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Altered differentiation is central to HIV-specific CD4+ T cell dysfunction in progressive disease.

ABSTRACT: Dysfunction of virus-specific CD4+ T cells in chronic human infections is poorly understood. We performed genome-wide transcriptional analyses and functional assays of CD4+ T cells specific for human immunodeficiency virus (HIV) from HIV-infected people before and after initiation of antiretroviral therapy (ART). A follicular helper T cell (TFH cell)-like profile characterized HIV-specific CD4+ T cells in viremic infection. HIV-specific CD4+ T cells from people spontaneously controlling the virus (elite controllers) robustly expressed genes associated with the TH1, TH17 and TH22 subsets of helper T cells. Viral suppression by ART resulted in a distinct transcriptional landscape, with a reduction in the expression of genes associated with TFH cells, but persistently low expression of genes associated with TH1, TH17 and TH22 cells compared to the elite controller profile. Thus, altered differentiation is central to the impairment of HIV-specific CD4+ T cells and involves both gain of function and loss of function.

SUBMITTER: Morou A

PROVIDER: S-EPMC6642691 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Altered differentiation is central to HIV-specific CD4+ T cell dysfunction in progressive disease.

Morou Antigoni A Brunet-Ratnasingham Elsa E Dubé Mathieu M Charlebois Roxanne R Mercier Eloi E Darko Sam S Brassard Nathalie N Nganou-Makamdop Krystelle K Arumugam Sahaana S Gendron-Lepage Gabrielle G Yang Lifei L Niessl Julia J Baxter Amy E AE Billingsley James M JM Rajakumar Premeela A PA Lefebvre François F Johnson R Paul RP Tremblay Cécile C Routy Jean-Pierre JP Wyatt Richard T RT Finzi Andrés A Douek Daniel C DC Kaufmann Daniel E DE

Nature immunology 20190715 8

Dysfunction of virus-specific CD4+ T cells in chronic human infections is poorly understood. We performed genome-wide transcriptional analyses and functional assays of CD4+ T cells specific for human immunodeficiency virus (HIV) from HIV-infected people before and after initiation of antiretroviral therapy (ART). A follicular helper T cell (TFH cell)-like profile characterized HIV-specific CD4+ T cells in viremic infection. HIV-specific CD4+ ...[more]

PMID: 31308541

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Project description:BackgroundHIV 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.MethodsNinety-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.FindingsWe 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.InterpretationCellular 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.FundingThis 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).

Dataset Information

Altered differentiation is central to HIV-specific CD4+ T cell dysfunction in progressive disease.

Publications

Altered differentiation is central to HIV-specific CD4<sup>+</sup> T cell dysfunction in progressive disease.

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