Pathogenesis of Neuroinflammation and Neurocognitive Impairment In HIV-infected Young Adult Cannabis Users

项目摘要 HIV相关的神经认知障碍（HAND）和神经认知障碍（NCI）仍然是长期的， 尽管有有效的抗逆转录病毒治疗（ART），艾滋病毒感染的并发症。即使在早期艾滋病毒感染和 年轻人占新艾滋病毒感染者的37%，HAND影响日常功能， 发病率HAND在年轻人中的这种影响将影响全世界劳动力的生产力。目前， 我们对HIV感染者（PLWH）HAND发病机制的认识仍然有限， 存在经验证的生物标志物来诊断和管理NCI。据信，手是由持续的 神经炎症不幸的是，越来越多的证据表明炎症是由滥用药物调节的， 包括艾滋病病毒携带者的首选药物：大麻。玛丽安娜的免疫调节作用 在很大程度上是抗炎的，包括抑制T细胞功能和单核细胞活化，后者是 这是HAND免疫发病机制的关键。该提案利用现有的多机构 基础设施的重点是成人和青少年艾滋病毒阳性患者滥用药物。我们小组的数据显示 1）THC治疗减少单核细胞活化; 2）与未受损相比，受损患者 增加的神经元损伤的CSF标志物（神经丝（NFL）），和3）单细胞RNA测序（scRNA- seq）显示分化的髓样细胞表达 损伤相关小胶质细胞（DAM）基因（APOE和TREM 2）和其他单核细胞活化标志物。 该提案将调查大麻在调节神经炎症和HAND中的作用，并确定 一组有潜力在药物滥用的免疫调节背景下发挥作用的候选生物标志物。 理想的候选生物标志物是可以在HIV驱动的炎症背景下发挥作用的生物标志物， 滥用药物的免疫调节。这一提案将首次执行全面的、多领域的 免疫和转录组学分析研究大麻对全身和神经炎症的影响， 及其对艾滋病毒感染者认知的影响。在四组（NCI-/MJ-，NCI+/MJ-， NCI-/MJ+，NCI+/MJ+）我们将1）量化CNS和外周炎症生物标志物的差异， 神经元损伤的标志物; 2）评估大麻的潜在抗炎和神经保护作用 使用; 3）通过单细胞测定大麻对脑脊液（CSF）细胞转录组的影响 RNA测序（scRNA-seq）以鉴定用于未来干预的炎症途径;以及4）使用新的 PET/MR技术，通过放射性示踪剂定量小胶质细胞活化和神经炎症以及突触密度 （分别为外周苯二氮卓受体（PBR）111和UCB-J）。通过这些目标，本提案 将提供所需的深入了解手发病机制的背景下，药物使用。从增加的 使用新的免疫学和神经影像学来了解其发病机制，结果将最终有助于 识别炎症调节途径。这项研究的结果将增加我们对 大麻素和炎症之间的相互作用，无论是在艾滋病毒感染和未感染的年轻人。这 该提案很有可能为测试大麻素等新型疗法的研究奠定基础 受体配体和临床干预措施，以减少艾滋病毒感染的年轻人的手发病率。

Project Summary HIV-associated neurocognitive disorders (HAND) and neurocognitive impairment (NCI) remain long-term complications of HIV infection despite effective antiretroviral therapy (ART). Even in early HIV infection and in young adults who comprise 37% of new HIV infections, HAND impacts daily functioning and increases morbidity. This impact of HAND in the young will impact the productivity of the work force worldwide. Currently, our mechanistic insight into HAND pathogenesis in people living with HIV (PLWH) remains limited, and no validated biomarkers exist to diagnose and manage NCI. HAND is believed to result from sustained neuroinflammation. Unfortunately, growing evidence suggests inflammation is modulated by drugs of abuse, including the drug of choice among young adults with HIV: marijuana. Marijuana's immunomodulatory effects are largely anti-inflammatory, including suppression of T cell function and monocyte activation, the latter of which is pivotal to HAND immunopathogenesis. This proposal leverages an existing multi-institutional infrastructure focused on drugs of abuse in adult and adolescent HIV+ patients. Data from our group has found that 1) THC treatment reduces monocyte activation; 2) compared to unimpaired, impaired patients have increased CSF markers of neuronal injury (neurofilament (NFL), and 3) single cell RNA sequencing (scRNA- seq) of cerebrospinal fluid (CSF) from HIV-infected subjects reveals differentiated myeloid cells expressing damage-associated microglia (DAM) genes (APOE and TREM2) and other markers of monocyte activation. This proposal will investigate the role of marijuana in modulating neuroinflammation and HAND and identify a set of candidate biomarkers with potential to perform in the immunomodulatory context of substance abuse. An ideal candidate biomarker is one that can perform in the context of HIV driven inflammation and immunomodulation by drugs of abuse. This proposal will be the first to perform comprehensive, multi-domain immune and transcriptomic profiling to investigate the effects of marijuana on systemic and neuroinflammation, and its impact on cognition in young people living with HIV (YLWH). Within four groups (NCI-/MJ-, NCI+/MJ-, NCI-/MJ+, NCI+/MJ+) we will 1) quantify differences in CNS and peripheral inflammatory biomarkers and markers of neuronal injury; 2) evaluate the potential anti-inflammatory and neuroprotective impact of marijuana use; 3) determine the impact of marijuana on the cerebrospinal fluid (CSF) cellular transcriptome via single cell RNA sequencing (scRNA-seq) to identify inflammatory pathways for future interventions; and 4) using novel PET/MR techniques, quantify microglial activation and neuroinflammation and synaptic density via radiotracers (peripheral benzodiazepine receptor (PBR)111 and UCB-J, respectively). Via these objectives, this proposal will provided needed insight into HAND pathogenesis in the context of drug use. From an increased understanding of its pathogenesis using novel immunological and neuroimaging, results will ultimately help identify modulatory pathways of inflammation. Results from this study will add to our understanding of the interplay between cannabinoids and inflammation both within HIV-infected and uninfected young adults. This proposal has strong potential to lay the groundwork for studies to test novel therapeutics, such as cannabinoid receptor ligands, and clinical interventions to reduce HAND morbidity in young adults with HIV.