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: 10693315
• 负责人: Mahesh Mohan
• 金额: $ 78.47万
• 依托单位: NEW YORK MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10693315
• 关键词: 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; Epithelium; Exposure to; Extracellular Matrix; Fibrosis; Functional disorder; Gastrointestinal tract structure; Goals; HIV; HIV Infections; HIV/AIDS; 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; 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; programs; recruit; side effect; systemic inflammatory response; 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 细胞外蔬菜（EV）是载有介导细胞间通信的准纳米植物。 电动汽车由许多细胞类型释放，并且存在于体液中。电动汽车镜像的组成和功能 生产环境。这是指调节微生物发病机理，细胞外的evs 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 已经表明体液中的外泌体（例如阴道液和精液）具有抗HIV活性，并且 滥用药物的使用重新编程外泌体表型和功能。该多PI建议的目的是 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）的方式 调节HIV/SIV感染期间电动汽车的组成和功能，重点是胃肠道 （GI）和外周淋巴结使用SIV架猕猴模型。 HIV感染（HIV+）患者经常是 与药物滥用和大麻（大麻）合并症是最常用的滥用药物之一 艾滋病毒合并症的设置。大约有15-40％的艾滋病毒/艾滋病患者使用大麻治疗疾病 组合抗逆转录病毒疗法（CART）引起的症状和改善副作用。最近的研究 调查结果表明，大麻中最精神活性的抗炎大麻素的给药 与手推车处理的HIV+患者的全身注射和免疫激活的有益降低有关。 在SIV/猕猴模型中，THC改善了SIV疾病进展，肠道T细胞降低 激活/精疲力尽并防止淋巴结纤维化。 THC的好处是全身影响许多 器官，包括GI和淋巴系统。知识中的差距 - THC-的基本机制 HIV/SIV感染中介导的全身感染，免疫反应和淋巴结纤维化的降低为 不清楚。由于美国30个州允许将大麻素用于医疗目的，因此引用了艾滋病毒/艾滋病 适合这种治疗的疾病；重要的是要了解THC如何调节感染和 该人群的疾病进展。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电动汽车（VEH/SIV EV）的释放增加 和单核细胞和T细胞中的细胞骨架重塑。相反，用THC的慢性治疗导致秘密 数量较低的THC/SIV-EV，携带抗炎分子，并抵消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验数据，我们的总体 假设是恒河猕猴（RMS）的SIV感染导致含有VEH/SIV EV的脱落 促进慢性感染，上皮屏障功能障碍的促炎和促纤维化因素， 微生物易位和淋巴纤维化。此外，在购物车中的慢性THC治疗可能 通过调节EV来减少注射，微生物营养不良，淋巴纤维化和恢复免疫功能 分泌物和他们的货物。