Metabolism-dependent ferroptosis promotes mitochondrial dysfunction and inflammation in CD4+ T lymphocytes in HIV-infected immune non-responders

eBioMedicineeBioMedicineVolume 86, December 2022, 104382Journal home page for eBioMedicineAuthor links open overlay panelSummaryBackground

HIV immune non-responders (INRs) are described as a failure to reestablish a pool of CD4+ T lymphocytes (CD4 cells) after antiretroviral therapy (ART), which is related to poor clinical results. Ferroptosis is a newly discovered form of cell death characterised by iron-dependent lipid peroxidation and the accumulation of reactive oxygen species (ROS). The mechanism of unrecoverable CD4 cells in INRs and whether ferroptosis plays a role are not fully understood.

Methods

Ninety-two people living with HIV (PLHIVs) who experienced four-year ART with sustained viral suppression, including 27 INRs, 34 partial responders (PRs), and 31 complete responders (CRs); and 26 uninfected control participants (UCs) were analysed for 16 immune parameters with flow cytometry. Then plasma lipid, iron and oxidation, and antioxidant indicators were detected by ELISA, and CD4 cells were sorted out and visualised under transmission electron microscopy. Finally, ferroptosis inhibitors were added, and alterations in CD4 cell phenotype and function were observed.

Findings

We found decreased recent thymic emigrants (RTE), over-activation and over-proliferation phenotypes, diminished killing function, decreased IL-7R and more severe inflammation; increased lipid peroxidation in the mitochondria and disruptions of the mitochondrial structure, showing typical features of ferroptosis in CD4 cells in INRs. Additionally, ferroptosis inhibitors could reduce inflammation and repair mitochondrial damage. Meanwhile, ELISA results showed increased plasma free fatty acids (FFA) and an imbalance of oxidative and antioxidant systems in INRs. Flow cytometry results displayed alterations of both transferrin receptor (CD71) and lipid transporter (CD36) expressions on the surface of CD4 cells. Mechanistically, there was a stronger correlation between CD36 expression and mitochondrial lipid peroxidation production, ferroptosis makers, and inflammation indicators; while amino acid transporter (CD98) was more related to killing functions; and CD71 was more closely related to activation status in CD4 cells.

Interpretation

Cellular metabolism was closely correlated with its diverse functions in INRs. Ferroptosis was observed in CD4 cells of INRs, and inhibiting ferroptosis through modulating mitochondrial disorders and inflammation may offer an alternative immunological strategy for reinvigorating CD4 cells in INRs.

Funding

This research was supported by the 13th Five-year Plan, Ministry of Science and Technology of China (2018ZX10302-102), Beijing Municipal Administration of Hospitals' Ascent Plan (DFL20191802), and Beijing Municipal Administration of Hospitals Clinical Medicine Development of Special Funding Support (ZYLX202126).

Keywords

Human immunodeficiency virus (HIV)

Poor immune reconstitution (PIR)

Immune non-responder (INR)

Ferroptosis

Metabolism

Inflammation

© 2022 The Author(s). Published by Elsevier B.V.

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