In:
PLOS Pathogens, Public Library of Science (PLoS), Vol. 20, No. 3 ( 2024-3-11), p. e1012063-
Abstract:
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 (N total = 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.
Type of Medium:
Online Resource
ISSN:
1553-7374
DOI:
10.1371/journal.ppat.1012063
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10.1371/journal.ppat.1012063.g001
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10.1371/journal.ppat.1012063.g002
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10.1371/journal.ppat.1012063.g003
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10.1371/journal.ppat.1012063.g004
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10.1371/journal.ppat.1012063.g005
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10.1371/journal.ppat.1012063.g006
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10.1371/journal.ppat.1012063.s001
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10.1371/journal.ppat.1012063.s002
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10.1371/journal.ppat.1012063.s003
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10.1371/journal.ppat.1012063.s012
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10.1371/journal.ppat.1012063.s021
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10.1371/journal.ppat.1012063.s036
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10.1371/journal.ppat.1012063.s037
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10.1371/journal.ppat.1012063.s038
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10.1371/journal.ppat.1012063.s039
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10.1371/journal.ppat.1012063.s040
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10.1371/journal.ppat.1012063.s041
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10.1371/journal.ppat.1012063.r001
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10.1371/journal.ppat.1012063.r002
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10.1371/journal.ppat.1012063.r003
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10.1371/journal.ppat.1012063.r004
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2024
detail.hit.zdb_id:
2205412-1
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