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: 10406244
• 负责人: Luis J Montaner
• 金额: $ 92.56万
• 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 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10406244
• 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; Enrollment; Exposure to; Flow Cytometry; Future; Genetic Transcription; HIV; HIV Infections; HIV-1; HLA-DR Antigens; Harm Reduction; Heroin Abuse; Immune; Immunologics; Immunophenotyping; In Vitro; Individual; Inflammation; Interferons; Literature; 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; 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; base; clinical care; cohort; comorbidity; design; high dimensionality; immune activation; insight; intestinal fatty acid binding protein; macrophage; medical schools; medication-assisted treatment; microbial; monocyte; mortality; mu opioid receptors; novel; novel strategies; opioid use disorder; opioid user; 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 疾病和长期接触阿片类药物都与微生物易位增加有关 本研究的目的是确定 μ-阿片受体 (MOR) 的作用。 参与作为 ART 中免疫激活水平和病毒持久性的独立决定因素 我们将通过比较使用阿片类药物的个体来实现这一目标。 接受基于 μ-阿片受体激动剂的药物辅助治疗 (MAT) 的疾病 (OUD) （美沙酮、丁丙诺啡）或拮抗剂（长效纳曲酮）基于文献和我们的试点。 研究中，我们的主要假设是 ART 抑制了接受 MOR MAT 治疗的 OUD 个体 与 MOR 患者相比，激动剂将维持更高的骨髓激活和 HIV 持久性 拮抗剂纳曲酮（长效）归因于 A) 微生物易位 B) 免疫激活； 我们将通过研究三组 30 名 HIV-1 感染者来检验这一假设。 患有 OUD 的个体接受抑制性 ART（VL < 50 c/ml，持续 > 12 个月）和 (1) 美沙酮，(2) suboxone 或 (3) 长效纳曲酮 对照组的 HIV 感染者也将不使用 OUD。 我们将使用来自参与者的血液和直肠粘膜样本来： 具体目标 1. 评估持续或阻断 MOR 的临床、免疫学和病毒学相关性 参与艺术。 A. 确定免疫恢复的临床参数和慢性炎症的血清标志物。 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，重点关注骨髓单核细胞 室，使用多参数流式细胞术（16 色 FACS）对 PBMC 进行检测。 D. 确定 MOR 参与对 HIV 持久性的影响（HIV DNA/RNA，诱导型储存库）。 E. 通过评估 MOR 参与对 MOR 和 TLR 通路之间的相互作用 体外对 PBMC 衍生巨噬细胞中 TLR（2 和 4）介导的反应的反应。 具体目标 2. 确定肠道组织免疫细胞分布和骨髓细胞转录调节作为 我们将分析持续或阻断 MOR 参与 ART 时系统激活的核心决定因素。 将结直肠活检和血液单核细胞配对： A. 使用 CyTOF 定义 GALT（结直肠粘膜活检）的表型和功能状态 B. 定义与微生物相关的单细胞骨髓和 T 细胞转录组和通路分析 易位措施。 这项研究包括宾夕法尼亚大学 Jonathan Lax Treatment 之间建立的合作 中心、西奈山伊坎医学院和威斯塔研究所。 ！ ！