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

项目摘要 HIV相关性神经认知障碍(HAND)和神经认知障碍(NCI)仍然长期存在 尽管进行了有效的抗逆转录病毒治疗(ART)，但仍存在艾滋病毒感染的并发症。即使是在早期艾滋病毒感染和 年轻人占新感染艾滋病毒的37%，手部影响日常功能并增加 发病率。这种牵手年轻人的影响将影响世界各地劳动力的生产率。目前， 我们对艾滋病毒携带者(PLWH)手部发病机制的洞察仍然有限，没有 已有经过验证的生物标志物可用于诊断和管理NCI。手被认为是由持续的 神经炎。不幸的是，越来越多的证据表明，炎症是由滥用药物调节的， 包括感染艾滋病毒的年轻人的首选药物：大麻。大麻的免疫调节作用 主要是抗炎，包括抑制T细胞功能和单核细胞激活，后者 这在手部免疫发病机制中起关键作用。这项提议充分利用了现有的多机构 基础设施的重点是成人和青少年艾滋病毒+患者滥用药物。我们小组的数据发现 1)THC治疗降低了单核细胞的激活；2)与未受损的患者相比，受损患者 神经元损伤的脑脊液标志物增加(神经丝(NFL)，以及3)单细胞RNA测序(scRNA- HIV感染者脑脊液的序列分析显示分化的髓系细胞表达 损伤相关小胶质细胞(DAM)基因(APOE和TREM2)及其他单核细胞活化标志物。 这项提案将调查大麻在调节神经炎症和手部疾病中的作用，并确定 一组可能在药物滥用的免疫调节方面发挥作用的候选生物标记物。 理想的候选生物标记物是能够在艾滋病毒引起的炎症和 滥用药物的免疫调节作用。这项提案将是第一个全面、多领域地执行 免疫和转录图谱，以调查大麻对全身和神经炎症的影响， 以及它对艾滋病毒携带者(青壮年)认知的影响。在四组(NCI-/MJ-，NCI+/MJ-， NCI-/MJ+，NCI+/MJ+)我们将1)量化中枢和外周炎症生物标志物的差异，并 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细胞转录组的影响 RNA测序(scRNA-seq)以确定未来干预的炎症途径；以及4)使用新的 PET/MR技术，通过放射示踪剂量化小胶质细胞激活、神经炎症和突触密度 (外周苯二氮卓类受体(PBR)111和UCB-J)。通过这些目标，这项提案 威尔在药物使用的背景下提供了对手部发病机制的必要洞察。从增加的 使用新的免疫学和神经成像方法了解其发病机制，结果最终将有所帮助 确定炎症的调节途径。这项研究的结果将加深我们对 在感染艾滋病毒和未感染的年轻人中，大麻类物质和炎症之间的相互作用。这 该提案很有可能为测试新疗法(如大麻素)的研究奠定基础 受体配体，以及临床干预措施，以减少感染艾滋病毒的年轻人的手部发病率。

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.