Epigenetic Reprogramming Leads to Downregulation of CD4 and Functional Changes in African Green Monkey Memory CD4+ T Cells

Abstract

African green monkeys (AGMs), Chlorocebus pygerythrus, are a natural host for a lentivirus related to HIV, SIV. SIV-infected AGMs rarely progress to AIDS despite robust viral replication. Though multiple mechanisms are involved, a primary component is the animals' ability to downregulate CD4 expression on mature CD4 + Th cells, rendering these cells resistant to infection by SIV. These CD8aa + T cells retain functional characteristics of CD4 + Th cells while simultaneously acquiring abilities of cytotoxic CD8ab + T cells. To determine mechanisms underlying functional differences between T cell subsets in AGMs, chromatin accessibility in purified populations was determined by assay for transposase-accessible chromatin sequencing. Differences in chromatin accessibility alone were sufficient to cluster cells by subtype, and accessibility 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.

Walk on the wild side: SIV infection in African non-human primate hosts—from the field to the laboratory

“…This is a developmental process resulting in the increase of the initially low abundance of CD4 neg CD8αα + T cells with age. CD4 downregulation is evoked through epigenetic silencing mechanisms involving CpG methylation in the CD4 promoter ( 177 ), which colocalizes with inaccessible chromatin regions in the CD4 gene region, as determined using ATAC-seq ( 178 ). Differential chromatin accessibility across the genome attributable to the CD4-to-CD8αα conversion was associated with immune processes and T-cell biology, and binding sites for transcription factors involved in the immune processes.…”

“…In CD4 + memory T-cells, more accessible regions were enriched for high mobility group (HMG) family binding sites involved in T-cell development and differentiation. In CD8aa + T cells, open chromatin regions were enriched for binding sites for Runt domain transcription factor and erythroblast transformation specific (ETS) regulating hematopoiesis ( 178 ).…”

“…Leronlimab, a CCR5-specific antibody ( 206 ), effectively increases CCR5 + CD4 + T cells in circulation in infected humans and macaques ( 207 ), suppresses the virus in humans chronically infected with CCR5-tropic HIV-1 and RMs acutely infected with CCR5-tropic SHIV ( 208 ), and protects RMs from mucosal SHIV acquisition ( 209 ). Downregulation of CD4, which is a natural process in the maturation of CD4 + T cells into CD4 neg CD8aa + T-cells in non-progressing hosts and does not seem to lead to any pathologies, appears to be a potential approach to effectively prevent cell infection regardless of co-receptor usage ( 178 ). ( 5 ) SIV-related epigenetic modifications in genes associated with immunoregulation and tissue integrity may constitute novel candidates for immunotherapies ( 192 ).…”