{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T03:39:25Z","timestamp":1779248365051,"version":"3.51.4"},"reference-count":41,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2025,10,25]],"date-time":"2025-10-25T00:00:00Z","timestamp":1761350400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100010747","name":"CONCYTEC","doi-asserted-by":"crossref","award":["PE501083623-2023"],"award-info":[{"award-number":["PE501083623-2023"]}],"id":[{"id":"10.13039\/501100010747","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Direcci\u00f3n de Investigaci\u00f3n-Universidad Peruana de Ciencias Aplicadas","award":["2025 C-020-2025"],"award-info":[{"award-number":["2025 C-020-2025"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Background: The HPV16 E2 gene plays a crucial role in viral replication and oncogene regulation. This study aimed to assess the genetic variability of the E2 gene and to identify immunogenic epitopes of the E2 protein. Methods: The E2 gene was amplified and sequenced. T-cell epitope prediction and evaluation were performed using IEDB, NetMHCpan v4.0, NetMHCIIpan v4.1, VaxiJen, ToxNet, and pLM4Alg. Results: Phylogenetic analysis of 47 E2 sequences demonstrated co-circulation of the D (n = 4) and A (n = 43) HPV16 lineages in Cajamarca. Twenty-eight Single Nucleotide Polymorphism (SNPs) were identified in E2, 21 of which were nonsynonymous. Seventeen variations were associated with positive Papanicolaou (Pap) test results. Epitope prediction identified 2 MHC class I and 27 MHC class II epitopes classified as potentially antigenic, non-toxic, and non-allergenic, with an overall global population coverage across both MHC classes of 99.78%. Conclusions: The A HPV16 lineage predominated among the women studied. The identified SNPs indicate substantial variability in the E2 gene and a relationship with endocervical lesions. In total, 29 E2-derived T-cell epitopes with immunogenic potential were identified.<\/jats:p>","DOI":"10.3390\/v17111420","type":"journal-article","created":{"date-parts":[[2025,10,27]],"date-time":"2025-10-27T02:50:48Z","timestamp":1761533448000},"page":"1420","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Genetic Variability and Prediction of T Epitopes of the HPV16 E2 Gene in Asymptomatic Women from Cajamarca, Peru"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3589-4617","authenticated-orcid":false,"given":"Eliezer","family":"Bonifacio-Velez de Villa","sequence":"first","affiliation":[{"name":"Biomedicine Laboratory, Research Center of Faculty of Health Sciences, Universidad Peruana de Ciencias Aplicadas, Lima 15023, Peru"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Deysi","family":"Aguilar-Luis","sequence":"additional","affiliation":[{"name":"Biomedicine Laboratory, Research Center of Faculty of Health Sciences, Universidad Peruana de Ciencias Aplicadas, Lima 15023, Peru"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5360-7314","authenticated-orcid":false,"given":"Dayana","family":"Denegri-Hinostroza","sequence":"additional","affiliation":[{"name":"Biomedicine Laboratory, Research Center of Faculty of Health Sciences, Universidad Peruana de Ciencias Aplicadas, Lima 15023, Peru"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7023-3190","authenticated-orcid":false,"given":"Miguel Angel","family":"Aguilar-Luis","sequence":"additional","affiliation":[{"name":"Biomedicine Laboratory, Research Center of Faculty of Health Sciences, Universidad Peruana de Ciencias Aplicadas, Lima 15023, Peru"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wilmer","family":"Silva-Caso","sequence":"additional","affiliation":[{"name":"Biomedicine Laboratory, Research Center of Faculty of Health Sciences, Universidad Peruana de Ciencias Aplicadas, Lima 15023, Peru"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0740-4502","authenticated-orcid":false,"given":"Yordi","family":"Tarazona-Castro","sequence":"additional","affiliation":[{"name":"Biomedicine Laboratory, Research Center of Faculty of Health Sciences, Universidad Peruana de Ciencias Aplicadas, Lima 15023, Peru"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lorena","family":"Becerra-Goicochea","sequence":"additional","affiliation":[{"name":"Oncology Unit, Hospital Regional Docente de Cajamarca, Cajamarca 06003, Peru"},{"name":"Professional Academic School of Obstetrics, Universidad Nacional de Cajamarca, Cajamarca 06003, Peru"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9100-8547","authenticated-orcid":false,"given":"Ronald","family":"Aquino-Ortega","sequence":"additional","affiliation":[{"name":"Biomedicine Laboratory, Research Center of Faculty of Health Sciences, Universidad Peruana de Ciencias Aplicadas, Lima 15023, Peru"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Angela","family":"Cornejo-Tapia","sequence":"additional","affiliation":[{"name":"Biomedicine Laboratory, Research Center of Faculty of Health Sciences, Universidad Peruana de Ciencias Aplicadas, Lima 15023, Peru"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juana","family":"del Valle-Mendoza","sequence":"additional","affiliation":[{"name":"Biomedicine Laboratory, Research Center of Faculty of Health Sciences, Universidad Peruana de Ciencias Aplicadas, Lima 15023, Peru"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Kombe Kombe, A.J., Li, B., Zahid, A., Mengist, H.M., Bounda, G.-A., Zhou, Y., and Jin, T. (2021). Epidemiology and Burden of Human Papillomavirus and Related Diseases, Molecular Pathogenesis, and Vaccine Evaluation. Front. Public Health, 8.","DOI":"10.3389\/fpubh.2020.552028"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"S121","DOI":"10.1016\/S1995-7645(14)60217-0","article-title":"Identification of human papillomavirus as a preventive strategy for cervical cancer in asymptomatic women in the Peruvian Andes","volume":"7","author":"Vargas","year":"2014","journal-title":"Asian Pac. J. Trop. Med."},{"key":"ref_3","first-page":"209","article-title":"Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA Cancer J. Clin."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"e180","DOI":"10.1016\/S2214-109X(19)30488-7","article-title":"Global burden of cancer attributable to infections in 2018: A worldwide incidence analysis","volume":"8","author":"Georges","year":"2020","journal-title":"Lancet Glob. Health"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Poniewierza, P., and Panek, G. (2022). Cervical Cancer Prophylaxis\u2014State-of-the-Art and Perspectives. Healthcare, 10.","DOI":"10.3390\/healthcare10071325"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"del Valle-Mendoza, J., Becerra-Goicochea, L., Aguilar-Luis, M.A., Pinillos-Vilca, L., Carrillo-Ng, H., Silva-Caso, W., Palomares-Reyes, C., Taco-Masias, A.-A., Aquino-Ortega, R., and Tinco-Valdez, C. (2021). Genotype-specific prevalence of human papillomavirus infection in asymptomatic Peruvian women: A community-based study. BMC Res. Notes, 14.","DOI":"10.1186\/s13104-021-05588-7"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Hirose, Y., Yamaguchi-Naka, M., Onuki, M., Tenjimbayashi, Y., Tasaka, N., Satoh, T., Tanaka, K., Iwata, T., Sekizawa, A., and Matsumoto, K. (2020). High Levels of Within-Host Variations of Human Papillomavirus 16 E1\/E2 Genes in Invasive Cervical Cancer. Front. Microbiol., 11.","DOI":"10.3389\/fmicb.2020.596334"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Anayannis, N.V., Schlecht, N.F., Ben-Dayan, M., Smith, R.V., Belbin, T.J., Ow, T.J., Blakaj, D.M., Burk, R.D., Leonard, S.M., and Woodman, C.B. (2018). Association of an intact E2 gene with higher HPV viral load, higher viral oncogene expression, and improved clinical outcome in HPV16 positive head and neck squamous cell carcinoma. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0191581"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Requena, D., M\u00e9dico, A., Chac\u00f3n, R.D., Ram\u00edrez, M., and Mar\u00edn-S\u00e1nchez, O. (2020). Identification of Novel Candidate Epitopes on SARS-CoV-2 Proteins for South America: A Review of HLA Frequencies by Country. Front. Immunol., 11.","DOI":"10.3389\/fimmu.2020.02008"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2352908","DOI":"10.1080\/21645515.2024.2352908","article-title":"Design and evaluation of a multi-epitope DNA vaccine against HPV16","volume":"20","author":"Zhu","year":"2024","journal-title":"Hum. Vaccines Immunother."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Carrillo-Ng, H., Becerra-Goicochea, L., Tarazona-Castro, Y., Pinillos-Vilca, L., del Valle, L.J., Aguilar-Luis, M.A., Tinco-Valdez, C., Silva-Caso, W., Martins-Luna, J., and Pe\u00f1a-Tuesta, I. (2021). Variations in cervico-vaginal microbiota among HPV-positive and HPV-negative asymptomatic women in Peru. BMC Res. Notes, 14.","DOI":"10.1186\/s13104-020-05422-6"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"W502","DOI":"10.1093\/nar\/gkz452","article-title":"IEDB-AR: Immune epitope database\u2014Analysis resource in 2019","volume":"47","author":"Dhanda","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Doytchinova, I.A., and Flower, D.R. (2007). VaxiJen: A server for prediction of protective antigens, tumour antigens and subunit vaccines. BMC Bioinform., 8.","DOI":"10.1186\/1471-2105-8-4"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Rathore, A.S., Arora, A., Choudhury, S., Tijare, P., and Raghava, G.P.S. (2023). ToxinPred 3.0: An improved method for predicting the toxicity of peptides. Comput. Biol. Med., 179.","DOI":"10.1101\/2023.08.11.552911"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"752","DOI":"10.1021\/acs.jafc.3c07143","article-title":"pLM4Alg: Protein Language Model-Based Predictors for Allergenic Proteins and Peptides","volume":"72","author":"Du","year":"2024","journal-title":"J. Agric. Food Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1016\/j.meegid.2018.07.002","article-title":"The association of human papillomavirus type 16 E2 variations with cervical cancer in a Han Chinese population","volume":"64","author":"Dai","year":"2018","journal-title":"Infect. Genet. Evol."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Wang, L., Wang, F., Fu, S., Zhang, C., Zhe, X., Li, H., Li, D., Shao, R., and Pan, Z. (2021). Analysis of genetic variation in human papillomavirus type 16 E1 and E2 in women with cervical infection in Xinjiang, China. BMC Med. Genom., 14.","DOI":"10.1186\/s12920-021-01120-9"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"374","DOI":"10.1016\/j.ygyno.2013.08.026","article-title":"Virological characteristics of cervical cancers carrying pure episomal form of HPV16 genome","volume":"131","author":"Cheung","year":"2013","journal-title":"Gynecol. Oncol."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Smith, B., Chen, Z., Reimers, L., van Doorslaer, K., Schiffman, M., Desalle, R., Herrero, R., Yu, K., Wacholder, S., and Wang, T. (2011). Sequence imputation of HPV16 genomes for genetic association studies. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0021375"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"3895","DOI":"10.1016\/j.ygeno.2021.09.006","article-title":"Genetic characteristics of human papillomavirus type 16, 18, 52 and 58 in southern China","volume":"113","author":"Zu","year":"2021","journal-title":"Genomics"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1186\/1743-422X-5-5","article-title":"P53 represses human papillomavirus type 16 DNA replication via the viral E2 protein","volume":"5","author":"Brown","year":"2008","journal-title":"Virol. J."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"S2","DOI":"10.1038\/488S2a","article-title":"HPV: The global burden","volume":"488","author":"Crow","year":"2012","journal-title":"Nature"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1016\/j.bjid.2014.01.010","article-title":"Prevalence of high-risk human papillomavirus by cobas 4800 HPV test in urban Peru","volume":"18","author":"Iwasaki","year":"2014","journal-title":"Braz. J. Infect. Dis."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1038\/bjc.2012.508","article-title":"HPV16 genetic variation and the development of cervical cancer worldwide","volume":"108","author":"Cornet","year":"2013","journal-title":"Br. J. Cancer"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1016\/j.meegid.2018.08.001","article-title":"HPV16 E2 variants correlated with radiotherapy treatment and biological significance in cervical cell carcinoma","volume":"65","author":"Kahla","year":"2018","journal-title":"Infect. Genet. Evol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2845","DOI":"10.1007\/s00705-015-2559-z","article-title":"Lineage distribution and E2 sequence variation of high-risk human papillomavirus types isolated from patients with cervical cancer in Sichuan province, China","volume":"160","author":"Wu","year":"2015","journal-title":"Arch. Virol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1763","DOI":"10.1002\/ijc.22481","article-title":"High grade cervical lesions are caused preferentially by non-European variants of HPVs 16 and 18","volume":"120","author":"Sichero","year":"2007","journal-title":"Int. J. Cancer"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1002\/jmv.20154","article-title":"Analysis of human papillomavirus type-16 variants in Italian women with cervical intraepithelial neoplasia and cervical cancer","volume":"74","author":"Tornesello","year":"2004","journal-title":"J. Med. Virol."},{"key":"ref_29","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":"Schiffman","year":"2010","journal-title":"Cancer Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"e217","DOI":"10.1016\/S1470-2045(14)71179-9","article-title":"Next generation prophylactic human papillomavirus vaccines","volume":"16","author":"Schiller","year":"2015","journal-title":"Lancet Oncol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"e00844-17","DOI":"10.1128\/JVI.00844-17","article-title":"Whole-Genome Sequencing and Variant Analysis of Human Papillomavirus 16 Infections","volume":"91","author":"Meijer","year":"2017","journal-title":"J. Virol."},{"key":"ref_32","first-page":"8453","article-title":"Variants of human papillomavirus type 16 predispose toward persistent infection","volume":"8","author":"Zhang","year":"2015","journal-title":"Int. J. Clin. Exp. Pathol."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Gao, C., Pan, M.-M., Lei, Y.-J., Tian, L.-Q., Jiang, H.-Y., Li, X.-L., Shi, Q., Tian, C., Yuan, Y.K., and Fan, G.X. (2012). A point mutation in the DNA-binding domain of HPV-2 E2 protein increases its DNA-binding capacity and reverses its transcriptional regulatory activity on the viral early promoter. BMC Mol. Biol., 13.","DOI":"10.1186\/1471-2199-13-5"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"3761","DOI":"10.1128\/JVI.74.8.3761-3770.2000","article-title":"The Hinge of the Human Papillomavirus Type 11 E2 Protein Contains Major Determinants for Nuclear Localization and Nuclear Matrix Association","volume":"74","author":"Zou","year":"2000","journal-title":"J. Virol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1038\/nrc2373","article-title":"Immunotherapy of established (pre)malignant disease by synthetic long peptide vaccines","volume":"8","author":"Melief","year":"2008","journal-title":"Nat. Rev. Cancer"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2078","DOI":"10.1016\/S0140-6736(15)00239-1","article-title":"Safety, efficacy, and immunogenicity of VGX-3100, a therapeutic synthetic DNA vaccine targeting human papillomavirus 16 and 18 E6 and E7 proteins for cervical intraepithelial neoplasia 2\/3: A randomised, double-blind, placebo-controlled phase 2b trial","volume":"386","author":"Trimble","year":"2015","journal-title":"Lancet"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Bui, H.-H., Sidney, J., Li, W., Fusseder, N., and Sette, A. (2007). Development of an epitope conservancy analysis tool to facilitate the design of epitope-based diagnostics and vaccines. BMC Bioinform., 8.","DOI":"10.1186\/1471-2105-8-361"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"16547","DOI":"10.1021\/acsomega.4c00425","article-title":"Designing a Novel Multiepitope Vaccine from the Human Papilloma Virus E1 and E2 Proteins for Indonesia with Immunoinformatics and Molecular Dynamics Approaches","volume":"9","author":"Rizarullah","year":"2024","journal-title":"ACS Omega"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"eadm8951","DOI":"10.1126\/sciadv.adm8951","article-title":"Simultaneous analysis of pMHC binding and reactivity unveils virus-specific CD8 T cell immunity to a concise epitope set","volume":"10","author":"Kristensen","year":"2024","journal-title":"Sci. Adv."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1016\/S0928-0197(96)00267-X","article-title":"Diagnostic phase antibody response to the human papillomavirus type 16 E2 protein is associated with successful treatment of genital HPV lesions with systemic interferon alpha-2b","volume":"7","author":"Stellato","year":"1997","journal-title":"Clin. Diagn. Virol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"e20200389","DOI":"10.1084\/jem.20200389","article-title":"Profiling HPV-16-specific T cell responses reveals broad antigen reactivities in oropharyngeal cancer patients","volume":"217","author":"Bhatt","year":"2020","journal-title":"J. Exp. Med."}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/17\/11\/1420\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,28]],"date-time":"2025-10-28T05:17:12Z","timestamp":1761628632000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/17\/11\/1420"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,25]]},"references-count":41,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2025,11]]}},"alternative-id":["v17111420"],"URL":"https:\/\/doi.org\/10.3390\/v17111420","relation":{},"ISSN":["1999-4915"],"issn-type":[{"value":"1999-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,25]]}}}