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Altered memory CCR6+
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DOI：10.1016/j.ebiom.2024.105274.png)
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Abstract
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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+ + 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 ROR gamma t/RORC2 gamma t/RORC2 repressor NR1D1 was upregulated, while the ROR gamma t/RORC2 gamma t/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 fi cation 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. Copyright (c) 2024 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Keywords:
Th17 cells
CCR6
HIV infection
Transcriptomics
HIV persistence
DNA damage
DNA repair
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