Intracellular HIV-1 Tat regulator induces epigenetic changes in the DNA methylation landscape
IntroductionThe HIV regulatory protein Tat enhances viral transcription and also modifies host gene expression, affecting cell functions like cell cycle and apoptosis. Residual expression of Tat protein is detected in blood and other tissues even under antiretroviral treatment. Cohort studies have...
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Frontiers Media S.A.
2025-03-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1532692/full |
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| author | Andrea Rodríguez-Agustín Andrea Rodríguez-Agustín Rubén Ayala-Suárez Francisco Díez-Fuertes Francisco Díez-Fuertes María José Maleno Izar de Villasante Angelika Merkel Mayte Coiras Mayte Coiras Víctor Casanova Víctor Casanova José Alcamí José Alcamí José Alcamí José Alcamí Núria Climent Núria Climent Núria Climent |
| author_facet | Andrea Rodríguez-Agustín Andrea Rodríguez-Agustín Rubén Ayala-Suárez Francisco Díez-Fuertes Francisco Díez-Fuertes María José Maleno Izar de Villasante Angelika Merkel Mayte Coiras Mayte Coiras Víctor Casanova Víctor Casanova José Alcamí José Alcamí José Alcamí José Alcamí Núria Climent Núria Climent Núria Climent |
| author_sort | Andrea Rodríguez-Agustín |
| collection | DOAJ |
| description | IntroductionThe HIV regulatory protein Tat enhances viral transcription and also modifies host gene expression, affecting cell functions like cell cycle and apoptosis. Residual expression of Tat protein is detected in blood and other tissues even under antiretroviral treatment. Cohort studies have indicated that, despite virologic suppression, people with HIV (PWH) are at increased risk of comorbidities linked to chronic inflammation, accelerated immune ageing, and cellular senescence, sometimes associated with abnormal genomic methylation patterns. We analysed whether Tat influences DNA methylation and subsequently impacts the transcriptional signature, contributing to inflammation and accelerated ageing.MethodsWe transfected Jurkat cells with full-length Tat (Tat101), Tat’s first exon (Tat72), or an empty vector (TetOFF). We assessed DNA methylation modifications via the Infinium MethylationEPIC array, and we evaluated transcriptomic alterations through RNA-Seq. Methylation levels in gene promoters or body regions were correlated to their expression data, and subsequently, we performed an overrepresentation analysis to identify the biological terms containing differentially methylated and expressed genes.ResultsTat101 expression caused significant hyper- and hypomethylation changes at individual CpG sites, resulting in slightly global DNA hypermethylation. Methylation changes at gene promoters and bodies resulted in altered gene expression, specifically regulating gene transcription in 5.1% of differentially expressed genes (DEGs) in Tat101- expressing cells. In contrast, Tat72 had a minimal impact on this epigenetic process. The observed differentially methylated and expressed genes were involved in inflammatory responses, lipid antigen presentation, and apoptosis.DiscussionTat expression in HIV infection may constitute a key epigenetic modelling actor that contributes to HIV pathogenesis and chronic inflammation. Clinical interventions targeting Tat blockade may reduce chronic inflammation and cellular senescence related to HIV infection comorbidities. |
| format | Article |
| id | doaj-art-5ea2244bb9e24eb7bf797d2ac5ea4d4e |
| institution | DOAJ |
| issn | 1664-3224 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Immunology |
| spelling | doaj-art-5ea2244bb9e24eb7bf797d2ac5ea4d4e2025-08-20T02:46:28ZengFrontiers Media S.A.Frontiers in Immunology1664-32242025-03-011610.3389/fimmu.2025.15326921532692Intracellular HIV-1 Tat regulator induces epigenetic changes in the DNA methylation landscapeAndrea Rodríguez-Agustín0Andrea Rodríguez-Agustín1Rubén Ayala-Suárez2Francisco Díez-Fuertes3Francisco Díez-Fuertes4María José Maleno5Izar de Villasante6Angelika Merkel7Mayte Coiras8Mayte Coiras9Víctor Casanova10Víctor Casanova11José Alcamí12José Alcamí13José Alcamí14José Alcamí15Núria Climent16Núria Climent17Núria Climent18AIDS and HIV Infection Group, Fundació de Recerca Clínic Barcelona-Institut d’Investigacions Biomédiques August Pi i Sunyer (FRCB-IDIBAPS), Barcelona, SpainUniversitat de Barcelona (UB), Barcelona, SpainAIDS and HIV Infection Group, Fundació de Recerca Clínic Barcelona-Institut d’Investigacions Biomédiques August Pi i Sunyer (FRCB-IDIBAPS), Barcelona, SpainAIDS Immunopathology Unit, Centro Nacional de Microbiología, Instituto de Salud Carlos III (ISCIII), Madrid, SpainCentro de Investigación Biomédica en Red sobre Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III (ISCIII), Madrid, SpainAIDS and HIV Infection Group, Fundació de Recerca Clínic Barcelona-Institut d’Investigacions Biomédiques August Pi i Sunyer (FRCB-IDIBAPS), Barcelona, SpainBioinformatics Unit, Josep Carreras Leukaemia Research Institute (IJC), Badalona, SpainBioinformatics Unit, Josep Carreras Leukaemia Research Institute (IJC), Badalona, SpainCentro de Investigación Biomédica en Red sobre Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III (ISCIII), Madrid, SpainImmunopathology and Viral Reservoir Unit, Centro Nacional de Microbiología, Instituto de Salud Carlos III (ISCIII), Madrid, SpainAIDS and HIV Infection Group, Fundació de Recerca Clínic Barcelona-Institut d’Investigacions Biomédiques August Pi i Sunyer (FRCB-IDIBAPS), Barcelona, SpainUniversitat de Barcelona (UB), Barcelona, SpainAIDS and HIV Infection Group, Fundació de Recerca Clínic Barcelona-Institut d’Investigacions Biomédiques August Pi i Sunyer (FRCB-IDIBAPS), Barcelona, SpainUniversitat de Barcelona (UB), Barcelona, SpainAIDS Immunopathology Unit, Centro Nacional de Microbiología, Instituto de Salud Carlos III (ISCIII), Madrid, SpainCentro de Investigación Biomédica en Red sobre Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III (ISCIII), Madrid, SpainAIDS and HIV Infection Group, Fundació de Recerca Clínic Barcelona-Institut d’Investigacions Biomédiques August Pi i Sunyer (FRCB-IDIBAPS), Barcelona, SpainUniversitat de Barcelona (UB), Barcelona, SpainCentro de Investigación Biomédica en Red sobre Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III (ISCIII), Madrid, SpainIntroductionThe HIV regulatory protein Tat enhances viral transcription and also modifies host gene expression, affecting cell functions like cell cycle and apoptosis. Residual expression of Tat protein is detected in blood and other tissues even under antiretroviral treatment. Cohort studies have indicated that, despite virologic suppression, people with HIV (PWH) are at increased risk of comorbidities linked to chronic inflammation, accelerated immune ageing, and cellular senescence, sometimes associated with abnormal genomic methylation patterns. We analysed whether Tat influences DNA methylation and subsequently impacts the transcriptional signature, contributing to inflammation and accelerated ageing.MethodsWe transfected Jurkat cells with full-length Tat (Tat101), Tat’s first exon (Tat72), or an empty vector (TetOFF). We assessed DNA methylation modifications via the Infinium MethylationEPIC array, and we evaluated transcriptomic alterations through RNA-Seq. Methylation levels in gene promoters or body regions were correlated to their expression data, and subsequently, we performed an overrepresentation analysis to identify the biological terms containing differentially methylated and expressed genes.ResultsTat101 expression caused significant hyper- and hypomethylation changes at individual CpG sites, resulting in slightly global DNA hypermethylation. Methylation changes at gene promoters and bodies resulted in altered gene expression, specifically regulating gene transcription in 5.1% of differentially expressed genes (DEGs) in Tat101- expressing cells. In contrast, Tat72 had a minimal impact on this epigenetic process. The observed differentially methylated and expressed genes were involved in inflammatory responses, lipid antigen presentation, and apoptosis.DiscussionTat expression in HIV infection may constitute a key epigenetic modelling actor that contributes to HIV pathogenesis and chronic inflammation. Clinical interventions targeting Tat blockade may reduce chronic inflammation and cellular senescence related to HIV infection comorbidities.https://www.frontiersin.org/articles/10.3389/fimmu.2025.1532692/fullHIV infectionTatepigeneticsDNA methylationinflammation |
| spellingShingle | Andrea Rodríguez-Agustín Andrea Rodríguez-Agustín Rubén Ayala-Suárez Francisco Díez-Fuertes Francisco Díez-Fuertes María José Maleno Izar de Villasante Angelika Merkel Mayte Coiras Mayte Coiras Víctor Casanova Víctor Casanova José Alcamí José Alcamí José Alcamí José Alcamí Núria Climent Núria Climent Núria Climent Intracellular HIV-1 Tat regulator induces epigenetic changes in the DNA methylation landscape Frontiers in Immunology HIV infection Tat epigenetics DNA methylation inflammation |
| title | Intracellular HIV-1 Tat regulator induces epigenetic changes in the DNA methylation landscape |
| title_full | Intracellular HIV-1 Tat regulator induces epigenetic changes in the DNA methylation landscape |
| title_fullStr | Intracellular HIV-1 Tat regulator induces epigenetic changes in the DNA methylation landscape |
| title_full_unstemmed | Intracellular HIV-1 Tat regulator induces epigenetic changes in the DNA methylation landscape |
| title_short | Intracellular HIV-1 Tat regulator induces epigenetic changes in the DNA methylation landscape |
| title_sort | intracellular hiv 1 tat regulator induces epigenetic changes in the dna methylation landscape |
| topic | HIV infection Tat epigenetics DNA methylation inflammation |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1532692/full |
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