Morphine Alters Systemic Responses to SIV Infection of Rhesus Monkeys and Changes Brain Macrophage and Microglia Gene Expression Favoring Neuropathogenesis

In this study, we investigated longitudinal changes in response to SIV infection of rhesus monkeys in the presence of morphine, compared to animals administered saline, before and after cART treatment. Using single-cell and single-nucleus RNA sequencing (scRNA-seq and snRNA-seq), we examined the effect of morphine on brain-resident macrophages and microglia in these SIV-infected, cART-suppressed animals to better understand the factors responsible for the morphine-induced increased CNS reservoir and the role of opioids in neuropathogenesis. We probed systemic parameters as well as performed single-cell examination of the targets for infection in the brain, microglia and macrophages to investigate the interaction of morphine and SIV to identify novel host specific immune and neurological pathologies. Morphine treatment created an immunosuppressive environment, blunting initial responses to SIV infection which persisted during suppressive antiretroviral drug (ARV) therapy. ARV concentrations and penetration into the cerebrospinal fluid and brain were unchanged by morphine. However, in microglia and brain macrophages, their transcriptional signature was transformed to a neurodegenerative phenotype.

本研究针对暴露于吗啡的恒河猴猴免疫缺陷病毒（Simian Immunodeficiency Virus, SIV）感染应答的纵向变化展开探究，并与给予生理盐水的对照组动物进行对比，实验覆盖联合抗反转录病毒治疗（combined antiretroviral therapy, cART）前后的全阶段。本研究借助单细胞RNA测序（single-cell RNA sequencing, scRNA-seq）与单细胞核RNA测序（single-nucleus RNA sequencing, snRNA-seq）技术，对经SIV感染且接受cART病毒抑制的动物体内，吗啡对脑组织驻留巨噬细胞与小胶质细胞的影响进行分析，以期更深入阐明吗啡诱导中枢神经系统（Central Nervous System, CNS）病毒库扩增的相关机制，以及阿片类物质在神经发病机制中的作用。我们同时检测了全身系统性指标，并针对脑部感染靶点——小胶质细胞与巨噬细胞开展单细胞分析，以探究吗啡与SIV的相互作用，进而发掘全新的宿主特异性免疫与神经病理改变。吗啡给药可构建免疫抑制微环境，削弱机体针对SIV感染的初始应答，且该效应在抑制性抗反转录病毒药物（antiretroviral drug, ARV）治疗期间仍持续存在。吗啡不会改变ARV在脑脊液与脑组织中的浓度及穿透效率。但在小胶质细胞与脑组织巨噬细胞中，其转录特征会被重塑为神经退行性表型。