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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.

项目总结