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.

摘要 在艾滋病毒感染的联合抗逆转录病毒治疗（cART）时代，临床和科学研究的主要焦点是 研究表明，高风险的心血管疾病，神经认知障碍，肾病， 恶性肿瘤在许多其他非艾滋病并发症。此外，持续的问题，病人非- 遵守和随后的艾滋病毒复制的复苏导致美国国立卫生研究院优先考虑翻译艾滋病毒 研究的重点是查明和根除病毒储存库。在制定战略的同时， 为了识别和逆转潜伏池，必须进行平行的努力，以增强对病毒的免疫防御， 持久性以及重建免疫稳态。这种双重发现和机械论的焦点 一项提案是确定调节免疫的途径、分子靶点和小分子化合物， 保护艾滋病毒患者，其功能受到慢性阿片类药物使用和成瘾的损害。我们 假设T细胞、树突细胞和B细胞的无偏系统生物学评价 转录组将揭示影响HIV的特定分子靶点、途径或特征 持久性和水库大小以及非艾滋病并发症。这一假设的一个重要推论是 慢性阿片类药物成瘾，通过麻醉性止痛药，将扰乱这些网络， 随着艾滋病毒持续存在、储存库大小和全身炎症的增加。这项工作将利用 两个不同的病毒抑制HIV+患者队列（有和没有基于处方的成瘾， 麻醉止痛药Percocet），可在艾弗里博士的诊所在大都会健康医疗中心， 克利夫兰，俄亥俄州，和我们已经特征化的精英控制器队列。工作将围绕 具体目标： 目的1：鉴定CD 8+和CD 4 + T细胞记忆亚群以及先天性细胞中的分子网络， 在阿片类药物成瘾中受到差异调节，在精英控制者（EC）中受到差异调节 能自然控制艾滋病病毒感染 目的2：识别和剖析阿片类药物使用诱导的记忆CD 8+和CD 8+细胞的分子特征， CD 4 + T细胞与炎症、疲劳、免疫衰竭和HIV相关，而这些细胞在免疫缺陷病毒中是不存在的。 基因表达图谱的研究 目标3：开发和评估免疫缺陷和免疫缺陷的阿片类药物使用特异性生物标志物， 共同通知生物信息学方法，以确定重新使用的药物，以扭转改变的 网络. 将我们高度精炼的转录签名应用于生物标志物小组将使我们能够快速地 筛选大量的化合物，因为它们能够拯救阿片类药物使用相关的免疫失调， 来自cART抑制HIV+受试者的非常少量的原代细胞。因此，我们的总体目标是 产生一个治疗目标的药物恢复艾滋病毒免疫功能的细化列表- 需要阿片类药物治疗镇痛的受感染受试者。