. 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.

Public Health Relevance

This application focuses on the identification of the inflammatory mechanisms driving cardiovascular and cerebrovascular diseases in HIV-1-infected individuals. The results are expected to have positive translational impact because the definition of key mechanisms driving the development and progression of vascular diseases will open new horizons in the development of novel diagnostic and therapeutic approaches applicable to HIV-1 infection and other chronic inflammatory conditions.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Special Emphasis Panel (ZHL1-CSR-Q (M2))
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Kirby, Ruth
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University of Alabama Birmingham
Schools of Medicine
United States
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