1. Altered memory CCR6 + Th17-polarised T-cell function and biology in people with HIV under successful antiretroviral therapy and HIV elite controllers.
- Author
-
Yero A, Goulet JP, Shi T, Costiniuk CT, Routy JP, Tremblay C, Mboumba Bouassa RS, Alexandrova Y, Pagliuzza A, Chomont N, Ancuta P, and Jenabian MA
- Subjects
- Humans, Male, Adult, Female, Memory T Cells immunology, Memory T Cells metabolism, Middle Aged, Antiretroviral Therapy, Highly Active, Cytokines metabolism, Biomarkers, Viral Load, Gene Expression Profiling, HIV Infections drug therapy, HIV Infections immunology, HIV Infections virology, Receptors, CCR6 metabolism, Th17 Cells immunology, Th17 Cells metabolism, HIV-1 drug effects, Immunologic Memory
- Abstract
Background: Despite successful antiretroviral therapy (ART), frequencies and immunological functions of memory CCR6
+ Th17-polarised CD4+ T-cells are not fully restored in people with HIV (PWH). Moreover, long-lived Th17 cells contribute to HIV persistence under ART. However, the molecular mechanisms underlying these observations remain understudied., Methods: mRNA-sequencing was performed using Illumina technology on freshly FACS-sorted memory CCR6+ CD4+ T-cells from successfully ART-treated (ST), elite controllers (EC), and uninfected donors (HD). Gene expression validation was performed by RT-PCR, flow cytometry, and in vitro functional assays., Findings: Decreased Th17 cell frequencies in STs and ECs versus HDs coincided with reduced Th17-lineage cytokine production in vitro. Accordingly, the RORγt/RORC2 repressor NR1D1 was upregulated, while the RORγt/RORC2 inducer Semaphorin 4D was decreased in memory CCR6+ T-cells of STs and ECs versus HDs. The presence of HIV-DNA in memory CCR6+ T-cells of ST and EC corresponded with the downregulation of HIV restriction factors (SERINC3, KLF3, and RNF125) and HIV inhibitors (tetraspanins), along with increased expression of the HIV-dependency factor MRE11, indicative of higher susceptibility/permissiveness to HIV-1 infection. Furthermore, markers of DNA damage/modification were elevated in memory CCR6+ T-cells of STs and ECs versus HDs, in line with their increased activation (CD38/HLA-DR), senescence/exhaustion phenotype (CTLA-4/PD-1/CD57) and their decreased expression of proliferation marker Ki-67., Interpretation: These results reveal new molecular mechanisms of Th17 cell deficit in ST and EC PWH despite a successful control of HIV-1 replication. This knowledge points to potential therapeutic interventions to limit HIV-1 infection and restore frequencies, effector functions, and senescence/exhaustion in Th17 cells., Funding: This study was funded by the Canadian Institutes of Health Research (CIHR, operating grant MOP 142294, and the Canadian HIV Cure Enterprise [CanCURE 2.0] Team Grant HB2 164064), and in part, by the Réseau SIDA et maladies infectieuses du Fonds de recherche du Québec-Santé (FRQ-S)., Competing Interests: Declaration of interests We have no competing interest to declare., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)- Published
- 2024
- Full Text
- View/download PDF