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

项目摘要/摘要 这项研究旨在解决RFA的目标：利用基因组或核基因组信息 了解物质使用障碍患者的HIV潜伏期 为了迎接这一挑战，在R61阶段，我们建议确定 细胞激活途径、表观遗传控制和HIV整合模式之间的生物分子相互作用 受长期接触传统阿片类药物吗啡和芬太尼的影响。我们也 建议调查慢性暴露于一种创新的G蛋白信号偏向激动剂SR-17018， 其中类似的作用化合物被预测为保存阿片类药物诱导的镇痛和避免呼吸 抑制，引起与常规阿片类药物类似或不同的细胞艾滋病毒改变。这些研究的发现 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携带者和绝症患者提供的临床样本， 在我们特征良好的Last Gift队列中：(I)收到特征良好的阿片类药物(主要是吗啡) (Ii)选择在他们死前停止治疗，(Iii)经历病毒反弹，以及 (四)在死亡后不久提供全身(&lt；4小时尸检)，以推进新的艾滋病毒治疗和 解药。来自Last Gift队列的病毒、细胞和组织样本将被用来解决阿片类药物在 VIVO与类似的激活、基因组、表观遗传和潜伏期改变模式相关，在 我们研究的R61阶段。此外，我们建议确定在活动期间慢性阿片类药物暴露是否 体内HIV感染在抗逆转录病毒治疗停止和改变时调节HIV多样化的动态 补充艾滋病毒储存库和在循环T细胞和解剖组织中整合艾滋病毒，例如 各种脑区、淋巴结、脾和回肠末端相关淋巴组织。 我们的实验互补的R61和R33研究阶段将提供对机制的见解(S) 阿片类药物对艾滋病毒感染和潜伏期的影响，并将揭示开发目标 药物干预旨在中断受阿片类药物使用影响的艾滋病毒整合和潜伏期。

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.