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Abrupt and altered cell-type specific DNA methylation profiles in blood during acute HIV infection persists despite prompt initiation of ART.

ABSTRACT: HIV-1 disrupts the host epigenetic landscape with consequences for disease pathogenesis, viral persistence, and HIV-associated comorbidities. Here, we examined how soon after infection HIV-associated epigenetic changes may occur in blood and whether early initiation of antiretroviral therapy (ART) impacts epigenetic modifications. We profiled longitudinal genome-wide DNA methylation in monocytes and CD4+ T lymphocytes from 22 participants in the RV254/SEARCH010 acute HIV infection (AHI) cohort that diagnoses infection within weeks after estimated exposure and immediately initiates ART. We identified monocytes harbored 22,697 differentially methylated CpGs associated with AHI compared to 294 in CD4+ T lymphocytes. ART minimally restored less than 1% of these changes in monocytes and had no effect upon T cells. Monocyte DNA methylation patterns associated with viral load, CD4 count, CD4/CD8 ratio, and longitudinal clinical phenotypes. Our findings suggest HIV-1 rapidly embeds an epigenetic memory not mitigated by ART and support determining epigenetic signatures in precision HIV medicine. Trial Registration: NCT00782808 and NCT00796146.

SUBMITTER: Corley MJ

PROVIDER: S-EPMC8386872 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Abrupt and altered cell-type-specific DNA methylation profiles in blood during Acute HIV infection persists despite prompt initiation of ART

Project description:Genome-wide DNA methylation profiling of monocytes and CD4+ T cells during acute HIV infection and following ART.

2021-07-15 | GSE180130 | GEO

Abrupt and altered cell-type-specific DNA methylation profiles in blood during Acute HIV infection persists despite prompt initiation of ART

Project description:Abrupt and altered cell-type-specific DNA methylation profiles in blood during Acute HIV infection persists despite prompt initiation of ART

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Altered DNA methylation profiles in blood from patients with sporadic Creutzfeldt-Jakob disease.

Project description:Prion diseases are fatal and transmissible neurodegenerative disorders caused by the misfolding and aggregation of prion protein. Although recent studies have implicated epigenetic variation in common neurodegenerative disorders, no study has yet explored their role in human prion diseases. Here we profiled genome-wide blood DNA methylation in the most common human prion disease, sporadic Creutzfeldt-Jakob disease (sCJD). Our case-control study (n = 219), when accounting for differences in cell type composition between individuals, identified 38 probes at genome-wide significance (p < 1.24 × 10-7). Nine of these sites were taken forward in a replication study, performed in an independent case-control (n = 186) cohort using pyrosequencing. Sites in or close to FKBP5, AIM2 (2 probes), UHRF1, KCNAB2 successfully replicated. The blood-based DNA methylation signal was tissue- and disease-specific, in that the replicated probe signals were unchanged in case-control studies using sCJD frontal-cortex (n = 84), blood samples from patients with Alzheimer's disease, and from inherited and acquired prion diseases. Machine learning algorithms using blood DNA methylation array profiles accurately distinguished sCJD patients and controls. Finally, we identified sites whose methylation levels associated with prolonged survival in sCJD patients. Altogether, this study has identified a peripheral DNA methylation signature of sCJD with a variety of potential biomarker applications.

| S-EPMC7666287 | biostudies-literature

Specialized meltwater biodiversity persists despite widespread deglaciation.

Project description:Glaciers are important drivers of environmental heterogeneity and biological diversity across mountain landscapes. Worldwide, glaciers are receding rapidly due to climate change, with important consequences for biodiversity in mountain ecosystems. However, the effects of glacier loss on biodiversity have never been quantified across a mountainous region, primarily due to a lack of adequate data at large spatial and temporal scales. Here, we combine high-resolution biological and glacier change (ca. 1850-2015) datasets for Glacier National Park, USA, to test the prediction that glacier retreat reduces biodiversity in mountain ecosystems through the loss of uniquely adapted meltwater stream species. We identified a specialized cold-water invertebrate community restricted to the highest elevation streams primarily below glaciers, but also snowfields and groundwater springs. We show that this community and endemic species have unexpectedly persisted in cold, high-elevation sites, even in catchments that have not been glaciated in ∼170 y. Future projections suggest substantial declines in suitable habitat, but not necessarily loss of this community with the complete disappearance of glaciers. Our findings demonstrate that high-elevation streams fed by snow and other cold-water sources continue to serve as critical climate refugia for mountain biodiversity even after glaciers disappear.

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Genome-wide DNA methylation profiles altered by Helicobacter pylori in gastric mucosa and blood leukocyte DNA.

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Insulin resistance persists despite a metabolically healthy obesity phenotype.

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| S-EPMC9136885 | biostudies-literature

Altered DNA Methylation Profiles in SF3B1 Mutated CLL Patients.

Project description:Mutations in splicing factor genes have a severe impact on the survival of cancer patients. Splicing factor 3b subunit 1 (SF3B1) is one of the most frequently mutated genes in chronic lymphocytic leukemia (CLL); patients carrying these mutations have a poor prognosis. Since the splicing machinery and the epigenome are closely interconnected, we investigated whether these alterations may affect the epigenomes of CLL patients. While an overall hypomethylation during CLL carcinogenesis has been observed, the interplay between the epigenetic stage of the originating B cells and SF3B1 mutations, and the subsequent effect of the mutations on methylation alterations in CLL, have not been investigated. We profiled the genome-wide DNA methylation patterns of 27 CLL patients with and without SF3B1 mutations and identified local decreases in methylation levels in SF3B1mut CLL patients at 67 genomic regions, mostly in proximity to telomeric regions. These differentially methylated regions (DMRs) were enriched in gene bodies of cancer-related signaling genes, e.g., NOTCH1, HTRA3, and BCL9L. In our study, SF3B1 mutations exclusively emerged in two out of three epigenetic stages of the originating B cells. However, not all the DMRs could be associated with the methylation programming of B cells during development, suggesting that mutations in SF3B1 cause additional epigenetic aberrations during carcinogenesis.

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Altered functional connectivity in the brain default-mode network of earthquake survivors persists after 2 years despite recovery from anxiety symptoms.

Project description:Although acute impact of traumatic experiences on brain function in disaster survivors is similar to that observed in post-traumatic stress disorders (PTSD), little is known about the long-term impact of this experience. We have used structural and functional magnetic resonance imaging to investigate resting-state functional connectivity and gray and white matter (WM) changes occurring in the brains of healthy Wenchuan earthquake survivors both 3 weeks and 2 years after the disaster. Results show that while functional connectivity changes 3 weeks after the disaster involved both frontal-limbic-striatal and default-mode networks (DMN), at the 2-year follow-up only changes in the latter persisted, despite complete recovery from high initial levels of anxiety. No gray or WM volume changes were found at either time point. Taken together, our findings provide important new evidence that while altered functional connectivity in the frontal-limbic-striatal network may underlie the post-trauma anxiety experienced by survivors, parallel changes in the DMN persist despite the apparent absence of anxiety symptoms. This suggests that long-term changes occur in neural networks involved in core aspects of self-processing, cognitive and emotional functioning in disaster survivors which are independent of anxiety symptoms and which may also confer increased risk of subsequent development of PTSD.

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HIV-Infected Individuals on ART With Impaired Immune Recovery Have Altered Plasma Metabolite Profiles.

Project description:BackgroundMultiple host factors may influence immune reconstitution in HIV-infected people after the initiation of suppressive antiretroviral therapy (ART). Aberrant metabolic pathways have been reported in people with HIV (PWH) on ART. We hypothesized that alterations in plasma metabolites were associated with immune recovery following ART.MethodsIn this cross-sectional study, the plasma metabolomic profiles of PWH on ART were evaluated. PWH of slow and fast immune recovery were classified by increase in CD4 T cells following 2 years of ART. Targeted plasma metabolite profiling by liquid chromatography-mass spectrometry and gas chromatography-mass spectrometry to determine metabolite signatures for HIV recovery identified >200 metabolites.ResultsNotably, indole-3-propionic acid was downregulated during HIV, possibly reflecting impaired gastrointestinal epithelium homeostasis. The most important metabolite discriminating between the PWH with fast and slow immune recovery was cysteine. Upregulated cysteine and cysteine pathways may contribute to redox-balance maintenance and T-cell function in PWH with fast immune recovery. Additionally, serine and glycine metabolism and bile acid biosynthesis were the most perturbed metabolic pathways in PWH.ConclusionsThese results provide a starting point for developing biomarker candidates for immune recovery in PWH on ART and provide insight into the interplay of metabolism and immune response in HIV infection.

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CpG Methylation Profiles of HIV-1 Pro-Viral DNA in Individuals on ART.

Project description:The latent HIV-1 reservoir is comprised of stably integrated and intact proviruses with limited to no viral transcription. It has been proposed that latent infection may be maintained by methylation of pro-viral DNA. Here, for the first time, we investigate the cytosine methylation of a replication competent provirus (AMBI-1) found in a T cell clone in a donor on antiretroviral therapy (ART). Methylation profiles of the AMBI-1 provirus were compared to other proviruses in the same donor and in samples from three other individuals on ART, including proviruses isolated from lymph node mononuclear cells (LNMCs) and peripheral blood mononuclear cells (PBMCs). We also evaluated the apparent methylation of cytosines outside of CpG (i.e., CpH) motifs. We found no evidence for methylation in AMBI-1 or any other provirus tested within the 5' LTR promoter. In contrast, CpG methylation was observed in the env-tat-rev overlapping reading frame. In addition, we found evidence for differential provirus methylation in cells isolated from LNMCs vs. PBMCs in some individuals, possibly from the expansion of infected cell clones. Finally, we determined that apparent low-level methylation of CpH cytosines is consistent with occasional bisulfite reaction failures. In conclusion, our data do not support the proposition that latent HIV infection is associated with methylation of the HIV 5' LTR promoter.

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