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：
10405537
负责人：
Woong-Ki Kim
金额：
$ 66.91万
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 2022-12-15
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10405537
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 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.

项目概要尽管出现了高效抗逆转录病毒疗法 (HAART)，但 HIV 相关的神经认知障碍令人惊讶的是，HIV 和密切相关的猿猴免疫缺陷病毒 (SIV) 可能会持续存在。大脑的“避难所”，而其他有效的抗逆转录病毒药物的获取却受到限制。骨髓细胞独立于 CD4 T 细胞支持 HIV/SIV 感染，并且可能是病毒反弹的来源然而，迄今为止，在停止抑制性抗逆转录病毒治疗（ART）后，包括大脑在内的组织。针对骨髓细胞和中枢神经系统 (CNS) 中的 HIV 的治疗策略尚未该提案的总体目标是领导合作以利用已知的知识。药理学集落刺激因子 1 受体 (CSF1R) 抑制巨噬细胞靶向目标最近，我们首次发现中枢神经系统中长寿命感染的 CSF1Rhigh 骨髓细胞过度表达。中枢神经系统骨髓细胞中的 CSF1R 的激活，包括血管周围巨噬细胞 (PVM) 和激活的感染 SIV 的脑炎猕猴以及病毒受到抑制的 HIV 患者大脑中的小胶质细胞。我们还发现，CSF1R 体外阻断选择性地消除了恒河猴单核细胞来源的 CSF1Rhigh 我们的中心假设是大脑中常驻的 CSF1Rhigh 骨髓细胞有助于尽管进行了HAART检查，但仍存在持续的HIV脑部感染和神经炎症。通过 CSF1R 信号传导阻断感染的骨髓细胞将消除中枢神经系统中持久的病毒库。第一个目标是确定在急性感染期间中枢神经系统中 CSF1Rhigh 骨髓细胞的消融是否会产生影响。减少大脑中的 DNA 前病毒负荷，第二个目标将集中于消除 CSF1Rhigh 脑髓细胞。该应用中提出的研究具有创新性。因为它代表了与当前维持病毒抑制方法的全新不同我们对艾滋病毒感染者的贡献将是巨大的，因为这是发展的第一步。针对病毒感染的中枢神经系统骨髓细胞或抑制骨髓病毒感染的治疗策略一旦此类策略可用，就有希望消除持续性髓系艾滋病毒。可以从大脑和其他组织中根除储库。