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

摘要 细胞外囊泡（EV）是介导细胞间通讯的运载货物的准纳米囊泡。 EV由许多细胞类型释放，并存在于体液中。电动汽车后视镜的组成及功能 生产环境。因此，EV涉及调节微生物发病机制、细胞外 基质重组、上皮屏障功能障碍和炎性细胞募集。的确，我们和其他人 已经表明，来自体液如阴道液和精液的外来体具有抗HIV活性， 滥用药物的使用重新编程外来体表型和功能。这个多PI提案的目标是 利用我们的专业知识和资源，评估大麻素（δ-9-四氢大麻酚，THC） 在HIV/SIV感染期间调节EV的组成和功能，重点是胃肠道 (GI)和外周淋巴结。HIV感染者（HIV+）通常 与药物滥用和大麻（大麻）共病，是美国最常用的滥用药物之一。 艾滋病合并症的背景。大约15-40%的艾滋病毒/艾滋病患者使用大麻治疗疾病 症状和改善由于组合抗逆转录病毒疗法（cART）引起的副作用。最近的研究 研究结果表明，服用THC-大麻中最具精神活性的抗炎大麻素， 与cART治疗的HIV+患者中全身炎症和免疫激活的有益减少有关。 在SIV/猕猴模型中，THC改善了SIV疾病进展，减少了肠道T细胞 活化/耗竭和防止淋巴结纤维化。THC的好处是系统性的-影响许多人 器官，包括胃肠道和淋巴系统。知识差距-THC的潜在机制- 在HIV/SIV感染中介导的全身性炎症、免疫激活和淋巴结纤维化的减少， 不清楚由于美国有30个州允许将大麻素用于医疗目的， 一种适合这种治疗的疾病;重要的是要了解THC如何调节炎症， 在这个人群中，疾病的发展。我们的初步数据表明，SIV感染导致时间依赖性 促进炎症标志物表达的促炎性EV（VEH/SIV EV）释放增加 以及单核细胞和T细胞中的细胞骨架重塑。相比之下，THC的长期治疗导致分泌 THC/SIV-EV的数量较少，携带抗炎分子，并抵消VEH/SIV EV- 诱导细胞骨架重塑。根据我们发表的研究和这些试点数据，我们的总体 假设SIV感染恒河猴（RM）导致含有VEH/SIV EV的脱落 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，在cART背景下的慢性THC治疗可能 通过调节EV减少炎症、微生物生态失调、淋巴纤维化并恢复免疫功能 分泌物及其货物。

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.