{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T03:43:56Z","timestamp":1785210236059,"version":"3.55.0"},"update-to":[{"DOI":"10.1371\/journal.ppat.1014296","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T00:00:00Z","timestamp":1781222400000}}],"reference-count":54,"publisher":"Public Library of Science (PLoS)","issue":"6","license":[{"start":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T00:00:00Z","timestamp":1780876800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002347","name":"Bundesministerium f\u00fcr Bildung und Forschung","doi-asserted-by":"publisher","award":["BMBF 01KI2017"],"award-info":[{"award-number":["BMBF 01KI2017"]}],"id":[{"id":"10.13039\/501100002347","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Freiburg University Medical Center","award":["Hans A. Krebs Medical Scientist Program"],"award-info":[{"award-number":["Hans A. Krebs Medical Scientist Program"]}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>\n                    Severe HSV-1 disease is treated with potent antiviral drugs, in particular aciclovir (ACV) and its derivatives. However, long-term drug exposure in immunocompromised patients can lead to the emergence of ACV-resistant HSV-1 strains and clinical treatment failure. To understand how phenotypic resistances develop on a genomic level, we analyzed the influence of ACV selection pressure on the viral genome of different HSV-1 virus strains\n                    <jats:italic>in vitro<\/jats:italic>\n                    . Growth kinetics and IC\n                    <jats:sub>50<\/jats:sub>\n                    determination showed ACV resistance development within a single passage. Next, we performed ultra-deep, non-targeted full-genome Illumina sequencing of the parental and ACV-adapted HSV-1 strains. Interestingly, resistance-conferring mutations rapidly arose in the viral genes\n                    <jats:italic>UL23<\/jats:italic>\n                    and\n                    <jats:italic>UL30<\/jats:italic>\n                    and were already present in the parental ACV-na\u00efve strains at extremely low variant frequencies. Based on these findings, we hypothesized that low- frequency mutations develop during continued viral replication. To test this hypothesis, a primary rescued recombinant K17\u2009+\u2009strain was repeatedly passaged. Continued passaging indeed increased the proportion of a subset of minor variants and allowed resistance development after, but not before, 10 consecutive passages. In summary, we show that minor variants can facilitate adaptation of HSV-1 populations to selective pressures such as pharmacological inhibition of replication. These findings highlight that deep sequencing might allow early detection of resistance mutations potentially supporting antiviral drug stewardship.\n                  <\/jats:p>","DOI":"10.1371\/journal.ppat.1014296","type":"journal-article","created":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T17:43:55Z","timestamp":1780940635000},"page":"e1014296","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":2,"title":["Low frequency variants can predetermine antiviral drug resistance development in herpes simplex virus type 1"],"prefix":"10.1371","volume":"22","author":[{"given":"Lena","family":"Jaki","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florian","family":"Full","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Udo","family":"Gieraths","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valeria","family":"Falcone","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zsolt","family":"Ruzsics","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hartmut","family":"Hengel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcus","family":"Panning","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1974-212X","authenticated-orcid":true,"given":"Jonas","family":"Fuchs","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,6,8]]},"reference":[{"issue":"9","key":"ppat.1014296.ref001","doi-asserted-by":"crossref","first-page":"110652","DOI":"10.1016\/j.isci.2024.110652","article-title":"Epidemiology of herpes simplex virus type 1 in the United States: Systematic review, meta-analyses, and meta-regressions","volume":"27","author":"RA Ageeb","year":"2024","journal-title":"iScience"},{"issue":"1","key":"ppat.1014296.ref002","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1007\/s00705-008-0278-4","article-title":"The order Herpesvirales","volume":"154","author":"AJ Davison","year":"2009","journal-title":"Arch Virol"},{"issue":"5","key":"ppat.1014296.ref003","doi-asserted-by":"crossref","DOI":"10.1002\/rmv.2574","article-title":"Management of Refractory\/Resistant Herpes Simplex Virus Infections in Haematopoietic Stem Cell Transplantation Recipients: A Literature Review","volume":"34","author":"L Sall\u00e9e","year":"2024","journal-title":"Rev Med Virol"},{"key":"ppat.1014296.ref004","doi-asserted-by":"crossref","first-page":"115322","DOI":"10.1016\/j.bcp.2022.115322","article-title":"Acyclovir resistance in herpes simplex viruses: Prevalence and therapeutic alternatives","volume":"206","author":"HH Schalkwijk","year":"2022","journal-title":"Biochem Pharmacol"},{"key":"ppat.1014296.ref005","doi-asserted-by":"crossref","unstructured":"Anton-Vazquez V. 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