부산대학교 도서관

Background: Epigenome-wide association studies (EWAS) have identified CpG sites associated with HIV infection in blood cells in bulk, which offer limited knowledge of cell-type specific methylation patterns associated with HIV infection. In this study, we aim to identify differentially methylated CpG sites for HIV infection in immune cell types: CD4+ T-cells, CD8+ T-cells, B cells, Natural Killer (NK) cells, and monocytes. Methods: Applying a computational deconvolution method, we performed a cell-type based EWAS for HIV infection in three independent cohorts (Ntotal = 1,382). DNA methylation in blood or in peripheral blood mononuclear cells (PBMCs) was profiled by an array-based method and then deconvoluted by Tensor Composition Analysis (TCA). The TCA-computed CpG methylation in each cell type was first benchmarked by bisulfite DNA methylation capture sequencing in a subset of the samples. Cell-type EWAS of HIV infection was performed in each cohort separately and a meta-EWAS was conducted followed by gene set enrichment analysis. Results: The meta-analysis unveiled a total of 2,021 cell-type unique significant CpG sites for five inferred cell types. Among these inferred cell-type unique CpG sites, the concordance rate in the three cohorts ranged from 96% to 100% in each cell type. Cell-type level meta-EWAS unveiled distinct patterns of HIV-associated differential CpG methylation, where 74% of CpG sites were unique to individual cell types (false discovery rate, FDR <0.05). CD4+ T-cells had the largest number of unique HIV-associated CpG sites (N = 1,624) compared to any other cell type. Genes harboring significant CpG sites are involved in immunity and HIV pathogenesis (e.g. CD4+ T-cells: NLRC5, CX3CR1, B cells: IFI44L, NK cells: IL12R, monocytes: IRF7), and in oncogenesis (e.g. CD4+ T-cells: BCL family, PRDM16, monocytes: PRDM16, PDCD1LG2). HIV-associated CpG sites were enriched among genes involved in HIV pathogenesis and oncogenesis that were enriched among interferon-α and -γ, TNF-α, inflammatory response, and apoptotic pathways. Conclusion: Our findings uncovered computationally inferred cell-type specific modifications in the host epigenome for people with HIV that contribute to the growing body of evidence regarding HIV pathogenesis. Author summary: The host epigenome (i.e., the DNA methylome) plays a pivotal role in HIV-1 viral integration, maintenance, and activation or silencing. Epigenome-wide association studies have identified many DNA methylation CpG sites in bulk cells associated with HIV infection, which offer an aggregated view of the average DNA methylation across cell types. To understand the effect of DNA methylation on chronic HIV infection at the cell-type level, we applied a computational method to deconvolute DNA methylation from blood bulk cells into five cell types: CD4+ T cell, CD8+ T cell, B cell, Nature Killer cell, and Monocytes and conducted an epigenome-wide analysis for HIV infection in each inferred cell type. Our results show that most of the HIV infection associated CpG sites are unique to each cell type. The largest number of significant CpG sites for HIV infection are from inferred CD4+ T cells. Significant CpG sites are located on genes that are enriched in interferon-α and -γ pathways, which are known to be key players in HIV infection. The findings help us understand the cellular relationship between DNA methylation and HIV infection. [ABSTRACT FROM AUTHOR]