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: 9927835
• 负责人: Alan David Levine
• 金额: $ 7.06万
• 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/9927835
• 关键词: AIDS/HIV problem; Absence of pain sensation; Affect; Analgesics; Anti-Retroviral Agents; Antiviral Agents; B-Lymphocytes; Big Data; Bioinformatics; Biological; Blood; British Columbia; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Cardiovascular Diseases; Cell physiology; Cells; Cellular Immunity; Chronic; Clinic; Clinical; Collaborations; Communities; Comorbidity; Complex; Computational algorithm; Computer Analysis; Data; Data Analyses; Dendritic Cells; Disease; Evaluation; Event; Expression Profiling; Failure; Gene Expression; Gene Expression Profile; Goals; HIV; HIV Infections; Homeostasis; Human; Immune; Immune System Diseases; Immune system; Immunologic Markers; Immunologist; Immunotherapy; Individual; Inflammation; Interleukin-2; Interruption; Intestines; Investigation; Kidney Diseases; Lead; Life; Liver diseases; Malignant Neoplasms; Measurement; Medical; Medical center; Memory; Minority; Molecular; Molecular Profiling; Molecular Target; Morbidity - disease rate; Mucous Membrane; Narcotic Addiction; Narcotics; National Institute of Drug Abuse; Neurocognitive Deficit; Ohio; Opiate Addiction; Opioid user; Participant; Pathway interactions; Patient Noncompliance; Patients; Percocet; Pharmaceutical Preparations; Pharmacology; Phosphorylation; Population; Production; Recovery; Research; SIV; Social support; System; Systems Biology; T memory cell; T-Cell Proliferation; T-Cell Receptor; T-Lymphocyte; T-Lymphocyte Subsets; United States; United States National Institutes of Health; Viral; Viral reservoir; Virus; Virus Replication; Work; addiction; antiretroviral therapy; base; biological systems; biomarker panel; cardiovascular disorder risk; cardiovascular risk factor; chronic pain; cohort; comparative; delta opioid receptor; exhaustion; experience; high risk; human disease; immune function; innovation; memory CD4 T lymphocyte; mortality; neurocognitive disorder; new therapeutic target; non-opioid analgesic; nonhuman primate; novel; opioid therapy; opioid use; response; restoration; small molecule; specific biomarkers; therapeutic target; transcriptome; transcriptomics

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 在抗逆转录病毒疗法（CART）的时代，用于HIV感染，这是临床和科学的主要重点 调查在于心血管疾病，神经认知疾病，肾病和 许多其他非辅助并发症中的恶性肿瘤。此外，患者持续存在问题 合规性和随后的艾滋病毒复制复制使NIH优先考虑转化艾滋病毒 研究的重点是对病毒储层的识别和化合物。在制定策略时 为了识别和扭转潜在池，必须采取平行的努力来增强对病毒的免疫防御能力 持久性以及重新建立免疫稳态。这个双重发现和机械的重点 建议是鉴定调节免疫的途径，分子靶标和小分子化合物 艾滋病毒患者的保护，其功能受到慢性阿片类药物的使用和成瘾的损害。我们 假设T细胞，树突细胞和B细胞的无偏系统生物学评估 转录组将揭示影响HIV的特定分子靶，途径或特征 持久性和储层大小以及非AID并发症。该假设的关键推论是 通过麻醉止痛药物的慢性阿片类药物成瘾将使这些网络扰动并关联 随着HIV持久性，储层大小和全身注射的增加。这项工作将利用 在两种不同抑制的艾滋病毒+患者的同类群体中（有和没有处方的成瘾 麻醉性止痛药percocet），可在Avery博士的诊所的Metrohealth Medical Center的诊所获得 俄亥俄州的克利夫兰，我们已经描述了精英控制器的队列。工作将集中在 遵循特定目的： AIM 1：确定CD8+和CD4+ T细胞存储器子集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调节，在精英控制器（EC）中受到相互调节 自然控制HIV感染。 AIM 2：识别和剖析在记忆CD8+和 与注射，疲惫，免疫失败和HIV相关的CD4+ T细胞，在 来自精英控制器的基因表达谱。 AIM 3：开发和评估离散的Ooid使用免疫缺陷的特定生物标志物和 合并症，以告知生物信息学方法以识别重新利用的药物以扭转变化 网络。 我们高度精制的转录签名应用于生物标志物面板将使我们迅速 筛选大量化合物，以挽救与阿片类药物相关的免疫失调的能力 来自CART的主要细胞抑制了HIV+受试者。那，我们的总体目标是 生成精致的治疗靶标，以恢复HIV中免疫功能的药物恢复 需要阿片类药物治疗的受试者进行镇痛。