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

摘要 在艾滋病毒感染的联合抗逆转录病毒治疗(CART)时代，临床和科学的主要焦点 调查显示心血管疾病、神经认知障碍、肾病和 恶性肿瘤是许多其他非艾滋病并发症之一。此外，持续存在的问题与患者非 遵从性和随后艾滋病毒复制的死灰复燃导致美国国立卫生研究院优先考虑翻译艾滋病毒 研究的重点是确定和根除病毒库。在制定战略的同时 为了识别和逆转潜伏池，必须同时努力增强对病毒的免疫防御。 坚持以及重新建立免疫动态平衡。这种双重发现和机械论的焦点 建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。我们 假设T细胞、树突状细胞和B细胞的无偏系统生物学评估 转录组将揭示影响艾滋病毒的特定分子靶点、途径或签名 持久性和储存库大小以及非艾滋病并发症。这一假设的一个关键推论是 慢性阿片成瘾，通过麻醉性止痛药，将扰乱这些网络和联系 艾滋病毒持久度、储存库大小和全身炎症增加。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 麻醉性止痛药Perdicet)，可在#年MetroHealth医疗中心艾弗里医生的诊所获得 克利夫兰，俄亥俄州，以及我们已经具有特色的精英管制员队列。这项工作将围绕 以下是具体目标： 目的1：鉴定CD8和CD4T细胞记忆亚群以及天然细胞中的分子网络， 在阿片成瘾方面有不同的调控，而在精英控制者(EC)中是相互调控的 自然地控制艾滋病毒感染。 目的2：识别和剖析阿片类药物在记忆CD8和CD8中诱导的分子特征 与炎症、衰竭、免疫衰竭和HIV相关的CD4T细胞，这些细胞在 精英控制员的基因表达图谱。 目的3：利用免疫缺陷和免疫缺陷的特定生物标志物开发和评估离散阿片类药物 共病为生物信息学方法提供信息，以识别改变用途的药物以逆转改变 网络。 将我们高度精致的转录签名应用到Biomarker小组将使我们能够迅速 筛选大量化合物以观察它们拯救阿片类药物使用相关免疫失调的能力 来自CART的非常少量的原代细胞抑制了HIV受试者。因此，我们的总体目标是 为艾滋病病毒免疫功能的药物恢复制定一份精细化的治疗靶点清单- 需要阿片类药物止痛治疗的感染者。

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.