Implications of accumulation of clonally expanded and senescent CD4GNLY T cells in immunological non-responders of HIV-1 infection.

Increased CD4GNLY T cells have been confirmed to be inversely associated with CD4 T cell count in immunological non-responders (INRs), however, the underlying mechanisms are unknown. This study aimed to elucidate the characteristics of CD4GNLY T cells and their relationship with immune restoration. Single-cell RNA sequencing, single-cell TCR sequencing, and flow cytometry were used to analyze the frequency, phenotypes, and function of CD4GNLY T cells. Moreover, Enzyme linked immunosorbent assay was performed to detect plasma cytokines production in patients. CD4GNLY T cells were found to be highly clonally expanded, characterized by higher levels of cytotoxicity, senescence, P24, and HIV-1 DNA than CD4GNLY T cells. Additionally, the frequency of CD4GNLY T cells increased after ART, and further increased in INRs, and were positively associated with the antiretroviral therapy duration in INR. Furthermore, increased IL-15 levels in INRs positively correlated with the frequency and senescence of CD4GNLY T cells, suggesting that CD4GNLY T cells may provide new insights for understanding the poor immune reconstitution of INRs. In conclusion, increased, highly clonally expanded, and senescent CD4GNLY T cells may contribute to poor immune reconstitution in HIV-1 infection.