HIV-specific CD8 T cells from elite controllers have an epigenetic imprint that preserves effector functions

Several lines of evidence support a central role for CD8 T cells as key determinants in the control of HIV, particularly in rare "elite controllers" who control the virus to undetectable levels in the blood in the absence of antiretroviral therapy (ART). While HIV-specific CD8 T cells isolated from elite controllers have enhanced antiviral cytokine production and proliferative capacity in response to antigen stimulation when compared to cells isolated from viremic or even aviremic ART-suppressed non-controllers, the cell-intrinsic mechanisms underlying the enhanced T cell memory-like function of HIV-specific CD8 T cells in elite controllers remain largely undefined. To identify the transcriptional and epigenetic pathways that regulate functional capacity in HIV-specific CD8 T cells in elite controllers, we performed genome-wide transcriptional and DNA methylation analysis of MHC Class I multimer+ CD8 T cells sorted from aviremic elite controllers compared to aviremic non-controllers on suppressive ART. Co-omics analysis revealed enrichment for gene signatures that support a multipotent differentiation state, cell survival, and a long-lived effector cell fate in HIV-specific CD8 T cells from elite controllers. Specifically, we observed DNA methylation programs at the transcription factor binding sites of the stem-associated factors TCF-1 and LEF1 that delineate HIV-specific CD8 T cells from elite controllers versus ART-treated individuals. HIV-specific CD8 T cells in elite controllers also maintain T cell receptor and IL-12/STAT4 pathway signaling and have suppressed pro-apoptotic TNF pathway signaling. These findings show that HIV-specific CD8 T cells from elite controllers have enhanced expression and DNA methylation programs that maintain developmental potential and in turn promote long-term survival, proliferative potential, and effector capacity. These data also provide new insights into the relationship between stem-associated transcription factors and stable epigenetic restriction of T cell developmental capacity.