Methylation regulation of Antiviral host factors, Interferon Stimulated Genes (ISGs) and T-cell responses associated with natural HIV control

作者：Bruna Oriol-Tordera, María Berdasco, Anuska Llano, Beatriz Mothe, Cristina Gálvez, Javier Martínez‐Picado, Jorge Carrillo, Julià Blanco, Clara Duran-Castells, Carmela Ganoza, Jorge Sánchez, Bonaventura Clotet, M. Luz Calle, Álex Sánchez‐Pla, Manel Esteller, Christian Brander, Marta Ruiz‐Riol · 发表于：PLoS Pathogens · 年份：2020 · DOI：10.1371/journal.ppat.1008678 · 被引用次数：38 · 研究领域：HIV Research and Treatment、Epigenetics and DNA Methylation、HIV/AIDS Research and Interventions

GWAS, immune analyses and biomarker screenings have identified host factors associated with in vivo HIV-1 control. However, there is a gap in the knowledge about the mechanisms that regulate the expression of such host factors. Here, we aimed to assess DNA methylation impact on host genome in natural HIV-1 control. To this end, whole DNA methylome in 70 untreated HIV-1 infected individuals with either high (>50,000 HIV-1-RNA copies/ml, n = 29) or low (<10,000 HIV-1-RNA copies/ml, n = 41) plasma viral load (pVL) levels were compared and identified 2,649 differentially methylated positions (DMPs). Of these, a classification random forest model selected 55 DMPs that correlated with virologic (pVL and proviral levels) and HIV-1 specific adaptive immunity parameters (IFNg-T cell responses and neutralizing antibodies capacity). Then, cluster and functional analyses identified two DMP clusters: cluster 1 contained hypo-methylated genes involved in antiviral and interferon response (e.g. PARP9, MX1, and USP18) in individuals with high viral loads while in cluster 2, genes related to T follicular helper cell (Tfh) commitment (e.g. CXCR5 and TCF7) were hyper-methylated in the same group of individuals with uncontrolled infection. For selected genes, mRNA levels negatively correlated with DNA methylation, confirming an epigenetic regulation of gene expression. Further, these gene expression signatures were also confirmed in early and chronic stages of infection, including untreated, cAR...