Role of myeloid cells in system-level immunometabolic dysregulation during prolonged successful HIV-1 treatment

Abstract

Objective: Why people with HIV-1 on ART (PWHART) display convoluted metabolism and immune cell functions during prolonged suppressive therapy is not well evaluated. In this study, we aimed to address this question using multiomics methodologies to investigate immunological and metabolic differences between PWHART and HIV-1 negative individuals (HC). Design: Cross-sectional study Methods: Untargeted and targeted metabolomics was performed using gas and liquid chromatography/mass spectrometry, and targeted proteomics using Olink inflammation panel on plasma samples. The cellular metabolic state was further investigated using flow cytometry and intracellular metabolic measurement in single-cell populations isolated by EasySep cell isolation. Finally, flow cytometry was performed for deep-immunophenotyping of mononuclear phagocytes. Results: We detected increased levels of glutamate, lactate, and pyruvate by plasma metabolomics and increased inflammatory markers (e.g. CCL20 and CCL7) in PWHART compared to HC. The metabolite transporter detection by flow cytometry in T cells and monocytes indicated an increased expression of glucose transporter 1 (Glut1) and monocarboxylate transporter 1 (MCT-1) in PWHART. Single cell-type metabolite measurement identified decreased glucose, glutamate, and lactate in monocytic cell populations in PWHART. Deep-immunophenotyping of myeloid cell lineages subpopulations showed no difference in cell frequency, but expression levels of CCR5 were increased on classical monocytes and some dendritic cells. Conclusions: Our data thus suggest that the myeloid cell populations potentially contribute significantly to the modulated metabolic environment during suppressive HIV-1 infection.