Persistent dysfunction of Th17 cells in people with HIV on ART and in elite controllers

Th17 cells are rapidly depleted during HIV infection and their frequencies and functions are not fully restored by antiretroviral therapy (ART). In addition, Th17 cells contribute to viral persistence during ART. However, molecular mechanisms underlying these observations remain understudied. MemCCR6+ cells from STs vs. HDs showed alterations in the NOTCH and TGF-β1/smad2-3 pathways, indicative of impairments in their differentiation and stability. Consistently, the RORγt/C2 repressor NR1D1 was upregulated, while Semaphorin 4D, a RORγt/C2 inducer, was decreased in MemCCR6+ cells from STs vs. HDs. Frequencies of Th17 and Th1/Th17 cells within total MemCCR6+ cells were lower in STs and ECs compared to HD individuals, and expressed higher levels of activation and senescence/exhaustion markers. As a result, MemCCR6+ cells from STs produced less IL-17A/F, IL-22, and IFN-γ in vitro compared to HDs. Downregulation of HIV restriction factors (SERINC3, KLF3, and RNF125) and HIV inhibitors (tetraspanins), along with increased expression of MRE11 in MemCCR6+ cells from ST individuals supported higher susceptibility/permissiveness to HIV infection. MemCCR6+ cells from STs and ECs had lower TFAP4 expression and increased expression of EED and TP53BP1 vs. HDs, which is associated to HIV persistence. Markers of DNA damage/modification were elevated in STs and ECs compared to HDs, including NASP, RPA2, H2AX, PARP, and DNA methylases DNMT1/DNMT3A. Similar to the ST group, MemCCR6+ cells in ECs showed decreased expression of Semaphorin 4D and Notch1, along with higher expression of NR1D1 compared to HD donors. Despite successful ART, the transcriptional signature of MemCCR6+ cells revealed impaired differentiation, stability, functions, DNA damage/modifications, and higher susceptibility to HIV infection and viral persistence.