Identification of immune protective pathways dysregulated by opioid use in HIV infection, using a systems biology-based approach, toward the goal of pharmacological restoration of immune function

使用基于系统生物学的方法，识别 HIV 感染中阿片类药物使用失调的免疫保护途径，以实现免疫功能药理学恢复的目标

• 批准号: 9712238
• 负责人: Alan David Levine
• 金额: $ 6.47万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9712238
• 关键词: AIDS/HIV problem; Absence of pain sensation; Affect; Analgesics; Anti-Retroviral Agents; B-Lymphocytes; Bioinformatics; CD4 Positive T Lymphocytes; CD8B1 gene; Cells; Chronic; Clinic; Clinical; Comorbidity; Computer Analysis; Dendritic Cells; Evaluation; Expression Profiling; Failure; Gene Expression; Gene Expression Profile; Goals; HIV; HIV Infections; Homeostasis; Immune; Immune system; Immunologic Markers; Inflammation; Investigation; Kidney Diseases; Lead; Life; Malignant Neoplasms; Medical center; Memory; Minority; Molecular; Molecular Profiling; Molecular Target; Narcotics; Ohio; Opiate Addiction; Pathway interactions; Patient Noncompliance; Patients; Percocet; Pharmaceutical Preparations; Pharmacology; Research; Systems Biology; T-Lymphocyte; United States; United States National Institutes of Health; Viral; Viral reservoir; Work; addiction; antiretroviral therapy; base; biological systems; biomarker panel; cardiovascular disorder risk; chronic pain; cohort; exhaustion; high risk; immune function; memory CD4 T lymphocyte; neurocognitive disorder; new therapeutic target; opioid therapy; opioid use; response; restoration; small molecule; specific biomarkers; therapeutic target; transcriptome

Abstract In the era of combination antiretroviral therapy (cART) for HIV infection, a major focus of clinical and scientific investigation lies with the high risk of cardiovascular disease, neurocognitive disorders, nephropathy, and malignancy among many other non-AIDS complications. In addition, continuing problems with patient non- compliance and a subsequent resurgence of HIV replication have lead the NIH to prioritize translational HIV research focused on the identification and eradication of viral reservoirs. While strategies are being developed to identify and reverse the latent pool, a parallel effort must proceed to enhance immune defenses against viral persistence as well as re-establish immune homeostasis. The focus of this dual discovery and mechanistic proposal is to identify pathways, molecular targets, and small molecule compounds that regulate immune protection in the HIV patient, whose function is compromised by chronic opioid use and addiction. We hypothesize that an unbiased systems biological evaluation of the T cell, dendritic cell, and B cell transcriptome will reveal specific molecular targets, pathways, or signatures that affect HIV persistence and reservoir size as well as non-AIDS complications. A key corollary of this hypothesis is that chronic opioid addiction, via narcotic pain medication, will perturb these networks and associate with increased HIV persistence, reservoir size, and systemic inflammation. This work will take advantage of two distinct cohorts of virally suppressed HIV+ patients (with and without a prescription-based addiction to the narcotic pain medication Percocet), available in Dr. Avery’s clinic at MetroHealth Medical Center in Cleveland, Ohio, and our already characterized cohort of elite controllers. The work will focus around the following Specific Aims: Aim 1: Identify molecular networks in CD8+ and CD4+ T cell memory subsets, as well as in innate cells, that are differentially regulated in opioid addiction and reciprocally regulated in elite controllers (EC) that naturally control HIV infection. Aim 2: Identify and dissect molecular signatures that are induced by opioid use in memory CD8+ and CD4+ T cells that correlate with inflammation, exhaustion, immune failure, and HIV that are absent in gene expression profiles from elite controllers. Aim 3: Develop and evaluate discrete opioid use specific biomarkers of immune deficiency and comorbidity to inform bioinformatic approaches to identify repurposed drugs to reverse the altered networks. The application of our highly refined transcriptional signature to a Biomarker panel will allow us to rapidly screen a high number of compounds for their ability to rescue opioid-use related immune dysregulation in a very small number of primary cells from cART suppressed HIV+ subjects. Thus, our overall goal is to generate a refined list of therapeutic targets for pharmacologic restoration of immune function in HIV- infected subjects that require opioid therapy for analgesia.

抽象的 在针对 HIV 感染的联合抗逆转录病毒疗法 (cART) 时代，临床和科学的主要焦点 调查发现，心血管疾病、神经认知障碍、肾病等疾病的风险很高。 此外，还有许多其他非艾滋病并发症中的恶性肿瘤。 依从性和随后 HIV 复制的复苏导致 NIH 优先考虑转化 HIV 研究重点是识别和消灭病毒储存库，同时正在制定策略。 为了识别和逆转潜伏池，必须同时努力增强针对病毒的免疫防御 持久性以及重建免疫稳态是这一双重发现和机制的重点。 提议是确定调节免疫的途径、分子靶点和小分子化合物 对艾滋病毒患者的保护，其功能因长期使用阿片类药物和成瘾而受到损害。 追求对 T 细胞、树突状细胞和 B 细胞进行公正的系统生物学评估 转录组将揭示影响艾滋病毒的特定分子靶点、途径或特征 该假设的一个关键推论是持久性和储存库大小以及非艾滋病并发症。 慢性阿片类药物成瘾，通过麻醉止痛药，会扰乱这些网络并关联 随着艾滋病毒持久性、储存库大小和全身炎症的增加，这项工作将发挥作用。 两组不同的病毒受到抑制的 HIV+ 患者（有和没有基于处方的药物成瘾） 麻醉止痛药 Percocet），可在 MetroHealth 医疗中心的 Avery 医生诊所购买 俄亥俄州克利夫兰和我们已经描述的精英控制人员群体的工作将集中在以下方面。 以下具体目标： 目标 1：识别 CD8+ 和 CD4+ T 细胞记忆亚群以及先天细胞中的分子网络， 在阿片类药物成瘾中受到不同的调节，在精英控制者（EC）中受到相互调节 自然控制艾滋病毒感染。 目标 2：识别并剖析记忆 CD8+ 和阿片类药物使用诱导的分子特征 CD4+ T 细胞与炎症、疲劳、免疫衰竭和 HIV 相关，而这些细胞在 来自精英控制者的基因表达谱。 目标 3：开发和评估离散的阿片类药物使用免疫缺陷和免疫缺陷的特定生物标志物 共病为生物信息学方法提供信息，以识别重新利用的药物以逆转 网络。 将我们高度精炼的转录特征应用于生物标记物组将使我们能够快速 筛选大量化合物，以确定它们是否能够挽救阿片类药物使用相关的免疫失调 来自 cART 的极少数原代细胞抑制了 HIV+ 受试者，因此，我们的总体目标是 制定一份详细的治疗靶点清单，用于药物恢复 HIV 免疫功能 需要阿片类药物镇痛治疗的感染受试者。