Dysregulated neutrophil subpopulations as a driving mechanism of liver and gastrointestinal disease in HIV-1-infected individuals

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7. PROJECT SUMMARY / ABSTRACT. Gastrointestinal (GI) mucosal damage and destruction of the gut epithelial barrier are the defining features of the pathogenesis of HIV-1 infection. Accumulated evidence indicates that neutrophils play a critical role in the gastrointestinal and liver damage in HIV-1 infection. Neutrophils infiltrate the GI tract in HIV-1- infected individuals at high levels and their presence is associated with damage to the epithelial barrier, elevated epithelial permeability, and increased disease severity in animal models and HIV-1-infected patients. In this application, we propose that microbial translocation and the resulting systemic innate immune dysregulation mediated by changes in neutrophil subpopulations in circulation, gut-associated lymphoid tissue (GALT), and liver plays a fundamental role in HIV-1 disease progression. The overall objectives of this proposal are to define the role of neutrophil subpopulations and NETosis as driving mechanisms of gastrointestinal and liver damage in HIV-1 infection and to identify the mechanisms responsible for chronic neutrophilic activation in HIV-1 infection in order to reveal the specific checkpoints for intervention. Our central hypothesis is that HIV-1 infection is associated with the induction and expansion of specific neutrophilic subpopulations with increased capacity to produce reactive oxygen species (ROS) and undergo NETosis. ROS and NETs released from activated neutrophils promote damage in the GI mucosa and liver and drive the progression of HIV-1 infection. This hypothesis has been formulated on the basis of our preliminary data and recently published reports demonstrating the critical role of neutrophils in HIV-1 infection. In preliminary studies, we optimized methods for detailed neutrophil characterization and demonstrated that neutrophils from HIV-1-infected individuals display an activated phenotype, immunosuppressive properties, specific transcriptional profile, increased rate of degranulation, and a high capacity to undergo NETosis. Specific properties of the newly identified neutrophil subpopulations strongly indicate that they play a critical role in damaging GI mucosa and the pathogenesis of liver disease in HIV-1-infected individuals. We propose to determine the effect of induction of specific neutrophil subpopulations on the progression of liver disease in ART-treated HIV-1-infected individuals, to identify specific properties of neutrophil subpopulations in the GALT and liver of HIV-1-infected individuals, and determine whether the innate immune dysregulation in these tissues is associated with a shift in the ratio of tissue macrophages exhibiting M1 versus M2 phenotype resulting in lowered efferocytosis and accumulation of neutrophils undergoing NETosis. The significance of the proposed studies is that once the role of neutrophils in the progression of HIV-1 infection is defined, neutrophil activation and induction of pathogenic populations can be pharmacologically targeted.