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Targeting SIV macrophage reservoirs in the CNS by CSF1R inhibition

通过抑制 CSF1R 靶向 CNS 中的 SIV 巨噬细胞储库

基本信息

批准号：
10846020
负责人：
Woong-Ki Kim
金额：
$ 103.81万
依托单位：
TULANE UNIVERSITY OF LOUISIANA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-19 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10846020
关键词：
Ablation Acquired Immunodeficiency Syndrome Acute Address Anti-Retroviral Agents Applications Grants Astrocytes Blood - brain barrier anatomy Blood Vessels Brain CD4 Positive T Lymphocytes CSF1 gene Central Nervous System 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 HIV/AIDS Highly Active Antiretroviral Therapy In Vitro Individual Infection Interruption Lead Lesion Link Macaca Macrophage Macrophage Colony-Stimulating Factor Receptor Microglia Modeling Myelogenous Myeloid Cells Outcome Patients Peripheral Phase Population Proliferating 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 blood-brain barrier crossing cell type chronic infection design in vivo inhibitor innovation kinase inhibitor monocyte neuroinflammation novel novel therapeutic intervention overexpression pharmacologic 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疗法(HAART)，但艾滋病毒相关的神经认知障碍仍然令人惊讶地普遍。艾滋病毒和密切相关的猿类免疫缺陷病毒(SIV)可能会持续存在大脑的“避难所”，在那里，原本有效的抗逆转录病毒药物的使用受到限制。现在越来越清楚的是，髓系细胞独立于CD4T细胞支持HIV/SIV感染，并可成为停止抑制性抗逆转录病毒治疗(ART)时包括大脑在内的组织。然而，到目前为止，针对髓系细胞和中枢神经系统(CNS)中的HIV的治疗策略尚未还没有被开发出来。这项提议的总体目标是引导合作开发已知的药理集落刺激因子-1受体抑制巨噬细胞靶向长寿感染CSF1R中枢神经系统中的高髓系细胞。最近，我们第一次发现了过度表达和CSF1R在包括血管周围巨噬细胞(PVM)在内的中枢神经系统髓系细胞中的激活和激活 SIV感染的脑炎猕猴的小胶质细胞，以及病毒抑制的艾滋病毒患者的大脑中的小胶质细胞。我们还发现，CSF1R体外阻断选择性地消融恒河猴单核细胞来源的CSF1RHigh 巨噬细胞。我们的中心假设是大脑中驻留的CSF1R高髓系细胞有助于尽管进行了HAART，但持续的艾滋病毒脑感染和神经炎症。因此，有选择性地瞄准通过CSF1R信号阻断感染髓系细胞将从中枢神经系统中消除持久的病毒库。第一个目标将确定在急性感染期间切除中枢神经系统中的CSF1R高髓系细胞是否将减少大脑中的DNA前病毒负荷。第二个目标将集中在消融CSF1R高位脑髓系在ART治疗慢性感染的背景下细胞。本申请中提出的研究具有创新性。因为它代表了一种与当前保持病毒抑制的方法完全不同的新方法感染艾滋病毒的患者。我们的贡献将是重大的，因为这是迈向发展的第一步靶向病毒感染的中枢神经系统髓系细胞或抑制髓系病毒感染的治疗策略中枢神经系统的细胞。一旦这种策略可用，就有望使持久的髓系艾滋病毒蓄水池可以从大脑和其他组织中根除。