Epigenetic reprogramming leads to down regulation of CD4 and functional changes in African green monkey memory CD4+ T cells

African green monkeys (AGMs) are a natural host for a lentivirus related to human immunodeficiency virus, simian immunodeficiency virus. SIV-infected AGM rarely progress to AIDS despite robust viral replication. Though multiple mechanisms are involved, a primary component is their ability to downregulate CD4 expression on mature helper CD4+ T cells, rendering these cells resistant to infection by SIV. These CD8aa+ T cells retain functional characteristics of helper CD4+ T cells while simultaneously aquiring abilities of cytoxic CD8ab+ T cells. To determine mechanisms underlying functional differences between T cell subsets in AGMs, chromatin accessibility in purified populations was determined by ATACseq. Differences in chromatin accessibility alone were sufficient to cluster cells by subtype, and acceesibility at the CD4 locus reflected changes in CD4 expression. DNA methylation at the CD4 locus also correlated with inaccessible chromatin. By associating accessible regions with nearby genes, gene expression was found to correlate with accessibility changes. T cell and immune system activation pathways were identified when comparing regions that changed accessibility from CD4+ T cells to CD8aa+ T cells. Different transcription factor binding sites are revealed as chromatin accessibility changes, and these differences may elicit downstream changes in differentiation. This comprehensive description of the epigenetic landscape of AGM T cells identified genes and pathways that could have translational value in therapeutic approaches recapitulating the protective effects CD4 downregulation. Overall design: This study involves ATAC-seq in 5 T cells populations from 10 separate african green monkeys, totalling 50 samples. Half of the monkeys have SIV and the other half do not.