{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,13]],"date-time":"2026-04-13T20:02:51Z","timestamp":1776110571508,"version":"3.50.1"},"reference-count":52,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2023,7,6]],"date-time":"2023-07-06T00:00:00Z","timestamp":1688601600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004488","name":"Croatian Science Foundation","doi-asserted-by":"publisher","award":["IP-2020-02-8961"],"award-info":[{"award-number":["IP-2020-02-8961"]}],"id":[{"id":"10.13039\/501100004488","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pathogens"],"abstract":"<jats:p>The molecular diversity of Epstein\u2013Barr virus (EBV) is exceptionally complex and based on the characterization of sequences coding for several viral genes. The aim of this study was to analyze the distribution of EBV types 1 and 2 and to characterize LMP1 variants in a cohort of 73 patients with infectious mononucleosis (IM), as well as to investigate a possible association between viral diversity and relevant clinical parameters. Population-based sequencing of EBNA-2 gene showed the presence of EBV type 1 in all IM patients. Analysis of LMP1 gene found a restricted repertoire of LMP1 variants with the predominance of wild-type B95-8, China1, Mediterranean and North Carolina variants with the presence of more than one LMP1 variant in 16.4% of patients. Co-infections with different LMP1 variants were associated with significantly higher levels of C-reactive protein and lower levels of maximal neutrophil counts and minimal platelet count. The results of this study have shown a narrow repertoire of LMP1 variants and an exclusive presence of EBV type 1 in a cohort of IM from Croatia, suggesting a characteristic local molecular pattern of this virus. The clinical importance of distinct immunobiological features of IM patients with LMP1 variant co-infections needs to be investigated further.<\/jats:p>","DOI":"10.3390\/pathogens12070915","type":"journal-article","created":{"date-parts":[[2023,7,7]],"date-time":"2023-07-07T02:37:29Z","timestamp":1688697449000},"page":"915","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Distribution of Epstein\u2013Barr Virus LMP1 Variants in Patients with Infectious Mononucleosis and Association with Selected Biochemical and Hematological Parameters"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9852-5806","authenticated-orcid":false,"given":"Snjezana","family":"Zidovec-Lepej","sequence":"first","affiliation":[{"name":"Department of Immunological and Molecular Diagnostics, University Hospital for Infectious Diseases, 10 000 Zagreb, Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Margarita","family":"Batovic","sequence":"additional","affiliation":[{"name":"Department of Medical and Laboratory Genetics, Children\u2019s Hospital Zagreb, 10 000 Zagreb, Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marija","family":"Rozman","sequence":"additional","affiliation":[{"name":"Department of Immunological and Molecular Diagnostics, University Hospital for Infectious Diseases, 10 000 Zagreb, Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1212-3302","authenticated-orcid":false,"given":"Kristian","family":"Boduli\u0107","sequence":"additional","affiliation":[{"name":"Research Department, University Hospital for Infectious Diseases, 10 000 Zagreb, Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura","family":"Prtori\u0107","sequence":"additional","affiliation":[{"name":"Pediatric Infectious Diseases Department, University Hospital for Infectious Diseases, 10 000 Zagreb, Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ante","family":"\u0160okota","sequence":"additional","affiliation":[{"name":"Pediatric Infectious Diseases Department, University Hospital for Infectious Diseases, 10 000 Zagreb, Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrea","family":"Nikcevic","sequence":"additional","affiliation":[{"name":"Pediatric Infectious Diseases Department, University Hospital for Infectious Diseases, 10 000 Zagreb, Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0776-3671","authenticated-orcid":false,"given":"Petra","family":"Simicic","sequence":"additional","affiliation":[{"name":"Department of Immunological and Molecular Diagnostics, University Hospital for Infectious Diseases, 10 000 Zagreb, Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Goran","family":"Te\u0161ovi\u0107","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, University of Zagreb School of Medicine, 10 000 Zagreb, Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,7,6]]},"reference":[{"key":"ref_1","unstructured":"International Committee on Taxonomy of Viruses ICTV (2023, May 10). Current ICTV Taxonomy Release: Taxon Details: Epstein-Barr Virus. Available online: https:\/\/ictv.global\/taxonomy\/taxondetails?taxnode_id=19780268."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1038\/s41392-020-00376-4","article-title":"Targeting the signaling in Epstein\u2013Barr virus-associated diseases: NCMechanism, regulation, and clinical study","volume":"6","author":"Cao","year":"2021","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e068877","DOI":"10.1136\/bmjopen-2022-068877","article-title":"Derivation and validation of clinical prediction rules for diagnosis of infectious mononucleosis: A prospective cohort study","volume":"13","author":"Boland","year":"2023","journal-title":"BMJ Open"},{"key":"ref_4","first-page":"211","article-title":"Infectious Mononucleosis","volume":"390","author":"Dunmire","year":"2015","journal-title":"Curr. Top. Microbiol. Immunol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"713","DOI":"10.3389\/fonc.2019.00713","article-title":"The Global Landscape of EBV-Associated Tumors","volume":"9","author":"Rickinson","year":"2019","journal-title":"Front. Oncol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1126\/science.abj8222","article-title":"Longitudinal analysis reveals high prevalence of Epstein-Barr virus associated with multiple sclerosis","volume":"375","author":"Bjornevik","year":"2022","journal-title":"Science"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1038\/s41582-023-00775-5","article-title":"Epstein-Barr virus as a leading cause of multiple sclerosis: Mechanisms and implications","volume":"19","author":"Bjornevik","year":"2023","journal-title":"Nat. Rev. Neurol."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Rozman, M., Kora\u0107, P., Jambrosic, K., and \u017didovec Lepej, S. (2022). Progress in Prophylactic and Therapeutic EBV Vaccine Development Based on Molecular Characteristics of EBV Target Antigens. Pathogens, 11.","DOI":"10.3390\/pathogens11080864"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"5222","DOI":"10.1128\/JVI.03614-14","article-title":"Genome diversity of Epstein-Barr virus from multiple tumor types and normal infection","volume":"89","author":"Palser","year":"2015","journal-title":"J. Virol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1002\/jmv.24633","article-title":"Epstein-Barr virus strains and variations: Geographic or disease-specific variants?","volume":"89","author":"Neves","year":"2017","journal-title":"J. Med. Virol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"e01718-16","DOI":"10.1128\/JVI.01718-16","article-title":"Epstein-Barr Virus LMP1-Mediated Oncogenicity","volume":"19","author":"Wang","year":"2017","journal-title":"J. Virol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e01857-20","DOI":"10.1128\/JVI.01857-20","article-title":"Epstein-Barr Virus-Encoded Latent Membrane Protein 1 and B-Cell Growth Transformation Induce Lipogenesis through Fatty Acid Synthase","volume":"95","author":"Hulse","year":"2021","journal-title":"J. Virol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1006\/viro.1999.9855","article-title":"Signature amino acid changes in latent membrane protein 1 distinguish Epstein-Barr virus strains","volume":"261","author":"Edwards","year":"1999","journal-title":"Virology"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Gantuz, M., Lorenzetti, M.A., Chabay, P.A., and Preciado, M.V. (2017). A novel recombinant variant of latent membrane protein 1 from Epstein Barr virus in Argentina denotes phylogeographical association. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0174221"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e02007","DOI":"10.1128\/JVI.02007-19","article-title":"Epstein-Barr Virus Genomes Reveal Population Structure and Type 1 Association with Endemic Burkitt Lymphoma","volume":"94","author":"Kaymaz","year":"2020","journal-title":"J. Virol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2045","DOI":"10.1086\/315521","article-title":"High prevalence of Epstein-Barr virus type 2 among homosexual men is caused by sexual transmission","volume":"181","author":"Hovenkamp","year":"2000","journal-title":"J. Infect. Dis."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1086\/505400","article-title":"A cohort study among university students: Identification of risk factors for Epstein-Barr virus seroconversion and infectious mononucleosis","volume":"43","author":"Crawford","year":"2006","journal-title":"Clin. Infect. Dis."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"474","DOI":"10.1086\/510854","article-title":"A study of risk factors for acquisition of Epstein-Barr virus and its subtypes","volume":"195","author":"Higgins","year":"2007","journal-title":"J. Infect. Dis."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"e00375-17","DOI":"10.1128\/JVI.00375-17","article-title":"Natural Variation of Epstein-Barr Virus Genes, Proteins, and Primary MicroRNA","volume":"91","author":"Correia","year":"2017","journal-title":"J. Virol."},{"key":"ref_20","first-page":"1802","article-title":"Clinical Significance of Peripheral Blood EBV-DNA Determination and Genotyping in Lymphoma Patients","volume":"29","author":"Wang","year":"2021","journal-title":"Zhongguo Shi Yan Xue Ye Xue Za Zhi"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1016\/j.clml.2012.11.010","article-title":"Detection of Epstein-Barr virus and genotyping based on EBNA2 protein in Mexican patients with hodgkin lymphoma: A comparative study in children and adults","volume":"13","author":"Palma","year":"2013","journal-title":"Clin. Lymphoma Myeloma Leuk."},{"key":"ref_22","first-page":"3153","article-title":"Prevalence of Epstein\u2013Barr Virus Genotypes in Pakistani Lymphoma Patients. Asian Pac","volume":"19","author":"Salahuddin","year":"2018","journal-title":"J. Cancer Prev."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"181","DOI":"10.11604\/pamj.2018.29.181.11847","article-title":"Evidence of EBV infection in lymphomas diagnosed in Lusaka, Zambia","volume":"29","author":"Kafita","year":"2018","journal-title":"Pan Afr. Med. J."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"693","DOI":"10.31557\/APJCP.2020.21.3.693","article-title":"Molecular Epidemiology of Epstein-Barr virus (EBV) in Patients with Hematologic Malignancies","volume":"21","author":"Tabibzadeh","year":"2020","journal-title":"Asian Pac. J. Cancer Prev."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2937","DOI":"10.1182\/blood.V82.10.2937.2937","article-title":"Deletions within the LMP1 oncogene of Epstein-Barr virus are clustered in Hodgkin\u2019s disease and identical to those observed in nasopharyngeal carcinoma","volume":"82","author":"Knecht","year":"1993","journal-title":"Blood"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"4053","DOI":"10.1182\/blood.V84.12.4053.bloodjournal84124053","article-title":"Identification of potential hot spots in the carboxy-terminal part of the Epstein-Barr virus (EBV) BNLF-1 gene in both malignant and benign EBV-associated diseases: High frequency of a 30-bp deletion in Malaysian and Danish peripheral T-cell lymphomas","volume":"84","author":"Sandvej","year":"1994","journal-title":"Blood"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1002\/ijc.2910620605","article-title":"Detection of an Epstein-Barr-virus variant in T-cell-lymphoma tissues identical to the distinct strain observed in nasopharyngeal carcinoma in the Taiwanese population","volume":"62","author":"Chang","year":"1995","journal-title":"Int. J. Cancer"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"3491","DOI":"10.1182\/blood.V88.9.3491.bloodjournal8893491","article-title":"Analysis of Epstein-Barr virus gene polymorphisms in normal donors and in virus-associated tumors from different geographic locations","volume":"88","author":"Khanim","year":"1996","journal-title":"Blood"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1016\/S0046-8177(99)90138-7","article-title":"High prevalence of a 30-base pair deletion in the Epstein-Barr virus (EBV) latent membrane protein 1 gene and of strain type B EBV in Mexican classical Hodgkin\u2019s disease and reactive lymphoid tissue","volume":"30","author":"Dirnhofer","year":"1999","journal-title":"Hum. Pathol."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Alves, P., Larrate, M., Garcia-Costa, A., Rohan, P., Gama, B.E., Abdelhay, E., Delatorre, E., and Hassan, R. (2022). Spatial Dispersal of Epstein-Barr Virus in South America Reveals an African American Variant in Brazilian Lymphomas. Viruses, 12.","DOI":"10.3390\/v14081762"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1038\/s41379-019-0415-5","article-title":"Mutational profile and EBV strains of extranodal NK\/T-cell lymphoma, nasal type in Latin America","volume":"33","author":"Chen","year":"2020","journal-title":"Mod. Pathol."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Begi\u0107, V., Kora\u0107, P., Ga\u0161parov, S., Rozman, M., Simicic, P., and Zidovec-Lepej, S. (2022). Molecular Characterisation of Epstein-Barr Virus in Classical Hodgkin Lymphoma. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms232415635"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"632","DOI":"10.1002\/jmv.23217","article-title":"Carboxy-terminal sequence variation of LMP1 gene in Epstein-Barr-virus-associated mononucleosis and tumors from Serbian patients","volume":"84","author":"Banko","year":"2012","journal-title":"J. Med. Virol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1515\/jomb-2015-0021","article-title":"Analysis of the Variability of Epstein-Barr Virus Genes in Infectious Mononucleosis: Investigation of the Potential Correlation with Biochemical Parameters of Hepatic Involvement","volume":"35","author":"Banko","year":"2016","journal-title":"Med. Biochem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1590\/S1413-86702008000300005","article-title":"Epstein-Barr virus nuclear antigen-2 detection and typing in immunocompromised children correlated with lymphoproliferative disorder biopsy findings","volume":"12","author":"Mendes","year":"2008","journal-title":"Braz. J. Infect. Dis."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1253","DOI":"10.1002\/jmv.21503","article-title":"The dominance of China 1 in the spectrum of Epstein-Barr virus strains from Cantonese patients with nasopharyngeal carcinoma","volume":"81","author":"Li","year":"2009","journal-title":"J. Med. Virol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"696","DOI":"10.1080\/10635150390235520","article-title":"A simple, fast and accurate algorithm to estimate large phylogenies by maximum likelihood","volume":"52","author":"Guindon","year":"2003","journal-title":"Syst. Biol."},{"key":"ref_38","first-page":"57","article-title":"Some probabilistic and statistical problems in the analysis of DNA sequences","volume":"17","year":"1986","journal-title":"Lect. Math. Life Sci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"763","DOI":"10.1086\/314672","article-title":"The molecular epidemiology and evolution of Epstein-Barr virus: Sequence variation and genetic recombination in the latent membrane protein-1 gene","volume":"179","author":"Walling","year":"1999","journal-title":"J. Infect. Dis."},{"key":"ref_40","unstructured":"R Development Core Team (2013). R: A Language and Environment for Statistical Computing, R Foundation for Statistical Computing. Available online: https:\/\/www.R-project.org\/."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"e00813-18","DOI":"10.1128\/JVI.00813-18","article-title":"Epstein-Barr Virus Type 2 Infects T Cells and Induces B Cell Lymphomagenesis in Humanized Mice","volume":"92","author":"Coleman","year":"2018","journal-title":"J. Virol."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Simbiri, K.O., Smith, N.A., Otieno, R., Wohlford, E.E., Daud, I.I., Odada, S.P., Middleton, F., and Rochford, R. (2015). Epstein-Barr virus genetic variation in lymphoblastoid cell lines derived from Kenyan pediatric population. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0125420"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2301","DOI":"10.1128\/JVI.03001-14","article-title":"Epstein-Barr virus type 2 latently infects T cells, inducing an atypical activation characterized by expression of lymphotactic cytokines","volume":"89","author":"Coleman","year":"2015","journal-title":"J. Virol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"670","DOI":"10.1093\/infdis\/jix363","article-title":"Epstein-Barr Virus Type 2 Infects T Cells in Healthy Kenyan Children","volume":"216","author":"Coleman","year":"2017","journal-title":"J. Infect. Dis."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"754","DOI":"10.3389\/fimmu.2018.00754","article-title":"Role of C-Reactive Protein at Sites of Inflammation and Infection","volume":"9","author":"Sproston","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1016\/j.bbi.2018.09.023","article-title":"Predictors of chronic fatigue in adolescents six months after acute Epstein-Barr virus infection: A prospective cohort study","volume":"75","author":"Pedersen","year":"2019","journal-title":"Brain Behav. Immun."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1016\/j.bbi.2019.04.040","article-title":"Clinical symptoms and markers of disease mechanisms in adolescent chronic fatigue following Epstein-Barr virus infection: An exploratory cross-sectional study","volume":"80","author":"Kristiansen","year":"2019","journal-title":"Brain Behav. Immun."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"e2023023","DOI":"10.4084\/MJHID.2023.023","article-title":"Hematological Abnormalities Beyond Lymphocytosis During Infectious Mononucleosis: Epstein-Barr Virus-Induced Thrombocytopenia","volume":"15","author":"Alende","year":"2023","journal-title":"Mediterr. J. Hematol. Infect. Dis."},{"key":"ref_49","first-page":"92","article-title":"Severe neutropenia in infectious mononucleosis","volume":"131","author":"Hammond","year":"1979","journal-title":"West. J. Med."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1060053","DOI":"10.3389\/fped.2023.1060053","article-title":"Characteristics of immunological events in Epstein-Barr virus infection in children with infectious mononucleosis","volume":"11","author":"Zhang","year":"2023","journal-title":"Front. Pediatr."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"e28572","DOI":"10.1002\/jmv.28572","article-title":"mRNA vaccines: The future of prevention of viral infections?","volume":"95","author":"Rzymski","year":"2023","journal-title":"J. Med. Virol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"5357","DOI":"10.1007\/s12274-022-5254-x","article-title":"A lipid-based LMP2-mRNA vaccine to treat nasopharyngeal carcinoma","volume":"16","author":"Guo","year":"2023","journal-title":"Nano Res."}],"container-title":["Pathogens"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-0817\/12\/7\/915\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T20:07:25Z","timestamp":1760126845000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-0817\/12\/7\/915"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,7,6]]},"references-count":52,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2023,7]]}},"alternative-id":["pathogens12070915"],"URL":"https:\/\/doi.org\/10.3390\/pathogens12070915","relation":{},"ISSN":["2076-0817"],"issn-type":[{"value":"2076-0817","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,7,6]]}}}