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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。

基本信息

批准号：
9788411
负责人：
David Mitchell Smith
金额：
$ 86.64万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-30 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9788411
关键词：
Absence of pain sensation Acute Address Agonist Anatomy Autopsy Behavior Brain region CCR5 gene CD4 Positive T Lymphocytes CXCR4 gene Cell model Cells Cessation of life Chromatin Chronic Clinical DNA Methylation Data Development Disease Progression Distal part of ileum Drug usage Enrollment Environmental Risk Factor Epidemic Epigenetic Process Exposure to Fentanyl GTP-Binding Proteins Gene Expression Genome Genomics Gifts Goals HIV HIV Infections HIV Receptors Histones Hour Human Immune Immune signaling In Vitro Individual Inguinal lymph node group Interruption Intervention Life Cycle Stages Lymphoid Tissue Maintenance Maps Medical Methylation Modernization Morphine Opioid Opioid agonist Outcome Participant Pathogenesis Pathway interactions Pattern Persons Pharmacology Phase Process Proteomics Receptor Signaling Research Risk Sampling Signal Induction Signal Pathway Signal Transduction Signaling Protein Spleen Stimulus Substance Use Disorder T-Lymphocyte Terminally Ill Testing Therapeutic Tissue Sample Tissues Viral Virus Latency acute infection antiretroviral therapy cell growth regulation cofilin cohort comparative density design epigenetic regulation experience experimental study in vivo innovation insight lymph nodes macrophage monocyte mu opioid receptors novel opioid exposure opioid use preservation reactivation from latency respiratory sample collection transmission process viral rebound

项目摘要

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