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

Abstract

Objective: Why people with HIV-1 on ART (PWH ART ) 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 PWH ART 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 PWH ART 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 PWH ART . Single cell-type metabolite measurement identified decreased glucose, glutamate, and lactate in monocytic cell populations in PWH ART . 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.

Lipid Droplets Accumulation in the Brain of HIV Transgenic Rat: Implication in the Accelerated Aging of HIV Infected Individuals

“…One facet of lipohypertrophy is ectopic fat depots into various tissues including the liver, muscle, and cardiovessels [12][13][14][15][16]. Such alteration on fat distribution (i.e., lipid metabolism dysregulation) has been well-known for increasing the expression of various inflammatory markers in peripheral systems which promote insulin resistance, obesity, and atherosclerosis in PLWHIV [17][18][19]. However, whether lipid metabolism could be also dysregulated in the brains and such dysregulation could be linked with neurological symptoms observed in PLWHIV remains much unexplored.…”

An army marches on its stomach: immunometabolic dysregulation in persons with HIV

“…The myeloid inflammatory marker MIP-3a (CCL20) and the chemoattractant MCP-3 (CCL7) were higher in ART-treated PWH, indicating a coordinated monocyte mobilization and trafficking to inflammation sites [13].…”

“…Akusja ¨rvi et al [13] bring light on the influence of metabolic reprogramming and altered chemokine signaling on monocyte trafficking and function in PWH on ART. These study findings demonstrate that myeloid cell populations significantly contribute to metabolic dysregulation during suppressive HIV infection.…”

“…Deep-immunophenotyping of mononuclear phagocytes was performed. Investigators observed an increased cell-surface expression of glucose transporter 1 (Glut1) and monocarboxylate transporter 1 (MCT-1) in both T-cells and monocytes from PWH compared with uninfected participants [13].…”

“…To address this knowledge gap, in this issue of AIDS , Akusjärvi et al . [13] have used state-of-the-art approaches to investigate immunometabolic pathways used by myeloid cell in ART-treated PWH. These investigators used cross-sectional and longitudinal studies to assess immunometabolic profiling using multiomics methodologies to investigate immunological and metabolic differences between PWH receiving ART compared with uninfected age-matched individuals.…”