The impact of naltrexone treatment on opioid-induced immune and viral dysregulation during HIV-infection

纳曲酮治疗对 HIV 感染期间阿片类药物引起的免疫和病毒失调的影响

基本信息

批准号：
10452590
负责人：
Christina Louise Lancioni
金额：
$ 61.34万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
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 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10452590
关键词：
Acquired Immunodeficiency Syndrome Address Animal Model Animals Anti-Inflammatory Agents Attenuated Binding Biological Assay Blood Coagulation Disorders Buprenorphine CD4 Positive T Lymphocytes Caring Cell physiology Cell surface Cessation of life Chronic Clinical Complex Consequences of HIV DNA Data Disease Disease Management Epidemiology Exhibits Exposure to Flow Cytometry Frequencies Funding HIV HIV Budding HIV Infections Health Immune Immune System Diseases Immune system Immunologic Markers In Vitro Individual Inflammation Inflammatory Response Intervention Intestinal permeability Intestines Lipopolysaccharides Measures Mediating Medical Messenger RNA Methadone MicroRNAs Morbidity - disease rate Naloxone Naltrexone National Institute of Drug Abuse Opioid Opioid Antagonist Opioid Receptor Opioid agonist Outcome Participant Pathway interactions Persons Pharmaceutical Preparations Phase Phenotype Plasma Population Production Property Proviruses Public Health Publishing Randomized Randomized Clinical Trials Recording of previous events Regulation Rest Risk Sampling Sepsis Substance Addiction Substance Use Disorder Substance abuse problem T-Cell Activation T-Lymphocyte T-Lymphocyte Subsets TLR4 gene Techniques Transcriptional Regulation Translations Viral Virion antiretroviral therapy base chemokine cohort cytokine exhaustion gag Gene Products immune activation immune function improved in vitro Model innovation miRNA expression profiling microbial monocyte mortality next generation sequencing novel opioid exposure opioid use opioid use disorder response secondary infection systemic inflammatory response treatment as usual treatment strategy

项目摘要

PROJECT SUMMARY Chronic opioid use among people living with HIV (PLHIV) is an on-going public health crisis. The interplay between opioids and HIV may accelerate HIV-associated immune dysregulation, chronic inflammation and coagulopathy, and predispose to AIDS and non-AIDS related mortality and morbidities. Published data from in vitro and animal models demonstrate that, in addition to their interactions with opioid receptors, opioids directly bind and activate Toll-like Receptor-4 (TLR-4), promote intestinal damage and microbial translocation, interfere with regulation of lipopolysaccharide (LPS)-induced inflammation, and facilitate HIV replication. Our own preliminary data support that opioid use is associated with advanced immune activation and dysregulated responses to LPS among PLHIV. We hypothesize that opioid exposure disrupts homeostatic anti-inflammatory miRNAs that normally limit TLR-4 mediated monocyte activation in response to LPS, leading to chronic innate immune activation and dysfunction. We propose that opioid exposure will be associated with evidence of advanced intestinal permeability, HIV-associated T cell activation and exhaustion, coagulopathy, and compromised antiviral capacity. In this proposal, we will capitalize on our access to longitudinal clinical samples from PLHIV who also suffer from opioid-use disorders (HIV+/OUD+), who are participating in an independent phase IIb randomized clinical trial (CTN-067) to determine optimal management of combined HIV infection and OUD. Trial participants will receive antiretroviral therapy (ART) plus 6 months of OUD therapy with either 1) the long-acting opioid-antagonist extended release naltrexone (XR-NTX); or 2) treatment-as- usual (TAU) with opioid-agonists. Based on published findings from in vitro and animal models, we propose that XR-NTX will be associated with significant reductions in gut permeability, immune activation and exhaustion, coagulopathy, and gains in T cell anti-viral capacity (Aim 1); will restore miRNAs that normally regulate LPS-induced immune activation (Aim 2); and will promote early viral control and reduction of the inducible HIV reservoir (Aim 3). To address these aims, we will use samples collected from CTN-067 trial participants (N=350), as well as a reference cohort of PLHIV with no history of substance dependency or opioid exposure (HIV+/OUD-; N=100). We will employ advanced techniques including: an ultrasensitive electrochemiluminescence-based platform to measure plasma cytokines; next generation sequencing (NGS) of miRNA and mRNA from resting and LPS-stimulated monocytes; a Tat/rev Induced Limiting Dilution Assay (TILDA) to quantify seeding of the inducible provirus reservoir; and a novel flow cytometry assay to quantify CD4+ T cell subsets that contain provirus expressing the gag protein and new budding cell surface virions. We hope to identify an OUD treatment strategy that simultaneously ameliorates immune dysregulation and promotes viral control; if successful, our findings would provide an innovative pathway to disease management in PLHIV both with and without OUD.

项目概要艾滋病毒感染者（PLHIV）长期使用阿片类药物是一场持续的公共卫生危机。相互作用阿片类药物和艾滋病毒之间的相互作用可能会加速艾滋病毒相关的免疫失调、慢性炎症和凝血障碍，并易患艾滋病和非艾滋病相关的死亡和发病。发布的数据来自体外和动物模型表明，除了与阿片受体相互作用外，阿片类药物还直接结合并激活 Toll 样受体 4 (TLR-4)，促进肠道损伤和微生物易位，干扰调节脂多糖 (LPS) 诱导的炎症，并促进 HIV 复制。我们自己的初步数据支持阿片类药物的使用与高级免疫激活和失调有关 PLHIV 患者对 LPS 的反应。我们假设阿片类药物暴露会破坏体内平衡抗炎作用通常限制 TLR-4 介导的单核细胞响应 LPS 激活的 miRNA，导致慢性先天性免疫激活和功能障碍。我们建议阿片类药物暴露与以下证据相关：肠道通透性增强、HIV 相关 T 细胞激活和耗竭、凝血障碍和抗病毒能力受损。在本提案中，我们将利用我们对纵向临床的访问来自同时患有阿片类药物使用障碍 (HIV+/OUD+) 的艾滋病病毒感染者的样本，他们正在参加一项独立的 IIb 期随机临床试验 (CTN-067) 以确定合并 HIV 的最佳管理感染和 OUD。试验参与者将接受抗逆转录病毒治疗 (ART) 加上 6 个月的 OUD 治疗 1) 长效阿片拮抗剂缓释纳曲酮 (XR-NTX)；或 2) 治疗-- 通常（TAU）与阿片类激动剂一起使用。根据已发表的体外和动物模型研究结果，我们建议 XR-NTX 与肠道通透性、免疫激活和肠道通透性显着降低有关疲劳、凝血障碍和 T 细胞抗病毒能力增强（目标 1）；将恢复正常情况下的 miRNA 调节 LPS 诱导的免疫激活（目标 2）；并将促进早期病毒控制和减少诱导型 HIV 储存库（目标 3）。为了实现这些目标，我们将使用从 CTN-067 试验中收集的样本参与者（N = 350），以及没有物质依赖史或阿片类药物暴露（HIV+/OUD-；N=100）。我们将采用先进技术，包括：基于电化学发光的血浆细胞因子测量平台；下一代测序（NGS）来自静息和 LPS 刺激的单核细胞的 miRNA 和 mRNA； Tat/rev 诱导的限制稀释测定（TILDA）量化诱导型原病毒库的接种；以及一种新颖的流式细胞术定量分析 CD4+ T 细胞亚群包含表达 gag 蛋白的原病毒和新的出芽细胞表面病毒粒子。我们希望找到一种 OUD 治疗策略，同时改善免疫失调和促进病毒控制；如果成功，我们的研究结果将为疾病管理提供一条创新途径在有或没有 OUD 的 PLHIV 中。