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.

项目总结/摘要 尽管抗逆转录病毒疗法（ART）成功抑制了病毒复制，但HIV仍在体内持续存在， 阻止病毒的根除即使是大脑中持续存在的低水平艾滋病毒也可能导致神经系统疾病 损害，因为30-50%的ART下的HIV抑制良好的个体发展出HIV相关的神经认知障碍。 疾病（手）。中枢神经系统中的这些异常由于阿片类药物滥用而进一步复杂化，如阿片类药物暴露 导致神经炎症加剧HIV和OUD诱导的CNS免疫激活是不完全的， 在细胞水平上理解。了解持续性CNS免疫激活的细胞基础至关重要 用于减少不断增长的HIV和OUD成年患者的神经系统发病率。的最新进展 大规模平行单细胞RNA测序已经广泛地发现了许多神经元和神经胶质细胞群体， 在健康和疾病中的中枢神经系统。这种方法提供了一种强有力的、公正的方法， 用于理解CNS的细胞和免疫网络的组织， 在单细胞水平上的特征。在这里，我们建议采用最先进的和新颖的方法， 神经科学，免疫生物学和计算生物学，以剖析在免疫系统中失调的免疫网络。 HIV和OUD患者的CNS以及HIV背景下对阿片类药物的细胞类型特异性反应我们将 应用最先进的单细胞转录组分析来揭示分子结构和免疫 在HIV和OUD患者中激活CSF。我们将利用我们的大型数据集人类大脑单一 在NIDA支持的单细胞阿片类药物CNS数据生成中心生成的核RNA测序 在耶鲁大学的艾滋病毒背景下的反应（Y-SCORCH），以表征神经免疫功能的改变， 在OUD和HIV中的通信。我们将开发和采用新的现代细胞类型特异性方法，如 作为离体培养系统，以确定脑免疫细胞类型（包括小胶质细胞和 脑内T细胞，在艾滋病病毒的背景下。确定的调控网络和分子机制， HIV对阿片类药物暴露的持续反应将极大地促进我们对HIV潜伏期的理解， 为治疗HAND和根除HIV中的HIV病毒提供了新的见解和许多药物靶点 阿片类药物使用障碍的持续性个体。