Neutrophil dysregulation as a driving mechanism of cardiovascular disease in HIV-1-infection

中性粒细胞失调是 HIV-1 感染者心血管疾病的驱动机制

• 批准号: 9341375
• 负责人: Zdenek Hel
• 金额: $ 57.3万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9341375
• 关键词: Acquired Immunodeficiency Syndrome; Address; Arterial Fatty Streak; Atherosclerosis; Automobile Driving; Bacterial Translocation; Blood Vessels; Bone Marrow; Cardiovascular Diseases; Cardiovascular system; Carotid Arteries; Cell Death; Cells; Cerebrovascular Disorders; Chronic; Chronic Disease; Clinical Trials; Consensus; Coronary artery; DNA; Data; Development; Disease; Disease Progression; Emergency Situation; Epithelial; Event; Exposure to; Genetic Transcription; Granulopoiesis; HIV Infections; HIV-1; Immune; Immunologics; Individual; Infection; Inflammation; Inflammatory; Intervention; Intestinal Mucosa; Intestines; Leukocytes; Link; Longitudinal prospective study; Mediator of activation protein; Methods; Morbidity - disease rate; Mucous Membrane; Myocardial Infarction; Myocardial Ischemia; Neutrophil Activation; Patients; Pharmacology; Phenotype; Population; Process; Production; Prognostic Marker; Proteins; Publishing; Recruitment Activity; Reporting; Research; Research Personnel; Retrospective Studies; Risk; Risk Factors; Role; Stimulus; Stroke; Testing; Thrombus; Vascular Diseases; antiretroviral therapy; arterial stiffness; base; cardiovascular disorder risk; cell type; cohort; cytokine; endothelial dysfunction; extracellular; intimal medial thickening; macrophage; microbial; mortality; neutrophil; novel; novel diagnostics; novel therapeutic intervention; progression marker; randomized trial; release factor; scaffold; translational impact; virology

7. PROJECT SUMMARY / ABSTRACT. HIV infection conveys a 1.5 – 2 fold increased risk for atherosclerotic cardiovascular diseases (CVD). HIV-1-infected individuals are disproportionately impacted by CVD with increased carotid artery intima- medial thickening, subclinical coronary artery atherosclerosis, endothelial dysfunction, arterial stiffness, and silent ischemic heart disease compared to uninfected controls. CVD and other chronic diseases are increasingly replacing AIDS-related complications as the most common causes of morbidity and mortality in ART-treated patients. There is a widespread consensus that chronic inflammation resulting from microbial translocation, persisting despite successful virological control, is responsible for this excess risk. However, the specific mechanisms and mediators of this process are not well understood. Neutrophils, the most abundant leukocyte population, have recently emerged as critical contributors to atherosclerosis and thrombotic disorders. Following activation, a subset of neutrophils undergoes a specific type of cell death referred to as NETosis characterized by a release of large extracellular neutrophil extracellular traps (NETs) composed of chromosomal DNA and neutrophil granular proteins. These NETs provide the stimulus and the scaffold for thrombus formation and prime macrophages for production of cytokines that amplify immune cell recruitment in atherosclerotic plaques. We have demonstrated that neutrophils from HIV-1-infected individuals display an activated phenotype, specific transcriptional profile, increased rate of degranulation, and a high capacity to undergo NETosis. The accumulated evidence strongly suggests that neutrophils undergoing NETosis accelerate CVD progression in HIV-1 infection. The overall objectives of this proposal are to: 1) define the role of activated neutrophils and NETosis as driving mechanisms of CVD in HIV-1-infected individuals, and 2) identify the mechanisms responsible for chronic neutrophilic activation in HIV-1-infected individuals in order to reveal specific checkpoints for intervention. Our central hypothesis is that chronic inflammation in intestinal mucosal tissue of HIV-1-infected individuals results in a release of factors inducing neutrophil activation and accelerated recruitment from bone marrow. The emerging neutrophil population has higher capacity to undergo NETosis following activation by bacterial products leaking across the damaged intestinal barrier. NETs released from activated neutrophils promote the progression of vascular dysfunction in HIV-1 infection. The overall objectives will be accomplished in three specific aims: 1) Determine the extent to which neutrophil activation and NETosis predict the progression of vascular dysfunction in HIV-1-infected individuals; 2) Define the mechanisms of chronic systemic neutrophil activation in HIV-1 infection; and 3) Define the neutrophil-based prognostic markers that are associated with vascular disease-related morbid events in HIV-1-infection. We expect that the proposed project will fundamentally advance our understanding of primary mechanisms of inflammation-driven vascular disease in HIV-1 infection. The definition of mechanisms driving the progression of vascular diseases in HIV-1-infected individuals will have significant translational impact and serve as a basis for novel diagnostic and therapeutic approaches.

7. 项目摘要/摘要。