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

总结 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 有助于免疫激活。本研究的目的是确定μ阿片受体（莫尔）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， 抑制HIV感染者。我们将通过比较使用阿片类药物的个人来解决这一目标 接受基于μ-阿片受体激动剂的药物辅助治疗（MAT）的疾病（OUD） （美沙酮、丁丙诺啡）或拮抗剂（长效纳洛酮）。根据文献和我们的飞行员 研究中，我们的主要假设是ART抑制了用莫尔进行MAT治疗的OUD患者 与莫尔患者相比，激动剂将维持更大的骨髓活化和HIV持续存在 拮抗剂纳曲酮（长效），由于更大的A）微生物易位; B）免疫激活和 炎症;和C）病毒储库。我们将通过研究三组30名HIV-1感染者来验证这一假设 接受抑制性ART（VL < 50 c/ml，> 12个月）和（1）美沙酮，（2） suboxone，或（3）长效纳洛酮。没有OUD的HIV感染者的对照组也将被 包括.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。评估持续性或阻滞性莫尔的临床、免疫学和病毒学相关性 参与艺术。 A.测定免疫恢复的临床指标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.定义慢性莫尔参与的免疫激活，重点关注骨髓单核细胞 通过在PBMC上使用多参数流式细胞术（16色FACS）在细胞室中进行流式细胞术。 D.确定莫尔参与对HIV持久性的影响（HIV DNA/RNA，诱导型储库）。 E.通过评估莫尔参与对TLR通路的影响，研究莫尔和TLR通路之间的相互作用。 在体外PBMC衍生的巨噬细胞中对TLR（2和4）介导的应答的应答。 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， 在持续或阻断莫尔参与ART后，系统激活的中心决定因素。我们将分析 配对结直肠活检和血液单核细胞： 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细胞转录组学和途径分析 易位措施。 这项研究包括宾夕法尼亚大学，乔纳森拉克斯治疗之间建立合作 中心，西奈山伊坎医学院和Wistar研究所。 ! !

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. ! !