{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,11]],"date-time":"2026-03-11T00:32:56Z","timestamp":1773189176589,"version":"3.50.1"},"reference-count":42,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2020,12,6]],"date-time":"2020-12-06T00:00:00Z","timestamp":1607212800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Oncolytic adenoviruses (Ad) have shown promising results in the therapeutic treatment of cancer. Ad type 5 (Ad5) is the most extensively utilized Ad type. However, several limitations exist to using Ad5 as an oncolytic virus, including high levels of anti-Ad5 neutralizing antibodies in the population, binding of the Ad5 hexon to blood coagulation factor X leading to liver sequestration and toxicity, and reduced expression of the primary receptor CAR on many tumors. Here, we use in vitro methods to explore the oncolytic potential of four alternative Ad types (Ad26, 28, 45, and 48) belonging to the species D Ad subgroup and developed replication-competent species D Ads expressing the human sodium iodide symporter protein (hNIS) for combination radiovirotherapy. We evaluated the species D Ad vectors transduction, replication, cytotoxicity, and gene expression in six different cancer cell lines. Species D Ads showed the greatest transduction and cytotoxic killing in the SKBR3 breast cancer cells, followed by 293, A549, and HepG2 cells, however the cytotoxicity was less than the wild type Ad5 virus. In contrast, species D Ads showed limited transduction and cytotoxicity in the Hela and SKOV3 cancer cell lines. These species D Ad vectors also successfully expressed the hNIS gene during infection leading to increased iodide uptake in multiple cancer cell lines. These results, the low seroprevalence of anti-species D antibodies, and the lack of binding to blood coagulation FX, support further exploration of species D Ads as alternative oncolytic adenoviruses against multiple types of cancer.<\/jats:p>","DOI":"10.3390\/v12121399","type":"journal-article","created":{"date-parts":[[2020,12,7]],"date-time":"2020-12-07T12:24:39Z","timestamp":1607343879000},"page":"1399","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Species D Adenoviruses as Oncolytic Viral Vectors"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6702-0079","authenticated-orcid":false,"given":"Brianna L.","family":"Bullard","sequence":"first","affiliation":[{"name":"Nebraska Center for Virology, School of Biological Sciences, University of Nebraska, Lincoln, NE 68503, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brigette N.","family":"Corder","sequence":"additional","affiliation":[{"name":"Nebraska Center for Virology, School of Biological Sciences, University of Nebraska, Lincoln, NE 68503, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5029-0662","authenticated-orcid":false,"given":"Eric A.","family":"Weaver","sequence":"additional","affiliation":[{"name":"Nebraska Center for Virology, School of Biological Sciences, University of Nebraska, Lincoln, NE 68503, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,12,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"642","DOI":"10.1038\/nrd4663","article-title":"Oncolytic viruses: A new class of immunotherapy drugs","volume":"14","author":"Kaufman","year":"2015","journal-title":"Nat Rev Drug Discov."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"6009","DOI":"10.3390\/v7112923","article-title":"Oncolytic adenovirus: Strategies and insights for vector design and immuno-oncolytic applications","volume":"7","author":"Davies","year":"2015","journal-title":"Viruses"},{"key":"ref_3","unstructured":"Fields, B.N., Knipe, D.M., and Howley, P.M. (2013). Fields Virology, Wolters Kluwer Health\/Lippincott Williams & Wilkins."},{"key":"ref_4","first-page":"351","article-title":"Prevalence of neutralizing antibodies to adenoviral serotypes 5 and 35 in the adult populations of the Gambia, South Africa, and the United States","volume":"11","author":"Nwanegbo","year":"2004","journal-title":"Clin. Diagnost. Lab. Immunol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"4654","DOI":"10.1128\/JVI.02696-06","article-title":"Comparative seroprevalence and immunogenicity of six rare serotype recombinant adenovirus vaccine vectors from subgroups B and D","volume":"81","author":"Abbink","year":"2007","journal-title":"J. Virol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1080\/14760584.2019.1588113","article-title":"A review of 65 years of human adenovirus seroprevalence","volume":"18","author":"Mennechet","year":"2019","journal-title":"Expert Rev. Vacc."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1553","DOI":"10.1089\/10430340050083289","article-title":"Pre-existent adenovirus antibody inhibits systemic toxicity and antitumor activity of CN706 in the nude mouse LNCaP xenograft model: Implications and proposals for human therapy","volume":"11","author":"Chen","year":"2000","journal-title":"Hum. Gene Ther."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2130","DOI":"10.1128\/JVI.02127-08","article-title":"Effect of preexisting immunity on oncolytic adenovirus vector INGN 007 antitumor efficacy in immunocompetent and immunosuppressed syrian hamsters","volume":"83","author":"Dhar","year":"2009","journal-title":"J. Virol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1412","DOI":"10.1007\/s00262-006-0158-2","article-title":"Targeted and shielded adenovectors for cancer therapy","volume":"55","author":"Hedley","year":"2006","journal-title":"Cancer Immunol. Immunother."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1137","DOI":"10.1089\/hum.2011.003","article-title":"Systemic delivery of a novel liver-detargeted oncolytic adenovirus causes reduced liver toxicity but maintains the antitumor response in a breast cancer bone metastasis model","volume":"22","author":"Zhang","year":"2011","journal-title":"Hum. Gene Ther."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1016\/j.cell.2008.01.016","article-title":"Adenovirus serotype 5 hexon mediates liver gene transfer","volume":"132","author":"Waddington","year":"2008","journal-title":"Cell"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.coviro.2016.06.009","article-title":"Recent advances in oncolytic adenovirus therapies for cancer","volume":"21","author":"Suzuki","year":"2016","journal-title":"Curr. Opin. Virol."},{"key":"ref_13","first-page":"325","article-title":"Loss of adenoviral receptor expression in human bladder cancer cells: A potential impact on the efficacy of gene therapy","volume":"59","author":"Li","year":"1999","journal-title":"Cancer Res."},{"key":"ref_14","first-page":"3","article-title":"Adenovirus-mediated cancer gene therapy and virotherapy","volume":"25","author":"Fukazawa","year":"2010","journal-title":"Int. J. Mol. Med."},{"key":"ref_15","first-page":"1057","article-title":"Coxsackie adenovirus receptor expression in carcinomas of the head and neck","volume":"32","author":"Wunder","year":"2012","journal-title":"Anticancer Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"6712","DOI":"10.1158\/1078-0432.CCR-11-0968","article-title":"Species D adenoviruses as oncolytics against B-cell cancers","volume":"17","author":"Chen","year":"2011","journal-title":"Clin. Cancer Res Offic. J. Am. Assoc. Cancer Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1095","DOI":"10.1089\/hum.2011.071","article-title":"Comparison of adenoviruses as oncolytics and cancer vaccines in an immunocompetent B cell lymphoma model","volume":"22","author":"Weaver","year":"2011","journal-title":"Hum. Gene Ther."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"5203","DOI":"10.1016\/j.vaccine.2011.05.025","article-title":"International seroepidemiology of adenovirus serotypes 5, 26, 35, and 48 in pediatric and adult populations","volume":"29","author":"Barouch","year":"2011","journal-title":"Vaccine"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"950","DOI":"10.1016\/j.vaccine.2009.10.145","article-title":"International epidemiology of human pre-existing adenovirus (Ad) type-5, type-6, type-26 and type-36 neutralizing antibodies: Correlates of high Ad5 titers and implications for potential HIV vaccine trials","volume":"28","author":"Mast","year":"2010","journal-title":"Vaccine"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"5691","DOI":"10.1016\/j.vaccine.2010.06.050","article-title":"Potent immune responses and in vitro pro-inflammatory cytokine suppression by a novel adenovirus vaccine vector based on rare human serotype 28","volume":"28","author":"Kahl","year":"2010","journal-title":"Vaccine"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"12125","DOI":"10.1128\/JVI.79.19.12125-12131.2005","article-title":"Adenovirus Receptors","volume":"79","author":"Zhang","year":"2005","journal-title":"J. Virol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"10862","DOI":"10.1128\/JVI.00928-12","article-title":"Adenovirus serotype 26 utilizes CD46 as a primary cellular receptor and only transiently activates T lymphocytes following vaccination of rhesus monkeys","volume":"86","author":"Li","year":"2012","journal-title":"J. Virol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1089\/hum.2013.215","article-title":"CD46-mediated transduction of a species D adenovirus vaccine improves mucosal vaccine efficacy","volume":"25","author":"Camacho","year":"2014","journal-title":"Hum. Gene Ther."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1089\/hum.2006.17.193","article-title":"Adenovirus vectors based on human adenovirus type 19a have high potential for human muscle-directed gene therapy","volume":"17","author":"Thirion","year":"2006","journal-title":"Hum. Gene Ther."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"3313","DOI":"10.2174\/1381612811209023313","article-title":"Radiovirotherapy: Principles and prospects in oncology","volume":"18","author":"Touchefeu","year":"2012","journal-title":"Curr. Pharma. Des."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1517\/14712598.2016.1100162","article-title":"The use of the NIS reporter gene for optimizing oncolytic virotherapy","volume":"16","author":"Miller","year":"2016","journal-title":"Expert Opin. Biol. Ther."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"6595","DOI":"10.1158\/1078-0432.CCR-09-0262","article-title":"Targeted Radionuclide Therapy Using a Wnt-Targeted Replicating Adenovirus Encoding the Na\/I Symporter","volume":"15","author":"Peerlinck","year":"2009","journal-title":"Clin. Cancer Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1159\/000108968","article-title":"In vivo radioiodide imaging and treatment of pancreatic cancer xenografts after MUC1 promoter-driven expression of the human sodium-iodide symporter","volume":"7","author":"Chen","year":"2007","journal-title":"Pancreatology"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"8045","DOI":"10.1158\/0008-5472.CAN-04-0893","article-title":"Long-term radioiodine retention and regression of liver cancer after sodium iodide symporter gene transfer in wistar rats","volume":"64","author":"Faivre","year":"2004","journal-title":"Cancer Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"5396","DOI":"10.1158\/1078-0432.CCR-08-2571","article-title":"Targeted radiotherapy for prostate cancer with an oncolytic adenovirus coding for human sodium iodide symporter","volume":"15","author":"Hakkarainen","year":"2009","journal-title":"Clin. Cancer Res."},{"key":"ref_31","first-page":"1208","article-title":"Molecular evolution of human species D adenoviruses","volume":"11","author":"Robinson","year":"2011","journal-title":"Inf. Gen. Evol. J. Mol. Epidemiol. Evolut. Gen. Inf. Dis."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"544","DOI":"10.4161\/hv.27238","article-title":"Vaccines within vaccines: The use of adenovirus types 4 and 7 as influenza vaccine vectors","volume":"10","author":"Weaver","year":"2014","journal-title":"Hum. Vacc.Immunother."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Weaver, E.A., and Barry, M.A. (2013). Low seroprevalent species D adenovirus vectors as influenza vaccines. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0073313"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/j.ab.2009.08.038","article-title":"A nonradioactive iodide uptake assay for sodium iodide symporter function","volume":"396","author":"Waltz","year":"2010","journal-title":"Analyt. Biochem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"5483","DOI":"10.1073\/pnas.0711757105","article-title":"Adenovirus serotype 5 hexon is critical for virus infection of hepatocytes in vivo","volume":"105","author":"Kalyuzhniy","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1016\/j.virol.2009.08.038","article-title":"Characterization of human adenovirus serotypes 5, 6, 11, and 35 as anticancer agents","volume":"394","author":"Shashkova","year":"2009","journal-title":"Virology"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"10522","DOI":"10.1128\/JVI.00450-10","article-title":"Adenovirus-based vaccines: Comparison of vectors from three species of adenoviridae","volume":"84","author":"Chen","year":"2010","journal-title":"J. Virol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"741","DOI":"10.1038\/s41467-019-08599-y","article-title":"Diversity within the adenovirus fiber knob hypervariable loops influences primary receptor interactions","volume":"10","author":"Baker","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_39","first-page":"e01474-18","article-title":"\u03b1v\u03b23 Integrin is required for efficient infection of epithelial cells with human adenovirus type 26","volume":"93","author":"Uil","year":"2018","journal-title":"J. Virol."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Stichling, N., Suomalainen, M., Flatt, J.W., Schmid, M., Pacesa, M., Hemmi, S., Jungraithmayr, W., Maler, M.D., Freudenberg, M.A., and Pl\u00fcckthun, A. (2018). Lung macrophage scavenger receptor SR-A6 (MARCO) is an adenovirus type-specific virus entry receptor. PLoS Path., 14.","DOI":"10.1371\/journal.ppat.1006914"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"eaax3567","DOI":"10.1126\/sciadv.aax3567","article-title":"Human adenovirus type 26 uses sialic acid\u2013bearing glycans as a primary cell entry receptor","volume":"5","author":"Baker","year":"2019","journal-title":"Sci. Adv."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Uusi-Kerttula, H., Davies, J., Coughlan, L., Hulin-Curtis, S., Jones, R., Hanna, L., Chester, J.D., and Parker, A.L. (2016). Pseudotyped \u03b1v\u03b26 integrin-targeted adenovirus vectors for ovarian cancer therapies. Oncotarget, 7.","DOI":"10.18632\/oncotarget.8545"}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/12\/12\/1399\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:41:33Z","timestamp":1760179293000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/12\/12\/1399"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,12,6]]},"references-count":42,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2020,12]]}},"alternative-id":["v12121399"],"URL":"https:\/\/doi.org\/10.3390\/v12121399","relation":{},"ISSN":["1999-4915"],"issn-type":[{"value":"1999-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,12,6]]}}}