Effects of Mu-opiate receptor engagement on the persistence of HIV-associated activation and viral reservoirs in individuals receiving medication assisted treatment for opioid use disorder

Mu-阿片受体参与对接受阿片类药物使用障碍药物辅助治疗的个体中 HIV 相关激活和病毒库持续性的影响

• 批准号: 10621847
• 负责人: Luis J Montaner
• 金额: $ 76.62万
• 依托单位: WISTAR INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10621847
• 关键词: Address; Agonist; Bacterial Translocation; Biopsy; Blood; Blood specimen; Buprenorphine; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cells; Chronic; Clinical; Collaborations; Color; Colorectal; Control Groups; Cytometry; DNA; Data; Development; Disease; Exposure to; Flow Cytometry; Future; Genetic Transcription; HIV; HIV Infections; HIV-1; HLA-DR Antigens; Harm Reduction; Heroin; Immune; Immunologics; Immunophenotyping; In Vitro; Individual; Inflammation; Interferons; Literature; Macrophage; Measures; Mediating; Methadone; Mucous Membrane; Myelogenous; Myeloid Cells; Naltrexone; Needle Sharing; Opioid; Opioid Receptor; Opioid agonist; Participant; Pathway Analysis; Pathway interactions; Pennsylvania; Peripheral Blood Mononuclear Cell; Persons; Pharmaceutical Preparations; Phenotype; Pilot Projects; Plasma; Population; Proviruses; RNA; Recovery; Rectum; Residual state; Role; Serum Markers; Specimen; Structure; Suboxone; T-Cell Activation; T-Lymphocyte; TLR2 gene; Testing; The Wistar Institute; Tissue Sample; Tissues; Toll-like receptors; Transcript; Universities; Viral; Viral reservoir; Virus Replication; Vulnerable Populations; antagonist; antiretroviral therapy; clinical care; cohort; comorbidity; design; high dimensionality; immune activation; insight; intestinal fatty acid binding protein; medical schools; medication-assisted treatment; microbial; monocyte; mortality; mu opioid receptors; novel; novel strategies; opioid use disorder; opioid user; participant enrollment; peripheral blood; prevent; rectal; response; therapy adherence; transcriptomics; treatment center; zonulin

SUMMARY Both HIV disease and chronic exposure to opioids are associated with increased microbial translocation contributing to immune activation. The objective of this study is to determine the role of μ-opioid receptor (MOR) engagement as an independent determinant of levels of immune activation and viral persistence in ART- suppressed HIV-infected individuals. We will address this objective by comparing individuals with opioid use disorder (OUD) receiving medication-assisted treatment (MAT) based on μ-opioid receptor agonists (methadone, buprenorphine) or antagonist (long-acting naltrexone). Based on the literature and our pilot studies, our primary hypothesis is that ART suppressed individuals with OUD under MAT treatment with MOR agonists will maintain greater myeloid activation and HIV persistence when compared to persons under MOR antagonist naltrexone (long-acting) due to greater A) microbial translocation; B) immune activation and inflammation; and C) viral reservoir. We will test this hypothesis by studying three groups of 30 HIV-1 infected individuals with OUD receiving suppressive ART (VL < 50 c/ml for > 12 months) and either (1) methadone, (2) suboxone, or (3) long-acting naltrexone. A control group of HIV-infected individuals without OUD will also be included. We will use blood and rectal mucosa specimens derived from out participants to: Specific Aim 1. Assess the clinical, immunological and virological correlates of sustained or blocked MOR engagement on ART. A. Determine clinical parameters of immune recovery and serum markers of chronic inflammation. B. Establish the extent of microbial translocation and mucosal integrity. C. Define immune activation with chronic MOR engagement, with a focus on the myelo-mononocytic compartment, using multiparameter flow cytometry (16-color FACS) on PBMC. D. Establish the effect of MOR engagement on HIV persistence (HIV DNA/RNA, inducible reservoirs). E. Study the interplay between MOR and TLR pathways by assessing the effect of MOR engagement on the response to TLR (2 and 4)-mediated responses in PBMC-derived macrophages in vitro. Specific Aim 2. Determine gut tissue immune cell distribution and myeloid cell transcriptional modulation as a central determinant of systemic activation upon sustained or blocked MOR engagement on ART. We will analyze paired colorectal biopsies and blood monocytes to: A. Define the phenotype and functional state of the GALT (colorectal mucosa biopsies) using CyTOF B. Define single cell myeloid and T-cell transcriptomic and pathway analysis in relation to microbial translocation measures. This study includes established collaboration between the University of Pennsylvania, Jonathan Lax Treatment Center, The Icahn School of Medicine at Mount Sinai, and The Wistar Institute. ! !

概括 HIV疾病和长期暴露于阿片类药物都与微生物易位增加有关 导致免疫激活。这项研究的目的是确定μ阿片受体（MOR）的作用 参与作为独立确定的免疫激活水平和艺术中的病毒持久性水平 受抑制的艾滋病毒感染者。我们将通过比较个人使用阿片类药物的使用来解决这一目标 基于μ阿片接收器激动剂接受药物辅助治疗（MAT）的疾病（OUD） （美沙酮，丁丙诺啡）或拮抗剂（长效纳曲酮）。根据文献和我们的飞行员 研究，我们的主要假设是，ART抑制了用MOR治疗的OUD的个体 与MOR下的人相比，激动剂将保持更大的髓样激活和HIV持久性 拮抗剂纳曲酮（长效）是由于较大的a）微生物易位； b）免疫激活和 炎;和c）病毒库。我们将通过研究30组HIV-1感染的三组来检验这一假设 OUD接受抑制作用的人（VL <50 c/ml> 12个月）和（1）Meadadone，（2） 亚智酮，或（3）长效纳曲酮。一个没有OUD的艾滋病毒感染者的对照组也将是 包括。我们将使用从参与者获得的血液和直肠粘膜标本： 特定目的1。评估持续或阻塞的临床，免疫学和病毒学相关性 参与艺术。 A.确定免疫发现的临床参数和慢性炎症的血清标记。 B.确定微生物易位和粘膜完整性的程度。 C.通过慢性MOR参与定义免疫激活，重点是髓鞘细胞 隔室，使用PBMC上的多参数流式细胞仪（16色FACS）。 D.建立MOR参与对HIV持久性的影响（HIV DNA/RNA，诱导储层）。 E.通过评估MOR参与对MOR和TLR途径之间的相互作用 对TLR（2和4）介导的PBMC衍生巨噬细胞的反应的反应。 具体目标2。确定肠道组织免疫细胞分布和髓样细胞转录调节作为A 在持续或阻止MOR参与艺术的情况下，集中确定全身激活。我们将分析 配对的结直活检和血单核细胞： 答：使用Cytof定义Galt（结直肠粘膜活检）的表型和功能状态 B.定义与微生物有关的单细胞髓样和T细胞转录组和途径分析 易位措施。 这项研究包括宾夕法尼亚大学乔纳森·洛克斯治疗之间的合作 中心，西奈山的伊坎医学院和维斯塔尔研究所。 呢 呢