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Despite prior detection of human endogenous retrovirus (HERV) activation in these diseases, the potential biomarker value of HERV expression profiles for their diagnosis, and the relationship of HERV expression profiles with patient immune systems and symptoms had remained unexplored. By using HERV-V3 high-density microarrays (including over 350k HERV elements and more than 1500 immune-related genes) to interrogate the transcriptomes of peripheral blood mononuclear cells from female patients diagnosed with ME\/CFS, FM, or both, and matched healthy controls (\n                    <jats:italic>n<\/jats:italic>\n                    = 43), this study fills this gap of knowledge. Hierarchical clustering of HERV expression profiles strikingly allowed perfect participant assignment into four distinct groups: ME\/CFS, FM, co-diagnosed, or healthy, pointing at a potent biomarker value of HERV expression profiles to differentiate between these hard-to-diagnose chronic syndromes. Differentially expressed HERV\u2013immune\u2013gene modules revealed unique profiles for each of the four study groups and highlighting decreased \u03b3\u03b4 T cells, and increased plasma and resting CD4 memory T cells, correlating with patient symptom severity in ME\/CFS. Moreover, activation of HERV sequences coincided with enrichment of binding sequences targeted by transcription factors which recruit SETDB1 and TRIM28, two known epigenetic silencers of HERV, in ME\/CFS, offering a mechanistic explanation for the findings. Unexpectedly, HERV expression profiles appeared minimally affected in co-diagnosed patients denoting a new nosological entity with low epigenetic impact, a seemingly relevant aspect for the diagnosis and treatment of this prevalent group of patients.\n                  <\/jats:p>","DOI":"10.7554\/elife.104441","type":"journal-article","created":{"date-parts":[[2025,2,5]],"date-time":"2025-02-05T06:25:07Z","timestamp":1738736707000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.104441","source":"Crossref","is-referenced-by-count":1,"title":["HERV activation segregates ME\/CFS from fibromyalgia while defining a novel nosologic entity"],"prefix":"10.7554","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9790-7327","authenticated-orcid":true,"given":"Karen","family":"Gim\u00e9nez-Orenga","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03d7a9c68","id-type":"ROR","asserted-by":"publisher"}],"name":"Escuela de Doctorado, Catholic University of Valencia","place":["Valencia, Spain"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"data-curation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3261-494X","authenticated-orcid":true,"given":"Eva","family":"Mart\u00edn-Mart\u00ednez","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0396mnx76","id-type":"ROR","asserted-by":"publisher"}],"name":"National Health Service, Manises Hospital","place":["Valencia, Spain"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"investigation","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1038-9083","authenticated-orcid":true,"given":"Lubov","family":"Nathanson","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/042bbge36","id-type":"ROR","asserted-by":"publisher"}],"name":"Institute for Neuro-Immune Medicine, Dr. Kiran C. 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