Dynamics and epigenetic signature of regulatory T-cells following antiretroviral therapy initiation in acute HIV infection.
Adult
Anti-HIV Agents
/ administration & dosage
Antigens, CD
/ genetics
Apyrase
/ genetics
DNA Methylation
Epigenesis, Genetic
Female
Forkhead Transcription Factors
/ genetics
HIV Infections
/ drug therapy
Humans
Integrin beta Chains
/ genetics
Male
Receptors, CCR
/ genetics
T-Lymphocytes, Regulatory
/ drug effects
Transforming Growth Factor beta
/ genetics
CD39
FoxP3
HIV
TGF-β1
antiretroviral therapy (ART)
regulatory T-cells (Tregs)
Journal
EBioMedicine
ISSN: 2352-3964
Titre abrégé: EBioMedicine
Pays: Netherlands
ID NLM: 101647039
Informations de publication
Date de publication:
Sep 2021
Sep 2021
Historique:
received:
27
05
2021
revised:
10
08
2021
accepted:
19
08
2021
pubmed:
10
9
2021
medline:
28
1
2022
entrez:
9
9
2021
Statut:
ppublish
Résumé
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. 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. 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-β1)), which remained unchanged following early ART. Expression of gut migration markers (CCR9, Integrin-β7) 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-β1) and CD39 remained higher despite early treatment. Additionally, the increase in LAP(TGF-β1) 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. 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).
Sections du résumé
BACKGROUND
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
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
RESULTS
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-β1)), which remained unchanged following early ART. Expression of gut migration markers (CCR9, Integrin-β7) 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-β1) and CD39 remained higher despite early treatment. Additionally, the increase in LAP(TGF-β1)
INTERPRETATION
CONCLUSIONS
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
BACKGROUND
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).
Identifiants
pubmed: 34500304
pii: S2352-3964(21)00363-7
doi: 10.1016/j.ebiom.2021.103570
pmc: PMC8429924
pii:
doi:
Substances chimiques
Anti-HIV Agents
0
Antigens, CD
0
CC chemokine receptor 9
0
FOXP3 protein, human
0
Forkhead Transcription Factors
0
Integrin beta Chains
0
Receptors, CCR
0
Transforming Growth Factor beta
0
integrin beta7
0
Apyrase
EC 3.6.1.5
CD39 antigen
EC 3.6.1.5
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
103570Informations de copyright
Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Competing Interest We have no competing of interest to declare.