Exploratory Research on HIV Contribution to Heart and Lung Comorbidities

HIV 对心肺合并症影响的探索性研究

基本信息

批准号：
10343825
负责人：
ANDREW G MACLEAN
金额：
$ 58.55万
依托单位：
TULANE UNIVERSITY OF LOUISIANA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10343825
关键词：
AIDS related cancer AIDS/HIV problem Acute Address Affect Aging Animal Model Animals Apoptosis Autopsy Back Biochemistry Biological Biological Assay Blood Blood Circulation Body Fluids Bronchoalveolar Lavage CASP3 gene Cancer Patient Cardiopulmonary Cardiovascular system Cell Adhesion Molecules Cell Communication Cell physiology Cells Cellular Morphology Cellular biology Chronic Clinical Collaborations Cytokine Activation Data Disease Distant Endothelial Cells Endothelium Exposure to Flow Cytometry Functional disorder Funding Gastrointestinal tract structure HIV HIV Infections Heart Human Immunohistochemistry Indiana Infection Inflammaging Infusion procedures Knowledge Label Leukocytes Link Liposomes Liquid substance Lung Macaca Macaca mulatta Measures Mediator of activation protein Methods MicroRNAs Modeling Monitor Monkeys Pathogenesis Patients Peripheral Persons Positioning Attribute Positron-Emission Tomography Primates Process Production Proteins Pulmonary Heart Disease Pulmonary Hypertension Pulmonary Inflammation RNA Research Resources Risk Role SIV Sampling Site Sleep Source Testing Therapeutic Time Tissues Transgenic Organisms United States National Institutes of Health Universities Up-Regulation Vesicle Viral Viral Pathogenesis Viral Proteins Work X-Ray Computed Tomography antiretroviral therapy automated analysis cell behavior cell type communication device comorbidity endothelial dysfunction exosome experience extracellular extracellular vesicles humanized mouse in vivo inflammatory milieu intercellular communication lymph nodes macrophage medical schools microvesicles mouse model nef Protein novel particle premature protein profiling pulmonary function response senescence tool

项目摘要

PROJECT SUMMARY ABSTRACT HIV infection results in cardiovascular/ pulmonary complications, with over 75% of patients with chronic HIV disease showing clinical manifestations, even when on long-term successful combination antiretroviral therapy (cART). Endothelial cell dysfunction is central to HIV-associated cardiopulmonary complications. Compromised endothelial cells result in increased leukocyte transmigration, HIV infection, and the establishment of a highly inflammatory environment, which further aggravates HIV-associated cardiopulmonary disease, including accel- erated aging or “inflammaging”. Extracellular vesicles are secreted from nearly every cell type. Many types of extracellular vesicle exist, which we shall refer to collectively as EVs. They are released into the circulation, influencing intercellular communication at both local and distant sites from their cellular source. Thus, pulmonary endothelial cells, and the underlying parenchyma are constantly exposed to EVs. Infection with SIV or HIV can affect the composition of EVs, facilitating viral pathogenesis and spread. EVs from productively-infected cells in peripheral reservoir sites, including lymph nodes and GI tract, can contain viral proteins, host microRNAs and proteins that trigger responses in the heart and lung, all of which can promote inflammaging. Our team of collab- orators showed this for EVs circulating in HIV-associated cancer patients and animal models, and in aviremic human patients. It is reasonable to assume that EVs containing viral proteins, including Nef, could contribute to HIV-associated cardiopulmonary complications. Several studies have demonstrated that these proteins inde- pendently trigger distinct changes in endothelial cell function through upregulation of adhesion molecules, se- cretion of cytokines and activation of caspase 3. However, EV production, composition and function, especially in the context of successful cART suppression of SIV infection, represents a significant gap in our knowledge. Therefore, there is a critical need to understand the role of EVs in pathogenesis of SIV-associated cardiopulmo- nary disease and how cART influences SIV EV-induced intercellular communication. This R01 application, which piggy-backs on several NIH-funded projects, seeks to address how long-term successful cART influences EV cargo and how EV from SIV-infected cells induce inflammaging, focusing on endothelial cell dysfunction.

项目摘要摘要 HIV感染会导致心血管/肺部汇编，其中超过75％的慢性HIB患者疾病表现出临床表现，即使在长期成功的组合抗逆转（购物车）。内皮细胞导致白细胞传播，HIV感染增加，并建立高度炎症环境进一步加剧了与HIV相关的心肺疾病，包括加速衰老或“炎症” 存在细胞外囊泡，我们将其称为EV。影响局部和远处的细胞间通信内皮细胞和潜在的实质暴露于SIV或HIB感染。影响电动汽车的组成，促进病毒发病机理和扩散。外围储层位点，含淋巴结和胃肠道，含有病毒蛋白，宿主microRNA和触发心脏和肺部反应的蛋白质，所有这些都会促进我们的炎症。演说家展示了这一点用于在与HIV相关的取消癌症患者和动物模型中循环人类患者。与HIV相关的心肺并发症。通过上调粘附分子，se-的上调，被触发了触发希瑟氏细胞细胞功能的明显变化细胞因子和caspase 3的激活3。但是，EV的产生，组成和功能，尤其是在成功推动SIV感染的推车的背景下，我们的知识上有很大的差距。因此，批判性需要了解EV中的作用 Nary病以及购物车如何影响SIV EV诱导的细胞间通信。关于严重性NIH资助的项目的背包，试图解决长期成功的购物车如何影响EV 货物以及来自SIV感染细胞的EV诱导炎症，重点是内皮细胞细胞细胞功能障碍。