Abstract
People living with HIV are at higher risk of atherosclerosis (AS). The pathogenesis of this risk is not fully understood. To assess the regulatory networks involved in AS we sequenced mRNA of the peripheral blood mononuclear cells (PBMCs) and measured cytokine and chemokine levels in the plasma of 13 persons living with HIV and 12 matched HIV-negative persons with and without AS. microRNAs (miRNAs) are known to play a role in HIV infection and may modulate gene regulation to drive AS. Hence, we further assessed miRNA expression in PBMCs of a subset of 12 HIV+ people with and without atherosclerosis. We identified 12 miRNAs differentially expressed between HIV+ AS+ and HIV+ , and validated 5 of those by RT-qPCR. While a few of these miRNAs have been implicated in HIV and atherosclerosis, others are novel. Integrating miRNA measurements with mRNA, we identified 27 target genes including SLC4A7, a critical sodium and bicarbonate transporter, that are potentially dysregulated during atherosclerosis. Additionally, we uncovered that levels of plasma cytokines were associated with transcription factor activity and miRNA expression in PBMCs. For example, BACH2 activity was associated with IL-1β, IL-15, and MIP-1α. IP10 and TNFα levels were associated with miR-124-3p. Finally, integration of all data types into a single network revealed increased importance of miRNAs in network regulation of the HIV+ group in contrast with increased importance of cytokines in the HIV+ AS+ group.
Highlights
Macrophages exert their phagocytic activity, engulfing lipids, and forming the characteristic foam cells
Micro-RNAs may be a major factor in the complex pathophysiology of A S27–29. miRNAs are short non-coding ribonucleotide molecules, typically 22 nt, that serve as critical regulators of gene expression across most life stages and tissues. miRNA dysregulation has been linked to AS through effects on cholesterol metabolism, lipid uptake by macrophages, inflammation, and a ngiogenesis[30,31,32]
Such miRNAs include miR-126-5p which has been shown to enhance the response of monocytes to lipopolysaccharide stimulation when levels are altered in persons with human immunodeficiency virus type-1 (HIV) infection[37], miR-132 which is associated with CD4 + T-cell activation and increased HIV r eplication[38], and let-7c, miR-34a, and miR-124a which modulate innate immune activity[39], among o thers[40,41,42,43]
Summary
Macrophages exert their phagocytic activity, engulfing lipids, and forming the characteristic foam cells. A number of miRNAs have been suggested as potential therapeutic targets and biomarkers for AS, as well as other diseases and environmental exposures[33,34,35,36] Such miRNAs include miR-126-5p which has been shown to enhance the response of monocytes to lipopolysaccharide stimulation when levels are altered in persons with HIV infection[37], miR-132 which is associated with CD4 + T-cell activation and increased HIV r eplication[38], and let-7c, miR-34a, and miR-124a which modulate innate immune activity[39], among o thers[40,41,42,43]. We find regulatory modes driven by cytokines and miRNAs play differential roles in HIV+ and HIV+ AS+
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