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

7.项目总结/摘要。 HIV感染可使动脉粥样硬化性心血管疾病的风险增加1.5 - 2倍 （CVD）。HIV-1感染者不成比例地受到心血管疾病的影响，颈动脉内膜增厚- 中膜增厚、亚临床冠状动脉粥样硬化、内皮功能障碍、动脉硬化， 无症状缺血性心脏病与未感染对照组的比较。心血管疾病和其他慢性疾病是 越来越多地取代艾滋病相关并发症，成为艾滋病发病和死亡的最常见原因， ART治疗的患者。有一个广泛的共识，慢性炎症引起的微生物 尽管病毒学控制成功，但易位仍持续存在，是造成这种过度风险的原因。但 对这一进程的具体机制和调解人还不甚了解。 中性粒细胞，最丰富的白细胞群体，最近出现的关键贡献者 动脉粥样硬化和血栓性疾病。在激活后，一部分中性粒细胞经历了一种特异性的 一种被称为NETosis的细胞死亡类型，其特征为大量细胞外中性粒细胞的释放 由染色体DNA和中性粒细胞颗粒蛋白组成的细胞外陷阱（NET）。这些蚊帐 为血栓形成提供刺激和支架，并引发巨噬细胞产生 在动脉粥样硬化斑块中放大免疫细胞募集的细胞因子。我们已经证明 来自HIV-1感染个体的嗜中性粒细胞显示活化的表型，特异性转录谱， 增加的脱粒速率和高的经历NETosis的能力。积累的证据有力地证明了 提示中性粒细胞经历NETosis加速HIV-1感染的CVD进展。整体 该提案的目标是：1）定义活化的中性粒细胞和NETosis作为驱动因素的作用 HIV-1感染者CVD的机制，以及2）确定慢性CVD的机制。 HIV-1感染者的嗜中性粒细胞活化，以揭示干预的特定检查点。我们 核心假设是HIV-1感染者肠粘膜组织的慢性炎症导致 在诱导中性粒细胞活化和加速从骨髓募集的因子的释放中。的 新兴的中性粒细胞群体在细菌激活后具有更高的经历NETosis的能力， 产品通过受损的肠道屏障泄漏。从活化的中性粒细胞释放的NET促进了 HIV-1感染中血管功能障碍的进展。总体目标将在三个方面实现 具体目的：1）确定中性粒细胞活化和NETosis预测进展的程度， HIV-1感染者的血管功能障碍; 2）确定慢性系统性中性粒细胞 HIV-1感染中的活化;和3）定义与HIV-1感染相关的基于嗜中性粒细胞的预后标志物。 HIV-1感染中与血管疾病相关的病理事件。 我们希望这个项目能从根本上促进我们对小学的理解。 HIV-1感染中炎症驱动的血管疾病的机制。机构驱动的定义 HIV-1感染个体中血管疾病的进展将具有显著的转化影响， 作为新的诊断和治疗方法的基础。

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.