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

摘要 艾滋病毒疾病和长期接触阿片类药物都与微生物移位增加有关 有助于免疫激活。本研究的目的是确定μ-阿片受体(MOR)的作用 参与作为ART中免疫激活和病毒持久性水平的独立决定因素- 被压制的艾滋病毒感染者。我们将通过比较使用阿片类药物的个体来解决这一目标 接受基于μ-阿片受体激动剂的药物辅助治疗(MAT)的障碍(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，在MAT治疗下，ART抑制了MOR治疗下的OUD患者 与处于MOR状态下的人相比，激动剂将保持更大的髓系激活和HIV持久性 拮抗剂纳曲酮(长效)，原因是A)微生物易位；B)免疫激活和 炎症；以及C)病毒库。我们将通过研究三组30名HIV-1感染者来验证这一假设 患有OUD的患者接受抑制ART(VL&lt；50c/ml，为期12个月)和(1)美沙酮，(2) 亚伯酮，或(3)长效纳曲酮。没有艾滋病病毒感染者的对照组也将被 包括在内。我们将使用来自外部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 对艺术的投入。 A.测定免疫恢复的临床参数和慢性炎症的血清标志物。 B.确定微生物移位和粘膜完整性的程度。 C.将免疫激活定义为慢性MOR参与，重点是骨髓单核细胞 用多参数流式细胞仪(16色FACS)对PBMC进行检测。 D.确定MOR参与对艾滋病毒持久性的影响(艾滋病毒DNA/RNA，可诱导的储存库)。 E.通过评估MOR参与对TLR通路的影响来研究MOR和TLR通路之间的相互作用 PBMC来源的巨噬细胞对TLR(2和4)介导的反应的体外反应。 特定目的2.确定肠道组织免疫细胞分布和髓系细胞转录调控作为 持续或阻断MOR参与抗逆转录病毒治疗时全身激活的中心决定因素。我们将分析 将大肠活检和单核细胞配对以： A.用细胞免疫荧光技术确定大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细胞和T细胞转录和通路分析 移位措施。 这项研究包括宾夕法尼亚大学与乔纳森·拉克斯治疗的合作 中心、西奈山伊坎医学院和维斯塔尔研究所。 好了！ 好了！

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. ! !