Dynamics and epigenetic signature of regulatory T-cells following antiretroviral therapy initiation in acute HIV infection.
EBioMedicine
; 71: 103570, 2021 Sep.
Article
em En
| MEDLINE
| ID: mdl-34500304
ABSTRACT
BACKGROUND:
HIV infection promotes the expansion of immunosuppressive regulatory T-cells (Tregs), contributing to immune dysfunction, tissue fibrosis and disease progression. Early antiretroviral treatment (ART) upon HIV infection improves CD4 count and decreases immune activation. However, Treg dynamics and their epigenetic regulation following early ART initiation remain understudied.METHODS:
Treg subsets were characterized by flow cytometry in 103 individuals, including untreated HIV-infected participants in acute and chronic phases, ART-treated in early infection, elite controllers (ECs), immunological controllers (ICs), and HIV-uninfected controls. The methylation status of six regulatory regions of the foxp3 gene was assessed using MiSeq technology.FINDINGS:
Total Treg frequency increased overtime during HIV infection, which was normalized in early ART recipients. Tregs in untreated individuals expressed higher levels of activation and immunosuppressive markers (CD39, and LAP(TGF-ß1)), which remained unchanged following early ART. Expression of gut migration markers (CCR9, Integrin-ß7) by Tregs was elevated during untreated HIV infection, while they declined with the duration of ART but not upon early ART initiation. Notably, gut-homing Tregs expressing LAP(TGF-ß1) and CD39 remained higher despite early treatment. Additionally, the increase in LAP(TGF-ß1)+ Tregs overtime were consistent with higher demethylation of conserved non-coding sequence (CNS)-1 in the foxp3 gene. Remarkably, LAP(TGF-ß1)-expressing Tregs in ECs were significantly higher than in uninfected subjects, while the markers of Treg activation and gut migration were not different.INTERPRETATION:
Early ART initiation was unable to control the levels of immunosuppressive Treg subsets and their gut migration potential, which could ultimately contribute to gut tissue fibrosis and HIV disease progression.FUNDING:
This study was funded by the Canadian Institutes of Health Research (CIHR, grant MOP 142294) and in part by the AIDS and Infectious Diseases Network of the Réseau SIDA et maladies infectieuses du Fonds de recherche du Québec-Santé (FRQ-S).Palavras-chave
Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Infecções por HIV
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Linfócitos T Reguladores
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Fármacos Anti-HIV
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Metilação de DNA
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Epigênese Genética
Limite:
Adult
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Female
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Humans
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Male
Idioma:
En
Revista:
EBioMedicine
Ano de publicação:
2021
Tipo de documento:
Article
País de afiliação:
Canadá