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。 HIV 感染者 (PWH) 中的恶性肿瘤。虽然正在制定战略来识别和扭转 潜在的病毒库，必须同时努力增强针对病毒的免疫防御 持久性以及重新建立免疫稳态。该机制提案的重点是确定 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到损害。我们假设定义独特的 来自阿片受体所有三种亚型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的特定分子靶标 艾滋病毒和阿片类药物使用障碍患者的系统。这项工作利用了我们最近的发现： G 蛋白偶联的 cAMP 和抑制蛋白相关的丝裂原激活蛋白激酶 (MAPK) 信号 内源性、半合成和合成阿片类药物触发的转导途径是独特的 在人类 T 淋巴细胞中受到调节。今年暑期实习生的项目将重点关注以下具体目标： NIDA 暑期本科生研究实习生的目标 1： 识别 CD8 和 CD4 T 细胞中差异触发的分子信号转导途径 通过阿片受体激动剂，对三种阿片受体中的每一种都有选择性。 我们的总体目标是生成一份详细的治疗靶点清单，用于免疫药理学恢复 需要阿片类药物镇痛治疗的艾滋病毒感染者的功能。

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.