Effect of HIV infection and antiretroviral therapy initiation on genome-wide DNA methylation patterns

Esteban-Cantos, Andrés; Rodríguez-Centeno, Javier; Silla, J.C.; Barrúz, Pilar; Sánchez-Cabo, Fátima; Saiz-Medrano, Gabriel; Nevado, Julián; Mena-Garay, Beatriz; Jiménez-González, María; Bernardino, José I; Montejano, Rocío; Cadiñanos, Julen; Marcelo, Cristina; Gutiérrez-García, Lucía; Martínez-Martín, Patricia; Wallet, Cédrick; Raffi, François; Rodés, Berta; Arribas, José Ramón

doi:10.1016/j.ebiom.2022.104434

Cited by 11 publications

(10 citation statements)

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“…10E), suggesting additional insights into the evolutionary components of aging-associated processes not previously detected. (69), accelerated in people living with HIV(74), responsive to antiretroviral therapy (74), and accurate in estimating long-term culture ages of human brain organoids (66). Finally, we demonstrate that retroelement clocks extend to diverse human tissues and across mammalian species using DNA methylation from GTEx (19) and from the Mammalian Methylation Consortium (20).…”

Section: Evidence Of Pan-mammalian Species Multi-tissue Retroelement ...mentioning

confidence: 79%

“…We also captured retroelement-based epigenetic clock CpGs in novel retroelements not previously linked to aging, suggesting a broader role of locus-specific retroelements in biological aging. Applying these retroelement-based epigenetic clocks to DNA methylation datasets, we find that retroelement clocks are reversed during transient epigenetic reprogramming( 69 ), accelerated in people living with HIV( 74 ), responsive to antiretroviral therapy( 74 ), and accurate in estimating long-term culture ages of human brain organoids( 66 ). Finally, we demonstrate that retroelement clocks extend to diverse human tissues and across mammalian species using DNA methylation from GTEx( 19 ) and from the Mammalian Methylation Consortium( 20 ).…”

Section: Discussionmentioning

confidence: 99%

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Retroelement-Age Clocks: Epigenetic Age Captured by Human Endogenous Retrovirus and LINE-1 DNA methylation states

Ndhlovu,

Bendall,

Dwaraka

et al. 2023

Preprint

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Human endogenous retroviruses (HERVs), the remnants of ancient viral infections embedded within the human genome, and long interspersed nuclear elements 1 (LINE-1), a class of autonomous retrotransposons, are silenced by host epigenetic mechanisms including DNA methylation. The resurrection of particular retroelements has been linked to biological aging. Whether the DNA methylation states of locus specific HERVs and LINEs can be used as a biomarker of chronological age in humans remains unclear. We show that highly predictive epigenetic clocks of chronological age can be constructed from retroelement DNA methylation states in the immune system, across human tissues, and pan-mammalian species. We found retroelement epigenetic clocks were reversed during transient epigenetic reprogramming, accelerated in people living with HIV-1, responsive to antiretroviral therapy, and accurate in estimating long-term culture ages of human brain organoids. Our findings support the hypothesis of epigenetic dysregulation of retroelements as a potential contributor to the biological hallmarks of aging.

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Section: Evidence Of Pan-mammalian Species Multi-tissue Retroelement ...mentioning

confidence: 79%

Section: Discussionmentioning

confidence: 99%

Retroelement-Age Clocks: Epigenetic Age Captured by Human Endogenous Retrovirus and LINE-1 DNA methylation states

Ndhlovu,

Bendall,

Dwaraka

et al. 2023

Preprint

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“…Those variables were adjusted for in the EWAS model. Demographic and clinical characteristics are presented in S1 Table . Cohort 3 (GSE217633) [14]. We leveraged a publicly available dataset to provide a replication cohort, followed by a meta-EWAS of the three cohorts.…”

Section: Sample Characteristics and Dna Methylation Profilingmentioning

confidence: 99%

“…ART initiation reverses patterns of DNA methylation in less than 1% of the altered CpG sites, leaving the majority of CpG sites with methylation states persisting into the chronic stage of infection even among virally suppressed individuals [13]. Of note, changes in DNA methylation following ART were only weakly associated with the treatment outcomes such as recovery of CD4+ T-cell counts and CD4+/CD8+ T-cell ratio [14]. Independently replicated studies have identified several CpG sites and genes associated with HIV infection, including three NLRC5 promoter CpG sites that are less methylated in PWH with or without ART compared to PWoH [15][16][17][18].…”

Section: Introductionmentioning

confidence: 99%

Computationally inferred cell-type specific epigenome-wide DNA methylation analysis unveils distinct methylation patterns among immune cells for HIV infection in three cohorts

Zhang,

Hu,

Vandenhoudt

et al. 2024

PLoS Pathog

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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.

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“…Epigenetic alterations , including changes in DNA methylation and histone modifications, are one level of transcriptional regulation that can be mediated by normal biological processes and in response to diseases. Epigenetic alterations among PLWH can occur in immune response genes [43 ▪ ], associate with inflammation-related single-nucleotide polymorphisms [44], and be used to generate machine learning models to predict mortality risk [45]. Methylation patterns are also used to generate epigenetic clocks to assess biological age and deviations from chronological age.…”

Section: Biological Aging Hallmarksmentioning

confidence: 99%

Decrypting biological hallmarks of aging in people with HIV

Premeaux

Ndhlovu

2023

Current Opinion in HIV and AIDS

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Purpose of review HIV infection adds further complexity to the heterogenous process of aging. In this focused review, we examine and discuss recent advances to better elucidate mechanisms of biological aging perturbed and accelerated in the context of HIV, particularly among those with viral suppression through the benefits of antiretroviral therapy (ART). New hypotheses from these studies are poised to provide an improved understanding of multifaceted pathways that converge and likely form the basis for effective interventions toward successful aging. Recent findings Evidence to date suggests multiple mechanisms of biological aging impact people living with HIV (PLWH). Recent literature delves and expands on how epigenetic alterations, telomere attrition, mitochondrial perturbations, and intercellular communications may underpin accelerated or accentuated aging phenotypes and the disproportionate prevalence of age-related complications among PLWH. Although most hallmarks of aging are likely exacerbated in the setting of HIV, ongoing research efforts are providing new insight on the collective impact these conserved pathways may have in the aging disease processes. Summary New knowledge on underlying molecular disease mechanisms impacting people aging with HIV are reviewed. Also examined are studies that may facilitate the development and implementation of effective therapeutics and guidance on improving geriatric HIV clinical care.

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Effect of HIV infection and antiretroviral therapy initiation on genome-wide DNA methylation patterns

Cited by 11 publications

References 46 publications

Retroelement-Age Clocks: Epigenetic Age Captured by Human Endogenous Retrovirus and LINE-1 DNA methylation states

Retroelement-Age Clocks: Epigenetic Age Captured by Human Endogenous Retrovirus and LINE-1 DNA methylation states

Computationally inferred cell-type specific epigenome-wide DNA methylation analysis unveils distinct methylation patterns among immune cells for HIV infection in three cohorts

Decrypting biological hallmarks of aging in people with HIV

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