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

Abstract CD8 T cells from HIV infected ‘elite controllers’ maintain long-lived protective properties including enhanced cytokine production and proliferative capacity over many years. With the advent of adoptive cellular therapy to treat chronic diseases it has become even more vital to understand the intrinsic cellular mechanisms of elite controller HIV specific CD8 T cells that enable lasting antiviral functionality. To identify epigenetic programs that regulate their functional capacity we performed genome-wide DNA methylation analysis of MHC Class I multimer+ CD8 T cells sorted from aviremic elite controllers compared to aviremic non-controllers on suppressive ART. Principle component analysis of the CpG sites broadly distinguished EC and ART HIV specific CD8 T cells, while deeper investigation of the differentially methylated region analysis revealed enrichment of pathways that support a multipotent differentiation state, cytokine signaling, and a long-lived effector cell fate in HIV-specific CD8 T cells from elite controllers. We also 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. These findings show that HIV-specific CD8 T cells from elite controllers have DNA methylation programs that maintain developmental potential and in turn enable 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. Supported by grants from NIH (R01AI114442 and R01CA237311 to BY, K23AI134327 to RLR), loan repayment program and National comprehensive Cancer Network Young Investigator Award (CZ), ASSISI foundation support (BY) and American Lebanese Syrian Associated Charities (ALSAC to BY)