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

阿片类药物对 T 细胞通路和表观遗传学的影响，可调节 HIV 整合、潜伏期和储库。

• 批准号: 10424634
• 负责人: David Mitchell Smith
• 金额: $ 86.23万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10424634
• 关键词: Opioid; Impacts; Cell; Pathways; Epigenetics

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.

项目摘要/摘要 这项研究旨在解决RFA的目标“将基因组或核心组信息开发到 了解具有物质使用障碍的人的艾滋病毒潜伏期”，可以“了解艾滋病毒潜伏期 为了应对这一挑战，在R61阶段，我们建议确定 细胞活化途径，表观遗传控制和HIV整合模式之间的二分子相互作用 受到常规阿片类药物吗啡和芬太尼的长期暴露影响。我们也是 提议研究创新G蛋白信号传导的长期暴露是否有偏见的激动剂SR-17018， 预计其中类似的作用化合物可以保留阿片类药物诱导的镇痛并避免呼吸 抑制，引起与常规阿片类药物相似或不同的细胞-HIV改变。这些研究的发现 将为我们的R33期研究提供实验指导。 在R33阶段，我们将利用艾滋病毒患者且最终ill和 在我们表现良好的最后一次礼物队列中，（i）接受了良好的阿片类药物（主要是吗啡） 镇痛病期间，（ii）选择在死亡之前停止治疗，（iii）经历了病毒反弹，并且 （iv）在死后不久（<4小时尸检）提供了整个身体，以推动新颖的艾滋病毒治疗和一个 治愈。最后一次礼物队列中的病毒，细胞和组织样品将用于解决阿片类药物在 体内与在发现的类似激活，基因组，表观遗传和潜伏期改变有关的模式有关 我们研究的R61阶段。此外，我们建议确定在活动期间的慢性阿片类药物暴露在 体内HIV感染在停止抗逆转录病毒治疗时调节HIV多样化的动力学 在循环T细胞和解剖组织中补充HIV储量和HIV整合，例如 各种大脑区域，淋巴结，脾和末端回肠相关淋巴组织。 我们实验完成的R61和R33研究阶段将提供有关机制的见解。 基础绿核酸对艾滋病毒感染和潜伏期的影响，将揭示发展的目标 药理干预措施旨在中断受阿片类药物影响影响的HIV整合和潜伏期。