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.

项目总结/文摘