All ETDs from UAB

Advisory Committee Chair

Zdenek Hel

Advisory Committee Members

Scott Barnum

Sonya L Heath

Amit Gaggar

Jessy Deshane

Document Type

Dissertation

Date of Award

2014

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

In recent years, a new appreciation of the role of neutrophils in regulating the immune system has emerged. Neutrophils are the most abundant leukocyte population and are traditionally recognized as essential effector cells of the innate immune system in the host defense against invading organisms. Neutrophils play a critical role in controlling bacterial and fungal infections by multiple mechanisms including phagocytosis, degranulation, and formation of neutrophil extracellular traps (NETs). Neutrophils have been shown to play important roles in viral pathogenesis, a knowledge gap exists in our understanding of the function of neutrophils in individuals infected with human immunodeficiency virus-1 (HIV-1). Despite 30 years of intensive research, our understanding of how HIV-1 virus undermines the ability of the immune system to fight common infections is limited. Although antiretroviral therapy (ART) has markedly improved survival in individuals infected with HIV-1, they remain at increased risk of morbidity and mortality owing to cardiovascular, malignant, and hepatic diseases. The work presented in this thesis contributes to our understanding of neutrophil function in HIV-1-infection. The accumulated data reveals the multifaceted role of neutrophils in HIV-1-infection where they exert both pro-inflammatory and anti-inflammatory effects. We demonstrate that chronic HIV-1-infection and ongoing microbial translocation is associated with the induction of neutrophils with immunosuppressive activity that significantly contribute to the suppression of T cell function in HIV-1-infection. In addition, we show that enhanced NET formation in HIV-1-infected subjects may contribute to the incidence of inflammation-driven disease through direct effects of NETs or indirectly through NET-mediated effects on macrophage function. These findings show that the role of neutrophils in HIV-1-infection is more complex than previously recognized. The work presented in this thesis provides a framework for future studies directed at further elucidation of the role of neutrophils in HIV-1-pathogenesis and the development of novel therapeutics aiming at the modulating of neutrophil function in HIV-1-infected individuals.

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