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: 10416609
• 负责人: Ya-Chi Ho
• 金额: $ 83.85万
• 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 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10416609
• 关键词: Evaluating; role; opioid; medication; assisted

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，200 万人中估计有 267,000 人感染艾滋病毒 (PLH) 2012 年注射毒品者人数。阿片类药物是注射毒品的主要类别，2013 年为 517,000 人 成年人报告在过去一年内吸食海洛因，与成人相比增加了约 150% 2007. 药物辅助治疗 (MAT)，采用阿片类激动剂联合美沙酮或 丁丙诺啡或阿片类拮抗剂以缓释纳曲酮 (XR-NTX) 的形式一起治疗 与其他减少伤害服务一起通过减少阿片类药物复发大大降低了艾滋病毒发病率，并且 为显着改善公共卫生作出贡献。 MAT 制剂对免疫的潜在生物学效应 反应和慢性炎症，特别是与 OUD PLH 相关的反应和慢性炎症，仍未得到完整研究 尽管有大量证据表明阿片类药物会引起免疫抑制。更重要的是，如果 任何人都评估了 MAT 对 HIV 潜伏期的影响。我们假设 MAT 以阿片类激动剂的形式存在， 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 µ 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，我们将使用 OUD 开展 PLH 的前瞻性纵向研究，开始 MAT，招募 来自康涅狄格州纽黑文最大的戒毒治疗中心。我们将在之前获取血液样本 MAT（第 0 天），以及 3 种 FDA 批准的不同 MAT 形式开始后的第 1 个月和第 3 个月。新鲜地 收集的全血样本将被处理以评估 HIV-1 RNA 分析、HIV-1 DNA 分析、HIV-1 HI-C 和 4C-seq 分析。 R61阶段将用于开发检查HIV-1表达的方法， PLH 样本中不同形式 MAT 的前病毒景观和基因组结构 与沉香木。在目标 1 中，我们将通过定量和系统发育序列检查 HIV-1 表达水平 分析。在目标 2 中，我们将使用有限稀释测序来检查 HIV-1 前病毒状况。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。如果在 R61阶段结束后，R33阶段将用于检查HIV-1病毒表达、原病毒 一大群患有 OUD 的 PLH 之前和期间的景观和人类基因组结构 使用 R61 阶段开发的方法进行三种形式的 MAT 治疗。综合起来，我们期望 这些研究提供了关于 MAT 对 HIV 潜伏期参数影响的新信息，这应该有助于 制定在患有 OUD 的 PLH 中选择特定 MAT 药物的指南。我们的 结合 OUD 治疗、HIV-1 潜伏期和人类基因组学方面的专业知识，很有可能 拟议的研究将实现本次 RFA 的一个关键目标：“产生可以为人们提供信息的基础知识 为 SUD 患者开发未来的 HIV 治疗方法。”