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However, widespread clinical implementation has been hampered by the lack of standardized, high-throughput diagnostic assays and limited understanding of the physiological variability of TTV viral loads over time. Here, we developed and analytically validated a novel fully automated high-throughput quantitative PCR assay for standardized TTV-DNA measurement in routine diagnostics and large-scale clinical studies. The assay demonstrated high analytical sensitivity and specificity, with a limit of detection of 32.3 copies\/ml. Using this platform, we performed longitudinal profiling of plasma and serum samples collected over up to 51 months from non-immunosuppressed individuals. We observed substantial inter- and intra-individual fluctuations in TTV-DNA levels in a subset of healthy subjects, revealing intrinsic biological variability independent of immunosuppressive therapy. These findings establish a robust platform for standardized TTV monitoring while demonstrating that longitudinal viral load dynamics must be interpreted in the context of natural biological variation. Our study provides an important framework for the clinical implementation of TTV-guided immune monitoring and the need for development of evidence-based thresholds for individualized immunosuppressive therapies.<\/jats:p>","DOI":"10.1038\/s44321-026-00540-3","type":"journal-article","created":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T15:21:56Z","timestamp":1791472916000},"page":"4618-4642","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A novel Torque teno virus qPCR assay reveals longitudinal viral load variability among non-immunosuppressed subjects"],"prefix":"10.1038","volume":"18","author":[{"given":"Lara","family":"Valder","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-5174-7563","authenticated-orcid":false,"given":"Thomas G","family":"Grigore","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Schaaf","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Quirin","family":"Bachmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lutz","family":"Renders","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1948-2057","authenticated-orcid":false,"given":"Samuel D","family":"Jeske","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc","family":"L\u00fctgehetmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sibylle","family":"Bierbaum","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3482-816X","authenticated-orcid":false,"given":"Hartmut","family":"Hengel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"D\u00e4chert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9421-1911","authenticated-orcid":false,"given":"Ulrike","family":"Protzer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4101-9280","authenticated-orcid":false,"given":"Jochen M","family":"Wettengel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,10,8]]},"reference":[{"key":"540_CR1","doi-asserted-by":"publisher","first-page":"951","DOI":"10.1080\/14737159.2019.1665999","volume":"19","author":"G Aretzweiler","year":"2019","unstructured":"Aretzweiler G, Leuchter S, Simon CO, Marins E, Frontzek A (2019) Generating timely molecular diagnostic test results: workflow comparison of the cobas\u00ae 6800\/8800 to Panther. 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ML received speaker honoraria and related travel expenses from Roche Diagnostics, as well as personal fees for participation on an advisory board from Roche Molecular Systems. UP is a co-founder, shareholder, and board member of SCG Cell Therapy and serves as an ad hoc advisor to Aligos, Arbutus, GSK, Roche, Sanofi, Vaccitech\/Barinthos, and Vir Bio. The remaining authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Disclosure and competing interests statement"}}]}}