Cannabinoid modulation of EV composition and function in HIV/SIV infection

摘要 胞外囊泡(EV)是一种携带货物的准纳米囊泡，可以调节细胞间的通讯。 EV由多种细胞类型释放，存在于体液中。电动汽车反光镜的组成和功能 生产环境的变化。因此，EVS参与调节微生物的致病机制，细胞外 基质重组、上皮屏障功能障碍和炎性细胞募集。事实上，我们和其他人 已经表明，来自体液的外切体，如阴道液和精液，具有抗艾滋病毒的活性，并且 滥用药物的使用改变了外切体的表型和功能。这项多PI提案的目标是 利用我们的专业知识和资源评估大麻素(德尔塔-9-四氢大麻酚，THC) 在HIV/SIV感染过程中调节肠道病毒的组成和功能，主要集中在胃肠道 使用SIV-恒河猴模型对胃肠道(GI)和外周淋巴结进行检测。感染艾滋病毒(HIV+)的患者通常 与药物滥用和大麻(大麻)并存是世界上最常用的滥用药物之一 艾滋病毒共病的背景。大约15%-40%的艾滋病毒/艾滋病患者使用大麻治疗疾病 症状和缓解联合抗逆转录病毒疗法(CART)引起的副作用。最新研究 研究结果表明，服用大麻中最具精神活性的抗炎大麻素 与CART治疗的HIV+患者的全身炎症和免疫激活有益地减少有关。 在SIV/猕猴模型中，THC改善了SIV疾病的进展，减少了肠道T细胞 激活/耗尽，防止淋巴纤维化。货柜码头处理费的好处是系统性的--影响了许多人 器官，包括胃肠道和淋巴系统。知识鸿沟--THC的根本机制-- HIV/SIV感染中全身炎症、免疫激活和淋巴结纤维化的介导性减少 不清楚。由于美国30个州允许将大麻类药物用于医疗目的，艾滋病毒/艾滋病的引用如下 一种适合于这种治疗的状态；了解THC如何调节炎症和 疾病在这一人群中的发展。我们的初步数据显示，SIV感染导致了一种时间依赖的 促进炎症标志物表达的促炎性血管内皮细胞(VEH/SIV EV)释放增加 单核细胞和T细胞的细胞骨架重塑。相比之下，长期服用THC会导致分泌物增加。 THC/SIV-EV数量较少，携带抗炎分子，并中和VEH/SIV EV- 诱导细胞骨架重塑。根据我们已发表的研究和这些试点数据，我们的总体情况 假设SIV感染恒河猴(RMS)会导致VEH/SIV EV的脱落，该病毒含有 促炎症和促纤维化因子，促进慢性炎症，上皮屏障功能障碍， 微生物易位和淋巴纤维化。此外，CART环境中的慢性THC治疗可能 通过调节肠道病毒，减少炎症、微生物失调、淋巴纤维化和恢复免疫功能 分泌物和他们的货物。

Abstract Extracellular vesicles (EVs) are cargo carrying, quasi-nanovesicles that mediate intercellular communication. EVs are released by many cell types and are present in body fluids. The composition and function of EVs mirror that of the producing environment. Thus, EVs are implicated in regulating microbial pathogenesis, extracellular matrix reorganization, epithelial barrier dysfunction, and inflammatory cell recruitment. Indeed, we and others have shown that exosomes from body fluids, such as vaginal fluid and semen possess anti-HIV activity, and that use of drugs of abuse reprograms exosome phenotype and function. The goal of this multi-PI proposal is to leverage our expertise and resources to evaluate how cannabinoid (delta-9-tetrahydrocannabinol, THC) modulates the composition and function of EVs during HIV/SIV infection, focusing on the gastrointestinal tract (GI) and peripheral lymph nodes using the SIV-rhesus macaque model. HIV-infected (HIV+) patients are often comorbid with drug abuse and cannabis (marijuana) is one of the most commonly used drugs of abuse in the setting of HIV comorbidity. Approximately, 15–40% of HIV/AIDS patients use cannabis to treat disease symptoms and ameliorate side effects due to combinatorial antiretroviral therapy (cART). Recent research findings indicate that administration of THC―the most psychoactive anti-inflammatory cannabinoid in cannabis is linked to beneficial reduction in systemic inflammation and immune activation in cART-treated HIV+ patients. In the SIV/macaque model, THC ameliorated SIV disease progression, reduced intestinal T cell activation/exhaustion and prevented lymph node fibrosis. The benefits of THC is systemic―affecting many organs, including the GI and lymphoid systems. Gap in knowledge - The underlying mechanisms of THC- mediated reduction in systemic inflammation, immune activation, and lymph node fibrosis in HIV/SIV infection is unclear. Since 30 U.S. states allow the use of cannabinoids for medical purposes, with citations of HIV/AIDS as a condition amenable to such treatment; it is important to understand how THC regulates inflammation and disease progression in this population. Our preliminary data show that SIV infection results in a time-dependent increase in the release of proinflammatory EVs (VEH/SIV EV) that promote expression of inflammatory markers and cytoskeletal remodeling in monocytes and T cells. In contrast, chronic treatment with THC results in secretion of THC/SIV-EV that are lower in number, carry anti-inflammatory molecules, and counteracts VEH/SIV EV- induced cytoskeletal remodeling. Based on our published studies and these pilot data, our overarching hypotheses are that SIV infection of rhesus macaques (RMs) results in the shedding of VEH/SIV EV containing pro-inflammatory and pro-fibrogenic factors that promote chronic inflammation, epithelial barrier dysfunction, microbial translocation, and lymphoid fibrosis. Furthermore, chronic THC treatment in the setting of cART may reduce inflammation, microbial dysbiosis, lymphoid fibrosis, and restore immune function by modulating EV secretion and their cargo.