{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T18:09:56Z","timestamp":1784138996454,"version":"3.55.0"},"reference-count":46,"publisher":"Public Library of Science (PLoS)","issue":"7","license":[{"start":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T00:00:00Z","timestamp":1784073600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/publicdomain\/zero\/1.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"name":"National Cancer Institute, National Institutes of Health","award":["Contract No. 75N91019D00024"],"award-info":[{"award-number":["Contract No. 75N91019D00024"]}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>Persistent infection with high-risk (HR)-HPV causes cervical cancer, however, it is unclear why most infections resolve while a minority progress. We deep sequenced the HPV genomes of 1,228 HR-HPV-positive serial samples from 351 women with persistent infections (2\u201310 serial samples per woman over 1\u20138 years), including 279 controls and 72 precancer\/cancer cases, to assess HR-HPV genome changes during infection and relation to infection outcomes. Seventy-seven percent of persistent infections (45\u201397% by HPV type) were infections with the same exact viral genome isolate; for HPV16, only 52% were persistent with the same isolate. This may suggest some infections include a type-specific isolate switch or new isolate infection during persistence. We additionally observed within-host change to the HPV genome estimated as gradual changes to intrahost single nucleotide variant (iSNV) frequency, and changes varied by HPV type, with HPV33 infections showing the most iSNV changes. Cases exhibited fewer viral genome changes during infection compared to controls (OR = 0.31, 95% CI\u2009=\u20090.1 \u2013 0.86, p\u2009=\u20090.019), suggesting a more stable and clonal viral genome in cases. By viral gene, E7 had fewer nonsynonymous mutations in the cases compared to controls that cleared within 2 years of infection (p\u2009=\u20090.012), which confirms the importance of E7 conservation and suggests mutations to E7 reduce persistence associated with progression. There was a similar pattern in E4 (p\u2009=\u20090.013), while E5 had more changes in the cases (p\u2009=\u20090.008). A subset of 28 infections had an intervening HPV-negative sample between HPV-positive visits; 93% of these infections had the same exact viral genome isolate in the samples before and after the negative, consistent with subclinical persistence and subsequent re-detection. Our data suggests that HR-HPV type-persistence can include a collection of viral isolates, and viral mutations during infection, particularly in E7, reduce HR-HPV persistence and thus carcinogenic potential.<\/jats:p>","DOI":"10.1371\/journal.ppat.1014362","type":"journal-article","created":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T17:40:48Z","timestamp":1784137248000},"page":"e1014362","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Longitudinal analysis of high-risk HPV infections reveals within-host viral genome changes over time"],"prefix":"10.1371","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8319-0599","authenticated-orcid":true,"given":"Sambit K.","family":"Mishra","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meredith","family":"Yeager","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6287-1598","authenticated-orcid":true,"given":"Chase W.","family":"Nelson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurie","family":"Burdett","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert D.","family":"Burk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Dean","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rolando","family":"Herrero","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Schiffman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana Cecilia","family":"Rodriguez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8485-0106","authenticated-orcid":true,"given":"Lisa","family":"Mirabello","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,7,15]]},"reference":[{"key":"ppat.1014362.ref001","first-page":"229","article-title":"Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"74","author":"F Bray","year":"2024","journal-title":"CA Cancer J Clin"},{"key":"ppat.1014362.ref002","volume-title":"Agents Classified by the IARC Monographs, Volumes 1\u2013129 \u2013 IARC Monographs on the Identification of Carcinogenic Hazards to Humans","author":"International Agency for Research on Cancer","year":"2021"},{"key":"ppat.1014362.ref003","article-title":"The biology and life-cycle of human papillomaviruses","author":"J Doorbar","year":"2012","journal-title":"Vaccine"},{"key":"ppat.1014362.ref004","doi-asserted-by":"crossref","first-page":"16086","DOI":"10.1038\/nrdp.2016.86","article-title":"Carcinogenic human papillomavirus infection","volume":"2","author":"M Schiffman","year":"2016","journal-title":"Nat Rev Dis Primers"},{"key":"ppat.1014362.ref005","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1016\/j.virol.2013.07.018","article-title":"Human papillomavirus genome variants","volume":"445","author":"RD Burk","year":"2013","journal-title":"Virology"},{"key":"ppat.1014362.ref006","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1002\/rmv.1822","article-title":"Human papillomavirus molecular biology and disease association","author":"J Doorbar","year":"2015","journal-title":"Rev Med Virol"},{"key":"ppat.1014362.ref007","doi-asserted-by":"crossref","first-page":"100293","DOI":"10.1016\/j.eclinm.2020.100293","article-title":"A study of type-specific HPV natural history and implications for contemporary cervical cancer screening programs","volume":"22","author":"M Demarco","year":"2020","journal-title":"EClinicalMedicine"},{"issue":"11","key":"ppat.1014362.ref008","doi-asserted-by":"crossref","first-page":"1048","DOI":"10.1016\/S1470-2045(10)70230-8","article-title":"Human papillomavirus genotype attribution in invasive cervical cancer: a retrospective cross-sectional worldwide study","volume":"11","author":"S de Sanjose","year":"2010","journal-title":"Lancet Oncol"},{"key":"ppat.1014362.ref009","doi-asserted-by":"crossref","first-page":"200258","DOI":"10.1016\/j.tvr.2023.200258","article-title":"Human papillomavirus genomics: understanding carcinogenicity","volume":"15","author":"CW Nelson","year":"2023","journal-title":"Tumour Virus Res"},{"issue":"9","key":"ppat.1014362.ref010","doi-asserted-by":"crossref","DOI":"10.1093\/jnci\/djw100","article-title":"HPV16 sublineage associations with histology-specific cancer risk using HPV whole-genome sequences in 3200 women","volume":"108","author":"L Mirabello","year":"2016","journal-title":"J Natl Cancer Inst"},{"issue":"6","key":"ppat.1014362.ref011","doi-asserted-by":"crossref","first-page":"1164","DOI":"10.1016\/j.cell.2017.08.001","article-title":"HPV16 E7 genetic conservation is critical to carcinogenesis","volume":"170","author":"L Mirabello","year":"2017","journal-title":"Cell"},{"issue":"10","key":"ppat.1014362.ref012","doi-asserted-by":"crossref","first-page":"2677","DOI":"10.1002\/ijc.33033","article-title":"Association of HPV35 with cervical carcinogenesis among women of African ancestry: evidence of viral-host interaction with implications for disease intervention","volume":"147","author":"M Pinheiro","year":"2020","journal-title":"Int J Cancer"},{"issue":"19","key":"ppat.1014362.ref013","doi-asserted-by":"crossref","DOI":"10.1128\/JVI.00844-17","article-title":"Whole-genome sequencing and variant analysis of human papillomavirus 16 infections","volume":"91","author":"P van der Weele","year":"2017","journal-title":"J Virol"},{"issue":"12","key":"ppat.1014362.ref014","doi-asserted-by":"crossref","DOI":"10.1128\/JVI.00017-18","article-title":"Within-host variations of human papillomavirus reveal APOBEC signature mutagenesis in the viral genome","volume":"92","author":"Y Hirose","year":"2018","journal-title":"J Virol"},{"issue":"1","key":"ppat.1014362.ref015","doi-asserted-by":"crossref","first-page":"886","DOI":"10.1038\/s41467-020-14730-1","article-title":"Mutations in the HPV16 genome induced by APOBEC3 are associated with viral clearance","volume":"11","author":"B Zhu","year":"2020","journal-title":"Nat Commun"},{"issue":"5","key":"ppat.1014362.ref016","article-title":"Changes in intrahost genetic diversity according to lesion severity in longitudinal HPV16 samples","volume":"96","author":"J-M Costanzi","year":"2024","journal-title":"J Med Virol"},{"issue":"10","key":"ppat.1014362.ref017","doi-asserted-by":"crossref","first-page":"2104","DOI":"10.3390\/v15102104","article-title":"Intra-patient genomic variations of human papillomavirus type 31 in cervical cancer and precancer","volume":"15","author":"G Kogure","year":"2023","journal-title":"Viruses"},{"issue":"1","key":"ppat.1014362.ref018","doi-asserted-by":"crossref","DOI":"10.1093\/ve\/veae013","article-title":"Improved detection of low-frequency within-host variants from deep sequencing: a case study with human papillomavirus","volume":"10","author":"SK Mishra","year":"2024","journal-title":"Virus Evol"},{"issue":"5873","key":"ppat.1014362.ref019","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1126\/science.1153201","article-title":"Evidence for editing of human papillomavirus DNA by APOBEC3 in benign and precancerous lesions","volume":"320","author":"J-P Vartanian","year":"2008","journal-title":"Science"},{"key":"ppat.1014362.ref020","doi-asserted-by":"crossref","first-page":"1833","DOI":"10.1016\/j.celrep.2014.05.012","article-title":"APOBEC-mediated cytosine deamination links PIK3CA helical domain mutations to human papillomavirus-driven tumor development","volume":"7","author":"S Henderson","year":"2014","journal-title":"Cell Rep"},{"issue":"17","key":"ppat.1014362.ref021","doi-asserted-by":"crossref","first-page":"4532","DOI":"10.1158\/0008-5472.CAN-18-3933","article-title":"The HPV16 genome is stable in women who progress to in situ or invasive cervical cancer: a prospective population-based study","volume":"79","author":"L-S Arroyo-M\u00fchr","year":"2019","journal-title":"Cancer Res"},{"issue":"10451","key":"ppat.1014362.ref022","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1016\/S0140-6736(24)01097-3","article-title":"Causal attribution of human papillomavirus genotypes to invasive cervical cancer worldwide: a systematic analysis of the global literature","volume":"404","author":"F Wei","year":"2024","journal-title":"Lancet"},{"issue":"9","key":"ppat.1014362.ref023","doi-asserted-by":"crossref","first-page":"1163","DOI":"10.1038\/s41416-018-0311-7","article-title":"Human papillomavirus type 16 genomic variation in women with subsequent in situ or invasive cervical cancer: prospective population-based study","volume":"119","author":"LS Arroyo-M\u00fchr","year":"2018","journal-title":"Br J Cancer"},{"issue":"19","key":"ppat.1014362.ref024","doi-asserted-by":"crossref","first-page":"4895","DOI":"10.3390\/cancers14194895","article-title":"HPV16 E7 nucleotide variants found in cancer-free subjects affect E7 protein expression and transformation","volume":"14","author":"H Lou","year":"2022","journal-title":"Cancers (Basel)"},{"key":"ppat.1014362.ref025","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1016\/j.virol.2013.07.008","article-title":"The E4 protein; structure, function and patterns of expression","volume":"445","author":"J Doorbar","year":"2013","journal-title":"Virology"},{"key":"ppat.1014362.ref026","doi-asserted-by":"crossref","first-page":"1307","DOI":"10.1099\/vir.0.80747-0","article-title":"Overlapping reading frames in closely related human papillomaviruses result in modular rates of selection within E2","volume":"86","author":"A Narechania","year":"2005","journal-title":"J Gen Virol"},{"issue":"2","key":"ppat.1014362.ref027","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/j.virusres.2005.03.030","article-title":"Patterns of nucleotide difference in overlapping and non-overlapping reading frames of papillomavirus genomes","volume":"113","author":"AL Hughes","year":"2005","journal-title":"Virus Res"},{"issue":"5","key":"ppat.1014362.ref028","doi-asserted-by":"crossref","first-page":"112508","DOI":"10.1016\/j.celrep.2023.112508","article-title":"Human papillomavirus E5 suppresses immunity via inhibition of the immunoproteasome and STING pathway","volume":"42","author":"S Miyauchi","year":"2023","journal-title":"Cell Rep"},{"key":"ppat.1014362.ref029","doi-asserted-by":"crossref","first-page":"198143","DOI":"10.1016\/j.virusres.2020.198143","article-title":"Structural and functional impacts of E5 genetic variants of human papillomavirus type 31","volume":"290","author":"RCDO Silva","year":"2020","journal-title":"Virus Res"},{"issue":"21","key":"ppat.1014362.ref030","doi-asserted-by":"crossref","DOI":"10.1158\/0008-5472.CAN-17-0337","article-title":"Variant review with the integrative genomics viewer","volume":"77","author":"JT Robinson","year":"2017","journal-title":"Cancer Res"},{"issue":"15","key":"ppat.1014362.ref031","doi-asserted-by":"crossref","first-page":"6884","DOI":"10.1128\/JVI.00667-16","article-title":"Measurements of intrahost viral diversity are extremely sensitive to systematic errors in variant calling","volume":"90","author":"JT McCrone","year":"2016","journal-title":"J Virol"},{"issue":"11","key":"ppat.1014362.ref032","doi-asserted-by":"crossref","first-page":"5512","DOI":"10.1002\/jmv.27978","article-title":"Longitudinal follow-up of HPV16 sequence after cervical infection: low intrahost variation and no correlation with clinical evolution","volume":"94","author":"A Debernardi","year":"2022","journal-title":"J Med Virol"},{"issue":"7463","key":"ppat.1014362.ref033","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1038\/nature12477","article-title":"Signatures of mutational processes in human cancer","volume":"500","author":"LB Alexandrov","year":"2013","journal-title":"Nature"},{"key":"ppat.1014362.ref034","doi-asserted-by":"crossref","first-page":"200268","DOI":"10.1016\/j.tvr.2023.200268","article-title":"The human papillomavirus twilight zone - latency, immune control and subclinical infection","volume":"16","author":"J Doorbar","year":"2023","journal-title":"Tumour Virus Res"},{"issue":"5","key":"ppat.1014362.ref035","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1016\/j.ygeno.2016.03.004","article-title":"Evaluating the efficacy of the new Ion PGM Hi-Q sequencing kit applied to bacterial genomes","volume":"107","author":"FL Pereira","year":"2016","journal-title":"Genomics"},{"issue":"8","key":"ppat.1014362.ref036","doi-asserted-by":"crossref","first-page":"3159","DOI":"10.1158\/0008-5472.CAN-09-4179","article-title":"A population-based prospective study of carcinogenic human papillomavirus variant lineages, viral persistence, and cervical neoplasia","volume":"70","author":"M Schiffman","year":"2010","journal-title":"Cancer Res"},{"issue":"5","key":"ppat.1014362.ref037","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1590\/S1020-49891997000500005","article-title":"Design and methods of a population-based natural history study of cervical neoplasia in a rural province of Costa Rica: the Guanacaste Project","volume":"1","author":"R Herrero","year":"1997","journal-title":"Rev Panam Salud Publica"},{"issue":"5","key":"ppat.1014362.ref038","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1093\/jnci\/djq001","article-title":"Longitudinal study of human papillomavirus persistence and cervical intraepithelial neoplasia grade 2\/3: critical role of duration of infection","volume":"102","author":"AC Rodr\u00edguez","year":"2010","journal-title":"J Natl Cancer Inst"},{"key":"ppat.1014362.ref039","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.pvr.2015.05.004","article-title":"Deep sequencing of HPV16 genomes: A new high-throughput tool for exploring the carcinogenicity and natural history of HPV16 infection","volume":"1","author":"M Cullen","year":"2015","journal-title":"Papillomavirus Res"},{"key":"ppat.1014362.ref040","doi-asserted-by":"crossref","DOI":"10.4161\/fly.19695","article-title":"A program for annotating and predicting the effects of single nucleotide polymorphisms, SnpEff: SNPs in the genome of Drosophila melanogaster strain w1118; iso-2; iso-3","volume":"6","author":"P Cingolani","year":"2012","journal-title":"Fly (Austin)"},{"issue":"21","key":"ppat.1014362.ref041","doi-asserted-by":"crossref","first-page":"2688","DOI":"10.1093\/bioinformatics\/btl446","article-title":"RAxML-VI-HPC: maximum likelihood-based phylogenetic analyses with thousands of taxa and mixed models","volume":"22","author":"A Stamatakis","year":"2006","journal-title":"Bioinformatics"},{"issue":"10","key":"ppat.1014362.ref042","doi-asserted-by":"crossref","first-page":"1948","DOI":"10.3390\/v13101948","article-title":"Phylogenomic analysis of human papillomavirus type 31 and cervical carcinogenesis: a study of 2093 viral genomes","volume":"13","author":"M Pinheiro","year":"2021","journal-title":"Viruses"},{"key":"ppat.1014362.ref043","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/j.pvr.2019.02.001","article-title":"Human papillomavirus 16 sub-lineage dispersal and cervical cancer risk worldwide: Whole viral genome sequences from 7116 HPV16-positive women","volume":"7","author":"GM Clifford","year":"2019","journal-title":"Papillomavirus Res"},{"issue":"6","key":"ppat.1014362.ref044","doi-asserted-by":"crossref","first-page":"1130","DOI":"10.1002\/ijc.35464","article-title":"Whole-genome sequencing of 1,083 HPV45 cases and controls identifies genetic variants associated with glandular cervical lesions","volume":"157","author":"AJ Koestler","year":"2025","journal-title":"Int J Cancer"},{"issue":"1","key":"ppat.1014362.ref045","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1038\/nbt.1754","article-title":"Integrative genomics viewer","volume":"29","author":"JT Robinson","year":"2011","journal-title":"Nat Biotechnol"},{"key":"ppat.1014362.ref046","article-title":"The Papillomavirus Episteme: a major update to the papillomavirus sequence database","volume":"45","author":"K Van Doorslaer","year":"2017","journal-title":"Nucleic Acids Res"}],"container-title":["PLOS Pathogens"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.ppat.1014362","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T17:40:56Z","timestamp":1784137256000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.ppat.1014362"}},"subtitle":[],"editor":[{"given":"Cary A.","family":"Moody","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2026,7,15]]},"references-count":46,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2026,7,15]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.ppat.1014362","relation":{},"ISSN":["1553-7374"],"issn-type":[{"value":"1553-7374","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,15]]}}}