Evaluating the role of opioid medication assisted therapies in HIV-1 Persistence for persons living with HIV and opioid use disorders

评估阿片类药物辅助疗法对艾滋病毒感染者和阿片类药物使用障碍患者的 HIV-1 持续存在的作用

• 批准号: 10458790
• 负责人: Ya-Chi Ho
• 金额: $ 81.44万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10458790
• 关键词: Address; Adult; Affect; Agonist; Applications Grants; Architecture; Biological; Blood specimen; Buprenorphine; Cells; Chromatin; Chromatin Conformation Capture and Sequencing; Chromosomes; Chronic; Clonal Expansion; Connecticut; Continuity of Patient Care; DNA analysis; Development; Drug Rehabilitation Centers; FDA approved; Foundations; Frequencies; Future; General Population; Genome; Genome Mappings; Genomics; Goals; Guidelines; HIV; HIV Infections; HIV-1; Harm Reduction; Hi-C; Human; Human Genetics; Human Genome; Immune response; Immunosuppression; Incidence; Individual; Inflammation; Injecting drug user; Intervention Studies; Knowledge; Length; Longitudinal Studies; Measures; Methadone; Methods; Naltrexone; North America; Opioid; Opioid Antagonist; Opioid agonist; Patients; Persons; Pharmaceutical Preparations; Phase; Phylogenetic Analysis; Prevalence; Process; Proviruses; Public Health; RNA; RNA analysis; Receptor Signaling; Relapse; Reporting; Research; Research Personnel; Role; Sampling; Sequence Analysis; Services; Substance Use Disorder; Time; United States; Viral; Whole Blood; Work; antagonist; cohort; heroin use; human genomics; integration site; medication-assisted treatment; method development; mu opioid receptors; next generation sequencing; opioid agonist therapy; opioid use; opioid use disorder; prescription opioid; prospective; recruit; response; transmission process; treatment duration; treatment group; viral genomics

Project Abstract In North America, there were an estimated 267,000 persons living with HIV infection (PLH) among 2 million persons who inject drugs in 2012. Opioids represent the dominant class of injected drug, and in 2013 517,000 adults reported heroin use within the past year, representing an approximately 150% increase compared to 2007. Medication assisted treatments (MAT) in the form of opioid agonist treatment with methadone or buprenorphine, or opioid antagonist treatment in the form of extended-release naltrexone (XR-NTX), together with other harm reduction services have greatly reduced HIV incidence by reducing opioid relapse, and contribute to significant public health improvement. The potential biologic effects of MAT agents on immune responses and chronic inflammation, particularly relevant in PLH with OUD, remain incompletely studied despite a substantial body of evidence for opioid-induced immunosuppression. More importantly, little work if any has evaluated the impact of MAT on HIV latency. We hypothesize that MAT in the form of opioid agonists, including methadone and buprenorphine; reactivate HIV-1 expression, while the opioid antagonist treatment of XR-NTX does not. We further hypothesize that the activation of opioid µ receptor signaling enhances HIV-1 reactivation through changing HIV-1 proviral and host genomic landscape. Using methods familiar to our research groups, we will carry out prospective, longitudinal studies of PLH with OUD starting MAT, recruited from the largest drug treatment centers in New Haven, Connecticut. We will obtain samples of blood at before MAT (day 0), and months 1 and 3 after the start of 3 three different FDA approved forms of MAT. Freshly collected samples of whole blood will be processed to assess HIV-1 RNA analysis, HIV-1 DNA analysis, HIV-1 HI-C and 4C-seq analyses. The R61 phase will be used to develop methods to examine HIV-1 expression, proviral landscape and genomic architecture in response to different forms of MAT among a sample of PLH with OUD. In Aim 1, we will examine HIV-1 expression level through quantitative and phylogenetic sequence analysis. In Aim 2, we will examine HIV-1 proviral landscape using limiting dilution sequencing. In Aim 3, we will examine the host chromosome architecture using Hi-C and HIV-1 4Cseq. If milestones are achieved at the conclusion of the R61 phase, then the R33 phase will be used to examine HIV-1 viral expression, proviral landscape and human genomic architecture among a larger cohort of PLH with OUD before and during treatment with the three forms of MAT using methods developed in the R61 phase. Taken together, we expect these studies to provide new information on the effects of MAT on parameters of HIV latency that should help in the development of guidelines for the selection of specific MAT agents among PLH with OUD. Our combination of expertise in treatment of OUD, HIV-1 latency and human genomics make it highly likely that the proposed studies will achieve a key goal of this RFA: “to yield foundational knowledge that may inform the development of a future HIV cure for patients with SUDs.”

项目摘要 在北美洲，估计200万人中有267 000人感染艾滋病毒 2012年注射毒品的人。类阿片是注射毒品的主要类别，2013年为517，000例， 成年人在过去一年中报告使用海洛因，与2008年相比， 2007.药物辅助治疗（MAT），以美沙酮阿片类激动剂治疗的形式，或 丁丙诺啡或缓释纳洛酮（XR-NTX）形式的阿片类拮抗剂治疗， 通过减少阿片类药物复吸， 有助于显著改善公共卫生。MAT制剂对免疫系统的潜在生物学效应 反应和慢性炎症，特别是与PLH伴OUD相关的反应和慢性炎症， 尽管有大量的阿片类药物诱导的免疫抑制的证据。更重要的是， 任何人都评估了MAT对HIV潜伏期的影响。我们假设MAT以阿片激动剂的形式存在， 包括美沙酮和丁丙诺啡;重新激活HIV-1表达，而阿片类拮抗剂治疗 XR-NTX没有。我们进一步假设阿片受体信号的激活增强了HIV-1 通过改变HIV-1前病毒和宿主基因组景观来重新激活。使用我们熟悉的方法 研究小组，我们将进行前瞻性，纵向研究PLH与OUD开始MAT，招募 康涅狄格州纽黑文市最大的戒毒中心我们将在之前获得血液样本 MAT（第0天），以及开始后的第1个月和第3个月，3种不同的FDA批准的MAT形式。新鲜 将对采集的全血样本进行处理，以评估HIV-1 RNA分析、HIV-1 DNA分析、HIV-1 HI-C和4C-seq分析。R61阶段将用于开发检测HIV-1表达的方法， 前病毒景观和基因组结构对PLH样本中不同形式MAT的响应 关于OUD目的1：通过定量和系统发育序列分析HIV-1的表达水平 分析.在目标2中，我们将使用有限稀释测序检查HIV-1前病毒景观。在目标3中，我们 将使用Hi-C和HIV-1 4Cseq检查宿主染色体结构。如果里程碑在 R61阶段结束后，R33阶段将用于检测HIV-1病毒表达、前病毒 景观和人类基因组结构之间的一个更大的队列PLH与OUD之前和期间 使用R61阶段开发的方法用三种形式的MAT治疗。综合来看，我们预计 这些研究提供了关于MAT对HIV潜伏期参数影响的新信息， 在PLH与OUD之间选择特定MAT剂的指南的发展。我们 结合治疗OUD，HIV-1潜伏期和人类基因组学的专业知识， 拟议的研究将实现本RFA的一个关键目标：“产生基础知识， 为SUD患者开发未来的HIV治疗方法。