Altered memory CCR6(+) Th17-polarised T-cell function and biology in people with HIV under successful antiretroviral therapy and HIV elite controllers

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 10.13039/501100000024Canadian 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).