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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：
10569641
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 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10569641
关键词：
AIDS related cancer Acceleration Acute Address Affect Aging Animal Model Animals Apoptosis Autopsy Biochemistry Biological Biological Assay Blood Body Fluids Bronchoalveolar Lavage CASP3 gene Cancer Patient Cardiopulmonary Cardiovascular system Cell Adhesion Molecules Cell Communication Cell physiology Cells Cellular Morphology Cellular biology Chronic Circulation Clinical Collaborations Color Data Disease Distant Endothelial Cells Endothelium Exposure to Flow Cytometry Functional disorder Funding Gastrointestinal tract structure HIV HIV Infections HIV/AIDS Heart Human Immunohistochemistry Indiana Infection Inflammaging Infusion procedures Intercellular Communication Induction Knowledge Label Leukocytes Link Liposomes Liquid substance Lung Macaca Macaca mulatta Macrophage Measures Mediator Methods MicroRNAs Modeling Monitor Monkeys PET/CT scan Pathogenesis Patients Peripheral Persons Positioning Attribute Primates Process Production Productivity 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 cytokine endothelial dysfunction exosome experience extracellular extracellular vesicles humanized mouse in vivo inflammatory milieu intercellular communication lymph nodes medical schools microvesicles migration 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