Epigenetic Profiling Provides Insights into AIDS Resistance in African Green Monkey

Abstract

AbstractAs a natural host of simian immunodeficiency virus (SIV), African green monkeys (AGM) do not develop AIDS although high levels of SIV replication were maintained. Low frequencies of CD4+ T cells and high frequencies of CD8dim T cells were observed in healthy adult AGM, which may partially explain the absence of SIV-induced disease progression. Elucidating the mechanisms that allow this natural host co-exist with SIV without progressive disease may facilitate knowledge of AIDS pathogenesis. Here we show: (1) Compared with junior AGM, 3 miRNA were up-regulated in adult AGM in which hsa-miR-151a-3p was shown to target both CD4 and MAZR; 15 miRNAs were down-regulated in adult AGM in which hsa-miR-140-5p, hsa-miR-126-3p and hsa-miR-194-5p were shown to target CD8α; (2) MeDIP sequencing analysis of adult AGM samples revealed that hypermethylation exists in the promoter region of CD4, CXCR6, CCR5, while hypomethylation exists in the promoter region of RUNX3, ICAM2; (3) Hypomethylation in the promoter region of PTK2 contributes to up-regulated expression of hsa-miR-151a-3p in adult AGM, while hypermethylation in the promoter region of WWP2 contributes to down-regulated expression of hsa-miR-140-5p. Our data for the first time demonstrates the link between miRNA and DNA methylation expression profile, which may together contribute to the phenotype of AIDS resistance in AGM.Author SummaryAfrican green monkeys (AGM) do not develop AIDS although high levels of SIV replication were maintained. Elucidating the mechanisms that allow this natural host co-exist with SIV without progressive disease may facilitate knowledge of AIDS pathogenesis. In this study, the miRNA expression patterns were found to be associated with the switch from CD4+ to CD4−CD8adim in adult AGM. The up-regulated hsa-miR-151a-3p was shown to target both AGM CD4 and MAZR, while the down-regulated hsa-miR-140-5p, hsa-miR-126-3p and hsa-miR-194-5p were shown to target AGM CD8α. And none of these miRNAs possess target sites in cynomolgus macaque (CM) CD4, CD8α and MAZR reflecting differences in AIDS resistance between these two species. Our data also demonstrates the link between miRNA and DNA methylation expression profile, indicating that multiple distinct mechanisms may contribute to AIDS resistance in AGM. Knowledge of the non-pathogenic nature of SIV infection in AGM may provide insight into development of new therapeutic strategies.