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 艾滋病毒携带者中的恶性肿瘤(PWH)。虽然正在制定战略来识别和扭转 对于潜在的病毒库，必须同时努力加强对病毒的免疫防御 坚持以及重新建立免疫动态平衡。这一机械性提案的重点是确定 调节HIV患者免疫保护的途径、分子靶点和小分子化合物， 其免疫功能因长期使用阿片类药物而受损。我们假设定义唯一的 阿片受体三种亚型在脑内的生化信号转导途径 人类T淋巴细胞将揭示影响免疫反应性的特定分子靶点 艾滋病毒和艾滋病毒中的系统--阿片类药物使用障碍者。这项工作充分利用了我们最近的发现 G蛋白偶联的cAMP和arrestin相关的丝裂原活化蛋白激酶(MAPK)信号 由内源性、半合成和合成阿片类药物触发的转导通路是独特和独特的 在人类T淋巴细胞中进行调节。今年暑期实习生的项目将聚焦于以下具体目标： NIDA夏季本科生研究实习生的目标1： 识别CD8和CD4T细胞中差异触发的分子信号转导途径 由阿片激动剂，对三种阿片受体中的每一种具有选择性。 我们的总体目标是为免疫的药理学恢复产生一个精炼的治疗靶点清单。 需要阿片类药物止痛的艾滋病毒携带者的功能。

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 persons with HIV (PWH). While strategies are being developed to identify and reverse the latent pool of viral reservoirs, a parallel effort must proceed to enhance immune defenses against viral persistence as well as re-establish immune homeostasis. The focus of this mechanistic proposal is to identify pathways, molecular targets, and small molecule compounds that regulate immune protection in the HIV patient, whose immune function is compromised by chronic opioid use. We hypothesize that defining the unique biochemical signal transduction pathways emanating from all three subtypes of opioid receptors in human T lymphocytes will reveal specific molecular targets that affect the responsiveness of the immune system in HIV+ and HIV- persons with Opioid Use Disorder. This work capitalizes on our recent findings that the G-protein coupled cAMP and the arrestin-associated Mitogen Activated Protein kinase (MAPK) signal transduction pathways triggered by endogenous, semi-synthetic, and synthetic opioids are distinctly and uniquely regulated in human T lymphocytes. This summer intern’s project will focus on the following Specific Aim: Aim 1 for the NIDA Summer Undergraduate Research Intern: Identify molecular signal transduction pathways in CD8+ and CD4+ T cells that are differentially triggered by opioid agonists, selective for each of the three opioid receptors. Our overall goal is to generate a refined list of therapeutic targets for pharmacologic restoration of immune function in persons with HIV that require opioid therapy for analgesia.