，体外CSF 1 R阻断剂选择性地消除了恒河猴单核细胞来源的CSF 1 Rhigh 巨噬细胞我们的中心假设是，大脑中的CSF 1 R高骨髓细胞有助于尽管有HAART，但仍存在持续的HIV脑感染和神经炎症。因此，选择性地针对通过CSF 1 R信号传导阻断感染的骨髓细胞将消除中枢神经系统中持续存在的病毒储存库。第一个目标是确定在急性感染期间清除CNS中的CSF 1 R高髓样细胞是否会减少大脑中的DNA前病毒负荷。第二个目标将集中于消融CSF 1 R高脑髓样细胞在ART治疗的慢性感染的情况下。本申请中提出的研究具有创新性因为它代表了一种全新的背离目前维持病毒抑制的方法，艾滋病毒感染者。我们的贡献将是重大的，因为这是朝着发展的第一步。靶向病毒感染的CNS髓样细胞或抑制病毒感染的髓样细胞的治疗策略 CNS中的细胞。一旦这些策略成为可能，持续的髓系艾滋病病毒有希望可以从大脑和其他组织中根除储存库。