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DNA methylation demonstrates bronchoalveolar cell senescence in people living with HIV: An observational cohort study

ABSTRACT: Background: Age-related comorbidities remain a burden in People living with HIV (PLWH). DNA methylation may be a link between HIV, aging, and the increased risk of lung comorbidities. Here, we investigate whether bronchoalveolar lavage (BAL) cells of PLWH demonstrate epigenome wide disruptions and advanced epigenetic aging. Methods: BAL cell DNA methylation profiles from 25 PLWH and 16 uninfected controls were tested for differential methylation of transposable elements Alu and LINE-1, a marker of aging. We used a weighted gene correlation network analysis to identify co-methylation networks associated with HIV and age. We tested the effect of HIV on DNA methylation using a robust linear model. An enrichment analysis was conducted to identify differentially methylated pathways (false discovery rate <0.10). Results: The BAL cells of PLWH were marked by global hypomethylation in both Alu and LINE-1 elements. Six co-methylated CpG networks were identified that were significantly associated with age; of these, the red module was significantly differentially methylated in PLWH and enriched pathways associated with HIV, Ras signaling, T cell receptors, and bacterial invasion of epithelial cells. We identified 6,428 differentially methylated sites associated with HIV. Conclusions: We have shown here for the first time that alterations in the DNA methylation of BAL cells (mainly macrophages) in the lung HIV show in a pattern of advanced aging. In conjunction with our findings in blood cells and airway cells, this study strongly support that HIV may contribute to increase the risk of lung comorbidities through the epigenetic regulation of aging.

ORGANISM(S): Homo sapiens

PROVIDER: GSE262656 | GEO | 2024/07/03

REPOSITORIES: GEO

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Project description:Background: Atherosclerosis (AS)-associated cardiovascular disease is an important cause of mortality in an aging population of people living with HIV (PLWH). This elevated risk of atherosclerosis has been attributed to viral infection, prolonged usage of anti-retroviral therapy, and subsequent chronic inflammation. Methods: To investigate dysregulated immune signaling in PLWH with and without AS, we sequenced 9368 peripheral blood mononuclear cells (PBMCs) from 8 PLWH, 4 of whom also had atherosclerosis (AS+). To develop executable models of signaling pathways that drive cellular states in HIV-associated atherosclerosis, we developed the single-cell Boolean Omics Network Invariant Time Analysis (scBONITA) algorithm. ScBONITA (a) uses single-cell RNA sequencing data to infer Boolean rules for topologically characterized networks, (b) prioritizes genes based on their impact on signaling, (c) performs pathway analysis, and (d) maps sequenced cells to characteristic signaling states. We used scBONITA to identify dysregulated pathways in different cell-types from AS+ PLWH and AS- PLWH. To compare our findings with pathways associated with HIV infection, we used scBONITA to analyze a publicly available dataset of PBMCs from subjects before and after HIV infection. Additionally, the executable Boolean models characterized by scBONITA were used to analyze observed cellular states corresponding to the steady states of signaling pathways Results: We identified an increased subpopulation of CD8+ T cells and a decreased subpopulation of monocytes in AS+ PLWH. Dynamic modeling of signaling pathways and pathway analysis with scBONITA provided a new perspective on the mechanisms of HIV-associated atherosclerosis. Lipid metabolism and cell migration pathways are induced by AS rather than by HIV infection. These pathways included AGE-RAGE and PI3K-AKT signaling in CD8+ T cells, and glucagon and cAMP signaling pathways in monocytes. Further analysis of other cell subpopulations suggests that the highly interconnected PI3K-AKT signaling pathway drives cell migratory state in response to dyslipidemia. scBONITA attractor analysis mapped cells to pathway-specific signaling states that correspond to distinct cellular states. Conclusions: Dynamic network modeling and pathway analysis with scBONITA indicates that dysregulated lipid signaling regulates cell migration into the vascular endothelium in AS+ PLWH. Attractor analysis with scBONITA facilitated pathway-based characterization of cellular states that are not apparent in gene expression analyses.

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DNA methylation demonstrates bronchoalveolar cell senescence in people living with HIV: An observational cohort study

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