Opioid Impacts on T Cell Pathways and Epigenetics to Modulate HIV Integration, Latency and Reservoirs.

项目概要/摘要 这项研究旨在解决RFA的目标“利用基因组或核组信息， 了解艾滋病毒潜伏期的个人与物质使用障碍”，可以“了解艾滋病毒潜伏期， 有物质使用障碍的人。“为了应付这项挑战，在R61阶段，我们建议找出 细胞活化途径、表观遗传控制和HIV整合模式之间的生物分子相互作用 长期暴露于传统阿片类药物吗啡和芬太尼的影响。我们也 建议研究是否长期暴露于一种创新的G蛋白信号传导偏向激动剂SR-17018， 其中类似的作用化合物被预测保留阿片样物质诱导的镇痛作用并避免呼吸抑制。 抑制，导致类似或不同的细胞-HIV的改变作为传统的阿片类药物。这些研究的结果 将为我们的R33阶段研究提供实验指导。 在R33阶段，我们将利用艾滋病毒感染者和绝症患者的临床样本， 在我们的特征良好的最后礼物队列中：（i）接受特征良好的阿片类药物（主要是吗啡）， （ii）在他们生病期间选择止痛，（iii）在他们死亡之前选择停止他们的治疗，（iii）经历了病毒反弹，以及 (iv)他们在死后不久（不到4小时尸检）提供了整个身体，以推进新的艾滋病毒治疗， 疗方来自最后一份礼物队列的病毒、细胞和组织样本将用于研究阿片类药物暴露是否与 在体内与发现的类似的激活模式、基因组、表观遗传和潜伏期改变相关， 我们研究的R61阶段。此外，我们建议确定是否慢性阿片类药物暴露期间积极的， 体内艾滋病毒感染在停止抗逆转录病毒治疗后调节艾滋病毒多样化的动态， HIV库的补充和HIV在循环T细胞和解剖组织中的整合，例如 各种脑区、淋巴结、脾和末端回肠相关淋巴组织。 我们的实验互补R61和R33研究阶段将提供机制的见解 阿片类药物对艾滋病毒感染和潜伏期的影响，并将揭示发展的目标， 药物干预旨在中断受阿片类药物使用影响的HIV整合和潜伏期。

Project Summary/Abstract This study is designed to address the goals of the RFA “Exploiting Genomic or Nucleomic Information to Understand HIV Latency in Individuals with Substance Use Disorders” that can “understand HIV latency in individuals with substance use disorders." To meet this challenge, in the R61 phase, we propose to identify the biomolecular interactions between cellular activation pathways, epigenetic controls, and HIV integration patterns that are impacted by chronic exposure from the conventional opioid therapeutics morphine and fentanyl. We also propose to investigate whether chronic exposure of an innovative G protein signaling biased agonist SR-17018, of which similar acting compounds are predicted to preserve opioid-induced analgesia and avoid respiratory suppression, cause similar or distinct cell-HIV alterations as conventional opioids. Findings from these studies will provide experimental guidance for our R33 phase studies. In the R33 stage, we will utilize clinical samples available from persons with HIV and who are terminally-ill and in our well-characterized Last Gift cohort and: (i) received well-characterized opioids (primarily morphine) for analgesia during their illness, (ii) choose to stop their therapy before they die, (iii) experienced viral rebound, and (iv) provided their entire bodies soon after death (<4 hours to autopsy) to advance novel HIV treatments and a cure. Viral, cell, and tissue samples from the Last Gift cohort will be used to address whether opioid exposure in vivo is associated with similar patterns of activation, genomic, epigenetic, and latency alterations uncovered in the R61 phase of our studies. Furthermore, we propose to determine if chronic opioid exposure during active in vivo HIV infection modulates dynamics of HIV diversification upon halting of anti-retroviral treatment and alters replenishment of the HIV reservoir and HIV integration in circulating T cells and anatomical tissues, such as various brain regions, lymph nodes, spleen and terminal ileum associated lymphoid tissues. Our experimentally complementary R61 and R33 research stages will provide insights into mechanism(s) underlying the effects of opioids on HIV infection and latency and will reveal targets for development of pharmacologic interventions aimed to interrupt HIV integration and latency impacted by opioid use.