Immune Network Dysregulation of the Central Nervous System with HIV Persistence and Opioid Abuse

HIV 持续存在和阿片类药物滥用导致中枢神经系统免疫网络失调

• 批准号: 10469837
• 负责人: Le Zhang
• 金额: $ 251.25万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-15 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10469837
• 关键词: Adult; Architecture; Area; Brain; Cell Nucleus; Cells; Communication; Computational Biology; Data; Development; Disease; Foundations; Future; Gene Expression Profile; Generations; HIV; HIV Infections; HIV-associated neurocognitive disorder; Health; Human; Immune; Immunobiology; Individual; Knowledge; Methodology; Methods; Microglia; Modernization; Molecular; Morbidity - disease rate; National Institute of Drug Abuse; Nervous System Trauma; Neuraxis; Neuroimmune; Neurologic; Neurons; Neurosciences; Opioid; Patients; Pharmacologic Substance; Population; Research; System; T-Lymphocyte; Technology; Therapeutic; Viral; Virus; Virus Replication; antiretroviral therapy; base; cell type; immune activation; innovation; insight; large datasets; neuroinflammation; novel; opioid abuse; opioid exposure; opioid use disorder; prevent; response; single-cell RNA sequencing; therapy development; transcriptome; transcriptome sequencing; transcriptomics

PROJECT SUMMARY/ABSTRACT HIV persists within the body despite successful suppression of viral replication with antiretroviral therapy (ART), preventing eradication of the virus. Even a low level of persistent HIV in the brain may cause neurological damage, as 30-50% of well-suppressed HIV individuals under ART develop HIV-associated neurocognitive disorders (HAND). These abnormalities in the CNS are further complicated by opioid abuse, as opioid exposure results in exaggerated neuroinflammation. CNS immune activation induced by HIV and OUD is incompletely understood at the cellular level. Understanding the cellular basis for persistent CNS immune activation is critical for reducing neurological morbidities in the growing population of adults with HIV and OUD. Recent advances in massively parallel single cell RNA sequencing have uncovered numerous neuronal and glial populations widely across the central nervous system in health and disease. Such methods provide a powerful and unbiased way for understanding the organization of the cellular and immune network of the CNS based on transcriptional profiles at the single cell level. Here, we propose to employ state-of-the-art and novel methodologies in neuroscience, immunobiology, and computational biology to dissect the dysregulated immune network in the CNS of patients with HIV and OUD and the cell-type-specific response to opioid in the context of HIV. We will apply state-of-the-art single cell transcriptome analysis to uncover the molecular architecture and immune activation of the CSF in the patients with HIV and OUD. We will leverage our large dataset of human brain single nucleus RNA sequencing generated at the NIDA-supported CNS data generation center of Single Cell Opioid Responses in the Context of HIV at Yale (Y-SCORCH) to characterize the alterations of neuroimmune communications in OUD and HIV. We will develop and employ novel modern cell-type-specific approaches, such as ex vivo culture system, to determine the opioid responses of brain immune cell types, including microglia and brain-resident T cells, in the context of HIV. Determining the regulatory networks and molecular mechanisms of HIV persistence in response to opioid exposure will greatly advance our understanding of HIV latency and may provide novel insights and numerous pharmaceutical targets for treating HAND and eradicating HIV virus in HIV persistent individuals with opioid use disorder.

项目摘要/摘要 尽管通过抗逆转录病毒疗法（ART）成功抑制病毒复制（ART），但HIV仍然存在于体内。 防止根除病毒。即使在大脑中持续的艾滋病毒的持久性较低也可能引起神经系统 损害，在ART下，有30％至50％的受抑制的艾滋病毒患者发展为艾滋病毒相关的神经认知 疾病（手）。阿片类药物滥用，中枢神经系统中的这些异常使阿片类药物暴露更加复杂 导致夸张的神经炎症。由HIV和OUD诱导的CNS免疫激活并不完全 在细胞水平上理解。了解持久性中枢神经系统免疫激活的细胞基础是至关重要的 用于减少艾滋病毒和OUD成年人不断增长的人群的神经病病毒。最近的进步 大量平行的单细胞RNA测序发现了许多神经元和神经胶质种群 整个中枢神经系统健康和疾病。这样的方法提供了一种强大而公正的方式 为了理解基于转录的中枢神经系统细胞和免疫网络的组织 单元级别的轮廓。在这里，我们建议在 神经科学，免疫生物学和计算生物学，以剖析失调的免疫网络 HIV和OUD患者的中枢神经系统以及在HIV背景下对阿片类药物的细胞型特异性反应。我们将 应用最先进的单细胞转录组分析以发现分子结构和免疫 CSF激活HIV和OUD患者。我们将利用我们的大脑数据集 在NIDA支持的CNS数据生成单细胞阿片类药物中产生的核RNA测序 在耶鲁大学（Y-Scorch）的艾滋病毒背景下的反应，以表征神经免疫的改变 Oud和HIV中的交流。我们将开发并采用新颖的现代细胞类型特异性方法 作为离体培养系统，以确定脑免疫细胞类型的阿片类药物反应，包括小胶质细胞和 在艾滋病毒的背景下，脑居住的T细胞。确定调节网络和分子机制 艾滋病毒对阿片类药物暴露的持续存在将大大提高我们对艾滋病毒潜伏期的理解，可能 提供新颖的见解和众多药物靶标，用于治疗HIV中的HIV病毒 持续存在阿片类药物使用障碍的人。