{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T16:01:26Z","timestamp":1792598486996,"version":"4.5.0"},"reference-count":68,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,6,26]],"date-time":"2025-06-26T00:00:00Z","timestamp":1750896000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>The human genome contains approximately 3,200 near full-length autonomous human endogenous retroviral (HERV) genomes distributed across the 23 chromosomes. These autonomous HERV proviral genomes include long terminal repeats (LTRs) capable of promoting RNA transcription. In quiescent cells, most HERV loci remain transcriptionally silent. However, environmental changes, such as epigenetic remodeling of chromatin, can activate these silenced loci.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>To study HERV reactivation, we previously analyzed autonomous HERV expression patterns in monocytes isolated from peripheral blood mononuclear cells (PBMCs) identified in single-cell RNA sequencing (scRNA-seq) databases using the Azimuth application. We developed a Window-based HERV Alignment (WHA) method, which analyzes aligned DNA sequences using sequential, non-overlapping windows of defined lengths. Samples were scored as positive (&amp;gt;= 9 good\/usable windows) or negative (&amp;lt;= 8 good\/usable windows).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Using WHA, we established a control set from 31 normal individuals, with fewer than 8 windows at selected HERV loci. We analyzed scRNA-seq data from three studies of hospitalized COVID-19 patients and found distinct HERV expression patterns in monocytes. Unique patterns were also found in patients with influenza, Dengue virus, or sepsis. We next examined HERV expression at early (&amp;lt;7 days) and late (&amp;gt;14 days) timepoints post COVID-19 recovery and detected HERV loci in both groups. Analyzing 12 patients with post-acute sequelae of COVID-19 (PASC), we identified three HERV loci expressed in all patients. Some loci showed amplified numbers of good\/usable windows, indicating longer transcripts and greater sequence depth. The most amplified locus was located within an intron of JAKMIP2, which, along with neighboring host genes, also showed increased transcription.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Previous studies have shown that viral infections, including COVID-19, influenza, and Dengue virus, as well as sepsis, can induce innate immune memory in monocytes through epigenetic remodeling of hematopoietic stem and myeloid precursor cells. The identification of co-amplified HERV loci and neighboring host gene transcripts in monocytes from PASC patients suggests expansion of epigenetically remodeled myeloid progenitors. The identification of these HERV-host gene patterns provides a foundation needed to understand the clinical features of patients with PASC.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2025.1621657","type":"journal-article","created":{"date-parts":[[2025,6,26]],"date-time":"2025-06-26T08:15:39Z","timestamp":1750925739000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["Amplification of select autonomous HERV loci and surrounding host gene transcription in monocytes from patients with post-acute sequelae of COVID-19"],"prefix":"10.3389","volume":"16","author":[{"given":"Hyunmin","family":"Koo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Casey D.","family":"Morrow","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,6,26]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-virology-091919-072546","article-title":"Shifting the immune memory paradigm: trained immunity in viral infections","volume":"9","author":"Taks","year":"2022","journal-title":"Annu Rev Virol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1006\/smim.1998.0142","article-title":"Introduction: the role of innate immunity in the adaptive immune response","volume":"10","author":"Janeway","year":"1998","journal-title":"Semin Immunol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.01642","article-title":"The ontogeny of monocyte subsets","volume":"10","author":"Wolf","year":"2019","journal-title":"Front Immunol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2011.01.003","article-title":"Myeloid derived suppressor cells in human diseases","volume":"11","author":"Greten","year":"2011","journal-title":"Int Immunopharmacol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1038\/s41418-020-0572-6","article-title":"Expansion of myeloid-derived suppressor cells in patients with severe coronavirus disease (COVID-19)","volume":"27","author":"Agrati","year":"2020","journal-title":"Cell Death Differentiation"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.135678","article-title":"Single cell RNA sequencing identifies an early monocyte gene signature in acute respiratory distress syndrome","volume":"5","author":"Jiang","year":"2020","journal-title":"JCI Insight"},{"key":"B7","doi-asserted-by":"publisher","first-page":"440","DOI":"10.1038\/s41467-021-27716-4","article-title":"Single-cell multi-omics reveals dyssynchrony of the innate and adaptive immune system in progressive COVID-19","volume":"13","author":"Unterman","year":"2022","journal-title":"Nat Commun"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1007\/s00281-017-0625-1","article-title":"Immune-mediated cytokine storm and its role in severe dengue","volume":"39","author":"Srikiatkhachorn","year":"2017","journal-title":"Semin immunopathology"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2021.05.039","article-title":"The single-cell epigenomic and transcriptional landscape of immunity to influenza vaccination","volume":"184","author":"Wimmers","year":"2021","journal-title":"Cell"},{"key":"B10","doi-asserted-by":"publisher","first-page":"101401","DOI":"10.1016\/j.beha.2022.101401","article-title":"COVID-19 disease and immune dysregulation","volume":"35","author":"Davitt","year":"2022","journal-title":"Best Pract Res Clin Haematology"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.08.001","article-title":"Severe COVID-19 is marked by a dysregulated myeloid cell compartment","volume":"182","author":"Schulte-Schrepping","year":"2020","journal-title":"Cell"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-021-01113-x","article-title":"Immunological dysfunction persists for 8 months following initial mild-to-moderate SARS-CoV-2 infection","volume":"23","author":"Phetsouphanh","year":"2022","journal-title":"Nat Immunol"},{"key":"B13","doi-asserted-by":"publisher","first-page":"882","DOI":"10.1038\/s41467-022-28505-3","article-title":"Cell specific peripheral immune responses predict survival in critical COVID-19 patients","volume":"13","author":"Amrute","year":"2022","journal-title":"Nat Commun"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1009928","article-title":"Induction of trained immunity by influenza vaccination-impact on COVID-19","volume":"17","author":"Debisarun","year":"2021","journal-title":"PloS Pathog"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2024.08.018","article-title":"Antiviral innate immune memory in alveolar macrophages following SARS-CoV-2 infection ameliorates secondary influenza A virus disease","volume":"57","author":"Lercher","year":"2024","journal-title":"Immunity"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1294959","article-title":"COVID-19 and trained immunity: the inflammatory burden of long covid","volume":"14","author":"Gu","year":"2023","journal-title":"Front Immunol"},{"key":"B17","doi-asserted-by":"publisher","first-page":"890","DOI":"10.1016\/j.chom.2023.05.004","article-title":"The role of trained immunity in COVID-19: Lessons for the next pandemic","volume":"31","author":"Netea","year":"2023","journal-title":"Cell Host Microbe"},{"key":"B18","doi-asserted-by":"publisher","first-page":"460","DOI":"10.1038\/s41392-023-01717-9","article-title":"Long-COVID-19: the persisting imprint of SARS-CoV-2 infections on the innate immune system","volume":"8","author":"Boes","year":"2023","journal-title":"Signal transduction targeted Ther"},{"key":"B19","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1186\/s12964-023-01122-3","article-title":"Spotlight on the impact of viral infections on Hematopoietic Stem Cells (HSCs) with a focus on COVID-19 effects","volume":"21","author":"Nasiri","year":"2023","journal-title":"Cell Communication Signaling"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2023.07.019","article-title":"Epigenetic memory of coronavirus infection in innate immune cells and their progenitors","volume":"186","author":"Cheong","year":"2023","journal-title":"Cell"},{"key":"B21","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1007\/s13238-019-0633-0","article-title":"New paradigms on hematopoietic stem cell differentiation","volume":"11","author":"Cheng","year":"2020","journal-title":"Protein Cell"},{"key":"B22","doi-asserted-by":"publisher","first-page":"27","DOI":"10.4049\/jimmunol.1302061","article-title":"Infection-induced changes in hematopoiesis","volume":"192","author":"Zaretsky","year":"2014","journal-title":"J Immunol"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2017.05.063","article-title":"Systemic virus infections differentially modulate cell cycle state and functionality of long-term hematopoietic stem cells in vivo","volume":"19","author":"Hirche","year":"2017","journal-title":"Cell Rep"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1038\/35057062","article-title":"Erratum: Initial sequencing and analysis of the human genome: international human genome sequencing consortium (Nature (2001) 409 (860-921))","volume":"412","author":"Lander","year":"2001","journal-title":"Nature"},{"key":"B25","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s12977-015-0232-y","article-title":"Classification and characterization of human endogenous retroviruses; mosaic forms are common","volume":"13","author":"Vargiu","year":"2016","journal-title":"Retrovirology"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1016\/j.gene.2009.06.020","article-title":"Endogenous retroviral LTRs as promoters for human genes: a critical assessment","volume":"448","author":"Cohen","year":"2009","journal-title":"Gene"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1814589115","article-title":"ERVmap analysis reveals genome-wide transcription of human endogenous retroviruses","volume":"115","author":"Tokuyama","year":"2018","journal-title":"Proc Natl Acad Sci"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1126\/science.aad5497","article-title":"Regulatory evolution of innate immunity through co-option of endogenous retroviruses","volume":"351","author":"Chuong","year":"2016","journal-title":"Science"},{"key":"B29","doi-asserted-by":"publisher","first-page":"884","DOI":"10.3390\/v12080884","article-title":"Silencing and transcriptional regulation of endogenous retroviruses: an overview","volume":"12","author":"Geis","year":"2020","journal-title":"Viruses"},{"key":"B30","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1186\/s12977-024-00652-z","article-title":"Shared and unique patterns of autonomous human endogenous retrovirus loci transcriptomes in CD14+ monocytes from individuals with physical trauma or infection with COVID-19","volume":"21","author":"Koo","year":"2024","journal-title":"Retrovirology"},{"key":"B31","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s43587-024-00745-6","article-title":"Reactivation of senescence-associated endogenous retroviruses by ATF3 drives interferon signaling in aging","author":"Mao","year":"2024","journal-title":"Nat Aging"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1016\/j.csbj.2021.10.037","article-title":"Human endogenous retroviruses in development and disease","volume":"19","author":"Mao","year":"2021","journal-title":"Comput Struct Biotechnol J"},{"key":"B33","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1038\/s41581-022-00633-5","article-title":"Trained immunity\u2014basic concepts and contributions to immunopathology","volume":"19","author":"Ochando","year":"2023","journal-title":"Nat Rev Nephrol"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1016\/j.medj.2021.04.008","article-title":"Mucosal-associated invariant T cell responses differ by sex in COVID-19","volume":"2","author":"Yu","year":"2021","journal-title":"Med"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.abd1554","article-title":"Immunophenotyping of COVID-19 and influenza highlights the role of type I interferons in development of severe COVID-19","volume":"5","author":"Lee","year":"2020","journal-title":"Sci Immunol"},{"key":"B36","doi-asserted-by":"publisher","first-page":"495","DOI":"10.1038\/nbt.3192","article-title":"Spatial reconstruction of single-cell gene expression data","volume":"33","author":"Satija","year":"2015","journal-title":"Nat Biotechnol"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2019.05.031","article-title":"Comprehensive integration of single-cell data","volume":"177","author":"Stuart","year":"2019","journal-title":"Cell"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-023-01654-3","article-title":"Global and cell type-specific immunological hallmarks of severe dengue progression identified via a systems immunology approach","volume":"24","author":"Ghita","year":"2023","journal-title":"Nat Immunol"},{"key":"B39","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1038\/s41541-024-00853-9","article-title":"Expansion of memory V\u03b42 T cells following SARS-CoV-2 vaccination revealed by temporal single-cell transcriptomics","volume":"9","author":"Terzoli","year":"2024","journal-title":"Vaccines"},{"key":"B40","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1038\/s41421-020-0168-9","article-title":"Immune cell profiling of COVID-19 patients in the recovery stage by single-cell sequencing","volume":"6","author":"Wen","year":"2020","journal-title":"Cell Discov"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1093\/ofid\/ofab640","article-title":"Persistence, magnitude, and patterns of postacute symptoms and quality of life following onset of SARS-CoV-2 infection: cohort description and approaches for measurement","volume":"9","author":"Peluso","year":"2022","journal-title":"Open Forum Infect diseases"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2021.109518","article-title":"Long-term SARS-CoV-2-specific immune and inflammatory responses in individuals recovering from COVID-19 with and without post-acute symptoms","volume":"36","author":"Peluso","year":"2021","journal-title":"Cell Rep"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1172\/JCI140491","article-title":"Sustained cellular immune dysregulation in individuals recovering from SARS-CoV-2 infection","volume":"131","author":"Files","year":"2021","journal-title":"J Clin Invest"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.151544","article-title":"Duration of post\u2013COVID-19 symptoms is associated with sustained SARS-CoV-2\u2013specific immune responses","volume":"6","author":"Files","year":"2021","journal-title":"JCI Insight"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1038\/s41556-021-00690-1","article-title":"Single-cell epigenomic landscape of peripheral immune cells reveals establishment of trained immunity in individuals convalescing from COVID-19","volume":"23","author":"You","year":"2021","journal-title":"Nat Cell Biol"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-023-01724-6","article-title":"Long COVID manifests with T cell dysregulation, inflammation and an uncoordinated adaptive immune response to SARS-CoV-2","volume":"25","author":"Yin","year":"2024","journal-title":"Nat Immunol"},{"key":"B47","doi-asserted-by":"publisher","first-page":"3315","DOI":"10.1038\/s41467-024-47720-8","article-title":"Improvement of immune dysregulation in individuals with long COVID at 24-months following SARS-CoV-2 infection","volume":"15","author":"Phetsouphanh","year":"2024","journal-title":"Nat Commun"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2019.01.041","article-title":"RNA-Seq signatures normalized by mRNA abundance allow absolute deconvolution of human immune cell types","volume":"26","author":"Monaco","year":"2019","journal-title":"Cell Rep"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.621333","article-title":"Innate immune memory in hematopoietic stem\/progenitor cells: myeloid-biased differentiation and the role of interferon","volume":"12","author":"Chen","year":"2021","journal-title":"Front Immunol"},{"key":"B50","doi-asserted-by":"publisher","first-page":"433","DOI":"10.1038\/s41597-023-02348-z","article-title":"Single cell transcriptome sequencing of stimulated and frozen human peripheral blood mononuclear cells","volume":"10","author":"Derbois","year":"2023","journal-title":"Sci Data"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2006.04.008","article-title":"Toll-like receptors on hematopoietic progenitor cells stimulate innate immune system replenishment","volume":"24","author":"Nagai","year":"2006","journal-title":"Immunity"},{"key":"B52","doi-asserted-by":"publisher","first-page":"595","DOI":"10.1186\/s12864-023-09663-0","article-title":"Mapping the epigenomic landscape of human monocytes following innate immune activation reveals context-specific mechanisms driving endotoxin tolerance","volume":"24","author":"Amarasinghe","year":"2023","journal-title":"BMC Genomics"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1111\/imm.v163.3","article-title":"Monocytes, macrophages, dendritic cells and neutrophils: an update on lifespan kinetics in health and disease","volume":"163","author":"Patel","year":"2021","journal-title":"Immunology"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2022.111447","article-title":"Influenza A virus infection instructs hematopoiesis to megakaryocyte-lineage output","volume":"41","author":"Rommel","year":"2022","journal-title":"Cell Rep"},{"key":"B55","doi-asserted-by":"publisher","first-page":"3649","DOI":"10.18632\/oncotarget.12278","article-title":"On the origin of myeloid-derived suppressor cells","volume":"8","author":"Millrud","year":"2016","journal-title":"Oncotarget"},{"key":"B56","doi-asserted-by":"publisher","first-page":"bio033282","DOI":"10.1242\/bio.033282","article-title":"Mammalian embryo comparison identifies novel pluripotency genes associated with the na\u00efve or primed state","volume":"7","author":"Bernardo","year":"2018","journal-title":"Biol Open"},{"key":"B57","doi-asserted-by":"publisher","first-page":"231","DOI":"10.1007\/s12672-023-00849-2","article-title":"Machine learning and experiments identifies SPINK1 as a candidate diagnostic and prognostic biomarker for hepatocellular carcinoma","volume":"14","author":"Yi","year":"2023","journal-title":"Discover Oncol"},{"key":"B58","doi-asserted-by":"publisher","first-page":"187","DOI":"10.1007\/s00018-022-04220-6","article-title":"Hematopoietic responses to SARS-CoV-2 infection","volume":"79","author":"Elahi","year":"2022","journal-title":"Cell Mol Life Sci"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.genet.42.110807.091501","article-title":"Effects of retroviruses on host genome function","volume":"42","author":"Jern","year":"2008","journal-title":"Annu Rev Genet"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btm455","article-title":"Idiographica: a general-purpose web application to build idiograms on-demand for human, mouse and rat","volume":"23","author":"Kin","year":"2007","journal-title":"Bioinformatics"},{"key":"B61","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1038\/nrg3117","article-title":"Repetitive DNA and next-generation sequencing: computational challenges and solutions","volume":"13","author":"Treangen","year":"2012","journal-title":"Nat Rev Genet"},{"key":"B62","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkab1020","article-title":"DISCO: a database of Deeply Integrated human Single-Cell Omics data","volume":"50","author":"Li","year":"2022","journal-title":"Nucleic Acids Res"},{"key":"B63","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.145108","article-title":"A road map from single-cell transcriptome to patient classification for the immune response to trauma","volume":"6","author":"Chen","year":"2021","journal-title":"JCI Insight"},{"key":"B64","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2021.108863","article-title":"Metabolic programs define dysfunctional immune responses in severe COVID-19 patients","volume":"34","author":"Thompson","year":"2021","journal-title":"Cell Rep"},{"key":"B65","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2711-0","article-title":"Human germinal centres engage memory and naive B cells after influenza vaccination","volume":"586","author":"Turner","year":"2020","journal-title":"Nature"},{"key":"B66","doi-asserted-by":"publisher","first-page":"14049","DOI":"10.1038\/ncomms14049","article-title":"Massively parallel digital transcriptional profiling of single cells","volume":"8","author":"Zheng","year":"2017","journal-title":"Nat Commun"},{"key":"B67","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btu494","article-title":"STAMP: statistical analysis of taxonomic and functional profiles","volume":"30","author":"Parks","year":"2014","journal-title":"Bioinformatics"},{"key":"B68","volume-title":"R: A language and environment for statistical computing [Computer software manual]","author":"Team","year":"2016"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1621657\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,6,26]],"date-time":"2025-06-26T08:15:41Z","timestamp":1750925741000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1621657\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,26]]},"references-count":68,"alternative-id":["10.3389\/fimmu.2025.1621657"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2025.1621657","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,6,26]]},"article-number":"1621657"}}