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

大麻素对 HIV/SIV 感染中 EV 组成和功能的调节

• 批准号: 10020177
• 负责人: Mahesh Mohan
• 金额: $ 78.74万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-30 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10020177
• 关键词: AIDS/HIV problem; Actins; Adhesions; Affect; Anti-Inflammatory Agents; Biochemical; Blood; Body Fluids; Cannabinoids; Cannabis; Cells; Characteristics; Chronic; Collagen; Cytoskeleton; Data; Deposition; Development; Disease; Disease Progression; Drug abuse; Drug usage; Environment; Epithelial; Epithelium; Exposure to; Extracellular Matrix; Fibrosis; Functional disorder; Gastrointestinal tract structure; Goals; HIV; HIV Infections; Homeostasis; In Vitro; Infection; Inflammation; Inflammatory; Interleukin-1 beta; Intestines; Knowledge; Length; Link; Lymphocyte; Lymphoid; MMP9 gene; Macaca; Macaca mulatta; Marijuana; Mediating; Medical; Modeling; Molecular; Mucous Membrane; Organ; Outcome; Pathogenesis; Patients; Peripheral; Phenotype; Plasma; Population; Production; Property; Proteome; Publishing; Research; Resources; Reticular Cell; SIV; Seminal fluid; Signal Transduction; Site; Symptoms; System; T-Cell Activation; T-Lymphocyte; TNF gene; Testing; Tetrahydrocannabinol; Time; Tissues; Transforming Growth Factor beta; Work; antiretroviral therapy; base; cannabinoid drug; cell type; chronic inflammatory disease; combinatorial; comorbidity; design; drug of abuse; dysbiosis; exhaustion; exosome; extracellular vesicles; immune activation; immune function; inflammatory marker; intercellular communication; intestinal epithelium; lymph nodes; marijuana use; microbial; monocyte; nanovesicle; prevent; recruit; side effect; transcriptome; vaginal fluid; vesicular release

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.

抽象的 细胞外囊泡（EV）是一种承载货物的准纳米囊泡，可介导细胞间通讯。 EV 由多种细胞类型释放并存在于体液中。电动汽车后视镜的组成及作用 指的是生产环境。因此，EVs 参与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症细胞募集。确实，我们和其他人 研究表明，来自体液（例如阴道液和精液）的外泌体具有抗 HIV 活性，并且 滥用药物的使用会重新编程外泌体的表型和功能。该多 PI 提案的目标是 利用我们的专业知识和资源来评估大麻素（delta-9-四氢大麻酚，THC） 在 HIV/SIV 感染期间调节 EV 的组成和功能，重点关注胃肠道 (GI) 和外周淋巴结使用 SIV-恒河猴模型。 HIV 感染者 (HIV+) 患者通常 与药物滥用和大麻（大麻）共存是最常用的滥用药物之一 HIV合并症的设置。大约 15-40% 的艾滋病毒/艾滋病患者使用大麻来治疗疾病 症状并改善联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，使用 THC——大麻中最具精神活性的抗炎大麻素 与 cART 治疗的 HIV+ 患者的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，减少肠道 T 细胞 激活/耗尽并防止淋巴结纤维化。 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 的基本机制 - 介导减少 HIV/SIV 感染中的全身炎症、免疫激活和淋巴结纤维化 不清楚。由于美国有 30 个州允许将大麻素用于医疗目的，其中艾滋病毒/艾滋病被列为 适合这种治疗的病症；了解 THC 如何调节炎症和 该人群的疾病进展。我们的初步数据表明，SIV 感染会导致时间依赖性 促炎性 EV（VEH/SIV EV）释放增加，促进炎症标记物的表达 以及单核细胞和 T 细胞的细胞骨架重塑。相反，长期使用 THC 治疗会导致分泌 THC/SIV-EV 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 假设恒河猴 (RM) 感染 SIV 会导致含有 VEH/SIV EV 的脱落 促进慢性炎症、上皮屏障功能障碍的促炎和促纤维形成因子， 微生物易位和淋巴纤维化。此外，cART 背景下的慢性 THC 治疗可能 通过调节 EV 减少炎症、微生物失调、淋巴纤维化并恢复免疫功能 分泌物及其货物。