DNA methylation patterns associated with prior tuberculosis infection in people with HIV
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ABSTRACT:
PROVIDER: PRJNA1298927 | ENA |
REPOSITORIES: ENA
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Project description:Background: Mechanisms by which prior tuberculosis (TB) increases long-term risk for cancer, cardiovascular, and neurological disorders remain unclear, particularly in people with HIV (PWH). This study investigated DNA methylation (DNAm) patterns and associated pathways in PWH with and without prior TB infection. Methods: DNAm was analyzed in blood samples from 30 PWH (10 with prior latent TB infection [LTBI], 10 with previous successfully treated active TB, and 10 with no TB) using the Illumina MethylationEPIC BeadChip covering over 850,000 CpG sites. Epigenetic age was estimated, and age acceleration was calculated. Differentially methylated CpGs (dmCpGs) and regions (DMRs) were identified, and functional enrichment analyses for Gene Ontology, KEGG pathways, PANTHER database, and gene set enrichment analysis (DisGeNET, dbGaP) were performed. Statistical significance was set at a false discovery rate (FDR) of <0.05. Results: PWH exhibited significant epigenetic age acceleration, with a mean of 19.32 ± 10.82 years greater than chronological age. This accelerated aging was more pronounced in individuals with any prior TB infection (21.60 ± 12.03 years) compared to those without TB (17.42 ± 9.38 years). In the prior active TB vs. no TB comparison, 7,461 dmCpGs were identified, corresponding to 150 DMRs (p<0.05), with top associated genes including GRAMD1C (hypomethylation), DPP6 (hypermethylation), and HDAC4 (hypomethylation). In the LTBI vs. no TB comparison, 8,598 dmCpGs were observed, corresponding to 39 DMRs (p<0.05), associated with genes such as PLEKHG5 (hypermethylation), STK32C (hypermethylation), and SPATC1L. When comparing any prior TB (active or latent) to no TB, 71,774 dmCpGs and 14 DMRs were identified, including genes like PLEKHG5, KCNN3, and BRSK2. Pathway analyses of prior TB (active or latent) vs. no TB revealed enrichment in neurogenesis, neuron differentiation, axon guidance, and neuroactive ligand signaling. Additional enriched pathways included those related to platelet activation, vascular muscle contraction, and chemokine signaling. Cancer-related pathways such as proteoglycans in cancer, small cell lung cancer, prostate cancer, breast cancer, hepatocellular carcinoma, and thyroid cancer were also enriched. PANTHER analysis showed consistent enrichment in the Wnt signaling pathway and inflammation-mediated pathways across compared groups. DisGeNET analysis linked prior TB DNAm patterns to lymphoid leukemia, while dbGaP analysis identified associations with phenotypes like asthma, body mass index, tunica media, and lymphocyte count Conclusion: Prior TB infection in PWH is associated with distinct DNAm changes in pathways related to neural function, cardiovascular health, and cancer risk, and is linked to more pronounced epigenetic age acceleration, suggesting epigenetic mechanisms for TB-related long-term complications.
2025-08-27 | GSE304107 | GEO
Project description:Mechanisms by which HIV causes susceptibility to respiratory pathogens remain incompletely understood. We obtained whole blood and bronchoalveolar lavage (BAL) from people with latent TB infection in the presence or absence of ARV-naïve HIV co-infection. Transcriptomic and flow cytometric analyses demonstrated HIV-associated cell proliferation and type I interferon activity in blood and effector memory CD8 T-cells in BAL. Both compartments displayed reduced induction of CD8 T cell-related IL-17A in people with HIV, associated with elevated T cell regulatory molecule expression. We propose dysfunctional CD8 T cell responses in uncontrolled HIV contribute to susceptibility to secondary bacterial infections, including tuberculosis.
2024-12-31 | GSE230738 | GEO
Project description:Mechanisms by which HIV causes susceptibility to respiratory pathogens remain incompletely understood. We obtained whole blood and bronchoalveolar lavage (BAL) from people with latent TB infection in the presence or absence of ARV-naïve HIV co-infection. Transcriptomic and flow cytometric analyses demonstrated HIV-associated cell proliferation and type I interferon activity in blood and effector memory CD8 T-cells in BAL. Both compartments displayed reduced induction of CD8 T cell-related IL-17A in people with HIV, associated with elevated T cell regulatory molecule expression. We propose dysfunctional CD8 T cell responses in uncontrolled HIV contribute to susceptibility to secondary bacterial infections, including tuberculosis.
2024-12-20 | GSE231628 | GEO
Project description:In this study we performed data-independet mass-spectrometry analysis of blood plasma collected from a cohort consisting of people living with HIV-1, people living with HIV-2, and HIV seronegative individuals. The data was used to infer signs of damage to a wide array of tissues and cell types.
2024-02-16 | PXD045155 | Pride
Project description:The preference of HIV to infect activated CD4 T cells has been proposed to contribute to a numerical reduction of antigen-specific T cells and the loss of T cell-mediated immunity. To date, our understanding of how HIV impact on vaccine-induced cellular immunity is limited. Moreover, the influence of chronic inflammation, that persist in treated HIV infection, is still unclear. Here, we investigated inflammation, immune activation and antigen-specific T cell responses in HIV-uninfected and cART-treated HIV people with prior measles virus and tetanus toxoid immunity. Our findings highlight lower antigen-induced T cell activation and lower cytokine production of antigen-specific CD4 T cells in the HIV group. These lower recall CD4 T cell responses associated with high plasma levels of multiple cytokines and with T cell hyperactivation. Transcriptome analysis of sorted antigen-specific CD4 T cells revealed that upon antigen reencounter, HIV people on cART had a reduced expression of gene sets previously reported to associate with vaccine-induced protective immunity against various pathogens. We further identified a consistent impairment of the IFN and IFN signaling pathways as a mechanism for the functional loss of antigen-specific CD4 T cell responses in cART-treated people with HIV. Together, our findings suggest that vaccine-induced cellular immunity may benefit from strategies to counteract inflammation in HIV infection.pecific
2024-10-16 | GSE273967 | GEO
Project description:To understand how HIV and timing of ART initiation affect the transcriptional profile of Mtb-specific CD4 T cells, we performed 10X single-cell RNA sequencing comparing Mtb-specific CD4 T cell transcriptomes from people without HIV, people with HIV prior to ART, and people with HIV after ART from the Mombasa Cohort in Mombasa, Kenya. PBMCs were stimulated overnight with Mycobacterium tuberculosis whole cell lysate and CD40L+CD69+ Mtb-specifc CD4 T cells were sorted for sequencing.
2025-07-10 | GSE299662 | GEO
Project description:Immune activation in people living with HIV on anti-retroviral therapy is associated with increased risk of morbidity and mortality, but the underlying mechanisms are poorly understood. To identify whether perturbation of immunological pathways persist at systems level, we compared genome-wide whole blood transcriptomes from 26 people living with HIV on long-term anti-retroviral therapy with 12 HIV-negative healthy controls. All participants were Caucasian male adults recruited from London, UK. People living with HIV were on anti-retroviral therapy for a median of 8.5 years (interquartile range 3-16 years). They had undetectable plasma HIV viral load (<40 copies/ml) and median circulating CD4 counts of 703 cells/µl (interquartile range 491-841 cells/µl).
2021-02-26 | E-MTAB-8891 | biostudies-arrayexpress
Project description:<p>Rare individuals are highly resistant to infection with human immunodeficiency virus (HIV). Studies of candidate genes resulted in the discovery of a 32bp deletion in the CC-chemokine receptor 5 gene (CCR5Δ32), which rendered this critical co-receptor for primary HIV infection to be non-functional. Pharmacologic and vaccine-induced blockade of CCR5 is being pursued to treat and prevent HIV infection and other conditions.</p> <p>The allele frequency of CCR5Δ32 among persons of European ancestry is approximately 10%. CCR5Δ32/Δ32 homozygotes are almost totally resistant to HIV infection. People with severe hemophilia A require frequent replacement with clotting Factor VIII (FVIII) to control hemorrhage. Prior to the discovery of HIV in 1984 and licensure of recombinant FVIII in the late 1980s, people with severe hemophilia A were treated with plasma-derived FVIII and thus were intensively exposed to HIV. Only 5% of such patients were not infected with HIV. Of these, approximately 1/3 were CCR5Δ32/Δ32 homozygotes. The remaining 2/3 of these people who were highly resistant to HIV remain unexplained. This project seeks to discover genome variations among people who are highly resistant to HIV infection. Such variation is likely to serve as a target for reducing the morbidity and incidence of HIV. </p>
| phs000445.v1.p1 | EGA
Project description:Genome-wide DNA methylation profiling of blood samples from people living with HIV HIV-1 infection impacts biological ageing, and epigenetic clocks highlight epigenetic age acceleration in people with HIV. Despite evidence indicating sex differences in clinical, immunological, and virological measures, females have been underrepresented in most HIV epigenetic studies. Hence, we generated a more representative epigenetic dataset to examine sex differences in epigenetic ageing and relationships to clinical phenotypes.
2025-03-05 | GSE283506 | GEO
Project description:Antiretroviral therapy (ART) is not curative due to the existence of cellular reservoirs of latent HIV-1 that persist during therapy 1. Current research efforts to cure HIV-1 infection include “shock and kill” strategies to disrupt latency using small molecules or latency-reversing agents (LRAs) to induce expression of HIV-1 enabling cytotoxic immune cells to eliminate infected cells 2. However, the modest success of current LRAs urges the field to identify novel drugs with increased clinical efficacy 3,4. Aminobisphosphonates that include pamidronate, zoledronate, or alendronate, are the first-line treatment of bone-related diseases including osteoporosis and bone malignancies 5. Here, we show the use of aminobisphosphonates as a novel class of LRA: we found in ex vivo assays using primary cells from ART-suppressed people living with HIV-1 that aminobisphosphonates induce HIV-1 from latency to levels that are comparable to the T cell activator phytohemagglutinin. RNA sequencing and mechanistic data suggested that reactivation may occur through activation of the activator protein 1 signaling pathway. Stored samples from a prior clinical trial aimed at analyzing the effect of alendronate on bone mineral density, provided further of alendronate-mediated latency reversal and activation of immune effector cells.Decay of the reservoir measured by IPDA was however not detected. Our results demonstrate the novel use of aminobisphosphonates to reverse HIV-1 latency while inducing immune effector functions. This preliminary evidence merits further investigation in a controlled clinical setting possibly in combination with therapeutic vaccination.
2023-09-13 | GSE224546 | GEO