{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,17]],"date-time":"2025-11-17T14:16:24Z","timestamp":1763388984031,"version":"3.45.0"},"reference-count":51,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2025,11,17]],"date-time":"2025-11-17T00:00:00Z","timestamp":1763337600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001786","name":"THE UNIVERSITY OF ADELAIDE","doi-asserted-by":"publisher","award":["122-13107182"],"award-info":[{"award-number":["122-13107182"]}],"id":[{"id":"10.13039\/501100001786","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>The pathogenesis of koala retrovirus (KoRV) has been explored in various contexts, yet its role in tumorigenesis remains incompletely understood. Unlike acute transforming retroviruses, KoRV lacks a viral oncogene but may contribute to oncogenesis via indirect mechanisms. However, the relationship between KoRV and telomere length, as a potential indicator of telomerase activity, has not been examined. This study investigates the effect of KoRV infection on telomere length in 47 samples from Southern Australian koalas in a novel telomere length quantification method. Telomere lengths of 30 KoRV-negative samples were compared to those of 17 KoRV-positive samples using the Absolute Human Telomere Length Quantification qPCR kit (ScienCell Research Laboratories, California, USA). The telomere length in KoRV-infected WBCs was significantly longer than the uninfected ones (t = \u22122.059, p-value = 0.045). In line with this, telomere length correlated positively with proviral load (r = 0.421, p-value = 0.003), further linking viral burden to telomere elongation. Furthermore, the effect of age on telomere length differed by infection status (\u03b2 = \u22125329.7, p-value = 0.0038); KoRV-positive individuals exhibited longer telomeres at a younger age but experienced more rapid telomere attrition over time compared to KoRV-negative individuals. These results suggest KoRV promotes telomerase elongation ability and modulates age-related telomere dynamics, potentially contributing to subsequent cellular immortality and oncogenesis. These pathways may overlap with other retroviruses, where telomerase dysregulation contributes to their oncogenic potential. This study provides new insights into KoRV pathogenesis and DNA quantification methodology, which could be valuable for future research by identifying predictive markers for tumour progression and potential therapeutic targets in affected koalas.<\/jats:p>","DOI":"10.3390\/v17111510","type":"journal-article","created":{"date-parts":[[2025,11,17]],"date-time":"2025-11-17T14:04:07Z","timestamp":1763388247000},"page":"1510","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Infection-Induced Telomere Length Variation: Insights into Pathogenesis of Koala Retrovirus"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-0430-3786","authenticated-orcid":false,"given":"Hiu Ming","family":"Cheung","sequence":"first","affiliation":[{"name":"School of Animal and Veterinary Sciences, The University of Adelaide, Roseworthy Campus, Roseworthy, SA 5371, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sze Wing Jamie","family":"Lin","sequence":"additional","affiliation":[{"name":"School of Animal and Veterinary Sciences, The University of Adelaide, Roseworthy Campus, Roseworthy, SA 5371, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hanh Thi Hong","family":"Nguyen","sequence":"additional","affiliation":[{"name":"School of Animal and Veterinary Sciences, The University of Adelaide, Roseworthy Campus, Roseworthy, SA 5371, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4634-8881","authenticated-orcid":false,"given":"Tamsyn","family":"Stephenson","sequence":"additional","affiliation":[{"name":"School of Animal and Veterinary Sciences, The University of Adelaide, Roseworthy Campus, Roseworthy, SA 5371, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5367-0241","authenticated-orcid":false,"given":"Natasha","family":"Speight","sequence":"additional","affiliation":[{"name":"School of Animal and Veterinary Sciences, The University of Adelaide, Roseworthy Campus, Roseworthy, SA 5371, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4572-8869","authenticated-orcid":false,"given":"Farhid","family":"Hemmatzadeh","sequence":"additional","affiliation":[{"name":"School of Animal and Veterinary Sciences, The University of Adelaide, Roseworthy Campus, Roseworthy, SA 5371, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"783","DOI":"10.1099\/vir.0.80547-0","article-title":"Real-time reverse transcriptase PCR for the endogenous koala retrovirus reveals an association between plasma viral load and neoplastic disease in koalas","volume":"86","author":"Tarlinton","year":"2005","journal-title":"J. General. Virol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e01871-17","DOI":"10.1128\/JVI.01871-17","article-title":"Molecular dynamics and mode of transmission of koala retrovirus as it invades and spreads through a wild Queensland koala population","volume":"92","author":"Quigley","year":"2018","journal-title":"J. Virol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1072","DOI":"10.1099\/jmm.0.001009","article-title":"Prevalence and clinical significance of koala retrovirus in two South Australian koala (Phascolarctos cinereus) populations","volume":"68","author":"Fabijan","year":"2019","journal-title":"J. Med. Microbiol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1316","DOI":"10.1038\/s41467-021-21612-7","article-title":"Retroviral integrations contribute to elevated host cancer rates during germline invasion","volume":"12","author":"McEwen","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"144366","DOI":"10.1016\/j.gene.2020.144366","article-title":"Novel insights into viral infection and oncogenesis from koala retrovirus (KoRV) infection of HEK293T cells","volume":"733","author":"Sarker","year":"2020","journal-title":"Gene"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1102","DOI":"10.1038\/s41588-018-0153-5","article-title":"Adaptation and conservation insights from the koala genome","volume":"50","author":"Johnson","year":"2018","journal-title":"Nat. Genet."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1007\/s11259-015-9629-2","article-title":"Interaction between Bovine leukemia virus (BLV) infection and age on telomerase misregulation","volume":"39","author":"Hemmatzadeh","year":"2015","journal-title":"Vet. Res. Commun."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1186\/s13567-022-01120-2","article-title":"Chicken telomerase reverse transcriptase promotes the tumorigenicity of avian leukosis virus subgroup J by regulating the Wnt\/beta-catenin signaling pathway","volume":"53","author":"Xiang","year":"2022","journal-title":"Vet. Res."},{"key":"ref_9","first-page":"100323","article-title":"The role of telomerase and viruses interaction in cancer development, and telomerase-dependent therapeutic approaches","volume":"27","author":"Badrzadeh","year":"2021","journal-title":"Cancer Treat. Res. Commun."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1002\/jmv.20855","article-title":"Telomerase activity, hTERT expression, and phosphorylation are downregulated in CD4+ T lymphocytes infected with human immunodeficiency virus type 1 (HIV-1)","volume":"79","author":"Franzese","year":"2007","journal-title":"J. Med. Virol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1155","DOI":"10.1111\/j.1349-7006.2008.00798.x","article-title":"Role of human T-cell leukemia virus type I Tax in expression of the human telomerase reverse transcriptase (hTERT) gene in human T-cells","volume":"99","author":"Hara","year":"2008","journal-title":"Cancer Sci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1089\/152581600419143","article-title":"Human T cell leukemia virus type II increases telomerase activity in uninfected CD34 hematopoietic progenitor cells","volume":"9","author":"Re","year":"2000","journal-title":"J. Hematotherapy Stem Cell Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1146\/annurev.biochem.73.071403.160049","article-title":"Regulation of telomerase by telomeric proteins","volume":"73","author":"Smogorzewska","year":"2004","journal-title":"Annu. Rev. Biochem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1921","DOI":"10.1002\/j.1460-2075.1992.tb05245.x","article-title":"Telomere shortening associated with chromosome instability is arrested in immortal cells which express telomerase activity","volume":"11","author":"Counter","year":"1992","journal-title":"EMBO J."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1038\/nrc2393","article-title":"Telomere dysfunction and tumour suppression: The senescence connection","volume":"8","author":"Deng","year":"2008","journal-title":"Nat. Rev. Cancer"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1962","DOI":"10.4049\/jimmunol.1801475","article-title":"New insights into lymphocyte differentiation and aging from telomere length and telomerase activity measurements","volume":"202","author":"Fali","year":"2019","journal-title":"J. Immunol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1016\/S0959-8049(97)00062-2","article-title":"A survey of telomerase activity in human cancer","volume":"33","author":"Shay","year":"1997","journal-title":"Eur. J. Cancer"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2315","DOI":"10.1182\/blood.V85.9.2315.bloodjournal8592315","article-title":"Telomerase activity in normal leukocytes and in hematologic malignancies","volume":"85","author":"Counter","year":"1995","journal-title":"Blood"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2011","DOI":"10.1126\/science.7605428","article-title":"Specific Association of Human Telomerase Activity with Immortal Cells and Cancer","volume":"266","author":"Kim","year":"1994","journal-title":"Science"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1016\/j.cell.2011.02.013","article-title":"Hallmarks of Cancer: The Next Generation","volume":"144","author":"Hanahan","year":"2011","journal-title":"Cell"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1038\/ng.3781","article-title":"Systematic analysis of telomere length and somatic alterations in 31 cancer types","volume":"49","author":"Barthel","year":"2017","journal-title":"Nat. Genet."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1163","DOI":"10.1158\/1541-7786.MCR-23-0144","article-title":"Telomerase upregulation induces progression of mouse BrafV600E-Driven thyroid cancers and triggers nontelomeric effects","volume":"21","author":"Landa","year":"2023","journal-title":"Mol. Cancer Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"391","DOI":"10.24425\/pjvs.2019.129299","article-title":"Determination of telomere length and telomerase activity in cattle infected with bovine leukaemia virus (BLV)","volume":"22","author":"Szczotka","year":"2019","journal-title":"Pol. J. Vet. Sci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1016\/j.vetmic.2007.08.016","article-title":"Measurement of telomerase activity in bovine leukaemia virus infected cows","volume":"127","author":"Suzuki","year":"2008","journal-title":"Vet. Microbiol."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Stephenson, T., Speight, N., Low, W.Y., Woolford, L., Tearle, R., and Hemmatzadeh, F. (2021). Molecular Diagnosis of Koala Retrovirus (KoRV) in South Australian Koalas (Phascolarctos cinereus). Animals, 11.","DOI":"10.3390\/ani11051477"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e2122680119","DOI":"10.1073\/pnas.2122680119","article-title":"Geographic patterns of koala retrovirus genetic diversity, endogenization, and subtype distributions","volume":"119","author":"Blyton","year":"2022","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1071\/WR9810275","article-title":"Age-specific fertility in three populations of the koala, Phascolarctos cinereus Goldfuss, in Victoria","volume":"8","author":"Martin","year":"1981","journal-title":"Wildl. Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2409","DOI":"10.1007\/s00705-020-04770-9","article-title":"Koala retrovirus epidemiology, transmission mode, pathogenesis, and host immune response in koalas (Phascolarctos cinereus): A review","volume":"165","author":"Kayesh","year":"2020","journal-title":"Arch. Virol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1093\/femsre\/fuaa024","article-title":"Helping koalas battle disease\u2014Recent advances in Chlamydia and koala retrovirus (KoRV) disease understanding and treatment in koalas","volume":"44","author":"Quigley","year":"2020","journal-title":"FEMS Microbiol. Rev."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Sarker, N., Fabijan, J., Owen, H., Seddon, J., Simmons, G., Speight, N., Kaler, J., Woolford, L., Emes, R.D., and Hemmatzadeh, F. (2020). Koala retrovirus viral load and disease burden in distinct northern and southern koala populations. Sci. Rep., 10.","DOI":"10.1038\/s41598-019-56546-0"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Sarker, N., Fabijan, J., Emes, R.D., Hemmatzadeh, F., Meers, J., Moreton, J., Owen, H., Seddon, J.M., Simmons, G., and Speight, N. (2018). Identification of stable reference genes for quantitative PCR in koalas. Sci. Rep., 8.","DOI":"10.1038\/s41598-018-21723-0"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1002\/path.2090","article-title":"Hallmarks of telomeres in ageing research","volume":"211","author":"Shay","year":"2007","journal-title":"J. Pathol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"3410","DOI":"10.1128\/jvi.68.5.3410-3414.1994","article-title":"Stabilization of short telomeres and telomerase activity accompany immortalization of Epstein-Barr virus-transformed human B lymphocytes","volume":"68","author":"Counter","year":"1994","journal-title":"J. Virol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1167","DOI":"10.1093\/carcin\/bgg085","article-title":"Transcriptional regulation of the telomerase hTERT gene as a target for cellular and viral oncogenic mechanisms","volume":"24","author":"Horikawa","year":"2003","journal-title":"Carcinogenesis"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1002\/hep.20271","article-title":"Hepatocellular telomere shortening correlates with chromosomal instability and the development of human hepatoma","volume":"40","author":"Plentz","year":"2004","journal-title":"Hepatology"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Akter, L., Hashem, M.A., Kayesh, M.E.H., Hossain, M.A., Maetani, F., Akhter, R., Hossain, K.A., Rashid, M.H.O., Sakurai, H., and Asai, T. (2024). A preliminary study of gene expression changes in Koalas Infected with Koala Retrovirus (KoRV) and identification of potential biomarkers for KoRV pathogenesis. BMC Vet. Res., 20.","DOI":"10.1186\/s12917-024-04357-5"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1007\/s11262-025-02169-9","article-title":"Elevated oncogene expressions in koala infected with multiple koala retrovirus subtypes: A preliminary study","volume":"61","author":"Akter","year":"2025","journal-title":"Virus Genes"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"494","DOI":"10.1038\/sj.onc.1205076","article-title":"Telomerase is not an oncogene","volume":"21","author":"Harley","year":"2002","journal-title":"Oncogene"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1118","DOI":"10.3390\/d2091118","article-title":"Telomere length diversity in cattle breeds","volume":"2","author":"Tilesi","year":"2010","journal-title":"Diversity"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"761","DOI":"10.1111\/j.1474-9726.2011.00718.x","article-title":"Comparative biology of mammalian telomeres: Hypotheses on ancestral states and the roles of telomeres in longevity determination","volume":"10","author":"Gomes","year":"2011","journal-title":"Aging Cell"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/S1040-8428(01)00188-3","article-title":"Telomerase in cancer and aging","volume":"41","author":"Granger","year":"2002","journal-title":"Crit. Rev. Oncol. Hematol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1619","DOI":"10.1016\/S0531-5565(01)00160-7","article-title":"Cellular senescence, cancer and aging: The telomere connection","volume":"36","author":"Campisi","year":"2001","journal-title":"Exp. Gerontol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1016\/S0167-5699(00)01714-X","article-title":"Ageing of lymphocytes and lymphocytes in the aged","volume":"21","author":"Globerson","year":"2000","journal-title":"Immunol. Today"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"861","DOI":"10.1189\/jlb.70.6.861","article-title":"Interplay between Telomere Length and Telomerase in Human Leukocyte Differentiation and Aging","volume":"70","author":"Weng","year":"2001","journal-title":"J. Leukoc. Biol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1059","DOI":"10.1128\/JVI.77.2.1059-1068.2003","article-title":"Long-Range Effects of Retroviral Insertion on c-myb: Overexpression May Be Obscured by Silencing during Tumor Growth In Vitro","volume":"77","author":"Hanlon","year":"2003","journal-title":"J. Virol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1179","DOI":"10.1101\/gad.240820.114","article-title":"MuLV-related endogenous retroviral elements and Flt3 participate in aberrant end-joining events that promote B-cell leukemogenesis","volume":"28","author":"Johnson","year":"2014","journal-title":"Genes Dev."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1038\/6010","article-title":"Direct activation of TERT transcription by c-MYC","volume":"21","author":"Wu","year":"1999","journal-title":"Nat. Genet."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"14183","DOI":"10.1074\/jbc.272.22.14183","article-title":"Bcl-2 Modulates Telomerase Activity","volume":"272","author":"Mandal","year":"1997","journal-title":"J. Biol. Chem."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1007\/s00277-017-3158-8","article-title":"MYC-dependent downregulation of telomerase by FLT3 inhibitors is required for their therapeutic efficacy on acute myeloid leukemia","volume":"97","author":"Zhang","year":"2018","journal-title":"Ann. Hematol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.jcpa.2020.02.003","article-title":"Pathological findings in koala retrovirus-positive koalas (Phascolarctos cinereus) from Northern and Southern Australia","volume":"176","author":"Fabijan","year":"2020","journal-title":"J. Comp. Pathol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1003","DOI":"10.1086\/301845","article-title":"Replicative senescence in the immune system: Impact of the Hayflick limit on T-cell function in the elderly","volume":"62","author":"Effros","year":"1998","journal-title":"Am. J. Hum. Genet."}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/17\/11\/1510\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,17]],"date-time":"2025-11-17T14:09:03Z","timestamp":1763388543000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/17\/11\/1510"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,17]]},"references-count":51,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2025,11]]}},"alternative-id":["v17111510"],"URL":"https:\/\/doi.org\/10.3390\/v17111510","relation":{},"ISSN":["1999-4915"],"issn-type":[{"value":"1999-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,17]]}}}