Abstract

Peripheral neutrophils in HIV-infected individuals are characterized by impairment of chemotaxis, phagocytosis, bactericidal activity, and oxidative burst ability regardless of whether patients are receiving antiretroviral therapy or not. Neutrophil dysfunction leads not only to increased susceptibility to opportunistic infections but also to tissue damage through the release of reactive oxygen species (ROS), proteases, and other potentially harmful effector molecules contributing to AIDS progression. In this study, we demonstrated high levels of histone H3 lysine K4 trimethylated (H3K4me3) and dysregulation of DNA transcription in circulating neutrophils of HIV-infected subjects. This dysregulation was accompanied by a deficient response of neutrophils to LPS, impaired cytokine/chemokine/growth factor synthesis, and increased apoptosis. Chromatin immunoprecipitation sequencing (ChIPseq) H3K4me3 histone analysis revealed that the most spectacular abnormalities were observed in the exons, introns, and promoter-TSS regions. Bioinformatic analysis of Gene Ontology, including biological processes, molecular function, and cellular components, demonstrated that the main changes were related to the genes responsible for cell activation, cytokine production, adhesive molecule expression, histone remodeling via upregulation of methyltransferase process, and downregulation of NF-κB transcription factor in canonical pathways. Abnormalities within H3K4me3 implicated LPS-mediated NF-κB canonical activation pathway that was a result of low amounts of κB DNA sites within histone H3K4me3, low NF-κB (p65 RelA) and TLR4 mRNA expression, and reduced free NF-κB (p65 RelA) accumulation in the nucleus. Genome-wide survey of H3K4me3 provided evidence that chromatin modifications lead to an impairment within the canonical NF-κB cell activation pathway causing the neutrophil dysfunction observed in HIV-infected individuals.

Highlights

  • Neutrophils, the most abundant peripheral blood cells of the immune system, are the first responders to most infections [1]

  • One of the wellknown mechanisms of chromatin remodeling in response to the pathogen relates to the polarization of naive T lymphocytes to CD4 or CD8 subpopulation described by Harrison group [35]

  • Human activated lymphocytes are characterized by coordinated changes at different levels of chromatin architecture

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Summary

Introduction

Neutrophils, the most abundant peripheral blood cells of the immune system, are the first responders to most infections [1]. During HIV infection, these cells may, in an uncontrolled way, release proinflammatory mediators in response to the gut bacteria [3], a phenomenon frequently encountered in HIV patients. In such conditions, neutrophil prompt reactions can contribute to the permanent inflammation observed even in patients with undetectable viral load during antiretroviral therapy (ART) or without it [4], a phenomenon known as microbial translocation. Some studies demonstrated that neutrophil involvement in HIV infection pathogenesis was mainly associated with their low frequencies and proapoptotic state [5], reduced antimicrobial activity [6], and contribution to the immunosuppression by enhanced release of amino acid depleting enzymes [7] and PD-L1 mediated suppression of T cells [8]. The basis of the dual function of the neutrophils during HIV infection have not been studied and, besides potential differences between peripheral blood and tissue neutrophils [9, 10], it can be a result of the specific molecular pattern of two main groups of determinants: the transcription factors with the central role of NF-kB in induction of a wide spectrum of proinflammatory genes and the presence of cell type-specific patterns of genes associated with chromatin organization [11]

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