{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T11:13:44Z","timestamp":1788261224656,"version":"build-2803163510"},"reference-count":42,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2025,1,26]],"date-time":"2025-01-26T00:00:00Z","timestamp":1737849600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"EU PANVIPREP","award":["101137229"],"award-info":[{"award-number":["101137229"]}]},{"name":"EU PANVIPREP","award":["101102733"],"award-info":[{"award-number":["101102733"]}]},{"name":"EU PANVIPREP","award":["202006380126"],"award-info":[{"award-number":["202006380126"]}]},{"name":"EU DURABLE","award":["101137229"],"award-info":[{"award-number":["101137229"]}]},{"name":"EU DURABLE","award":["101102733"],"award-info":[{"award-number":["101102733"]}]},{"name":"EU DURABLE","award":["202006380126"],"award-info":[{"award-number":["202006380126"]}]},{"name":"China Scholarship Council","award":["101137229"],"award-info":[{"award-number":["101137229"]}]},{"name":"China Scholarship Council","award":["101102733"],"award-info":[{"award-number":["101102733"]}]},{"name":"China Scholarship Council","award":["202006380126"],"award-info":[{"award-number":["202006380126"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Human parainfluenza virus type 3 (HPIV-3) can cause severe respiratory diseases, particularly in young children, the elderly and immunocompromised. There are no approved antiviral drugs against this virus. We report that the combination of ribavirin with either remdesivir or its parent nucleoside GS-441524 results in a pronounced antiviral effect against HPIV-3 in LLC-MK2 cells and in human airway epithelial cells grown at the air\u2013liquid interface. In AG129 mice intranasally inoculated with HPIV-3, the combined treatment with ribavirin and GS-441524 decreased infectious viral lung titers by &gt;2.5 log10 to undetectable levels in 4 out of 11 mice and by 1.6 log10 in the remaining 7 mice as compared with the vehicle. The lungs of all mice that received the combined treatment appeared histologically normal or virtually normal, whereas 8 of 11 vehicle-treated mice presented with bronchopneumonia. By contrast, ribavirin alone did not result in a reduction in infectious viral lung titers; GS-441524 alone reduced infectious viral lung titers by 1.2 log10. Moreover, several mice in the single-treatment groups exhibited severe lung pathology. These findings may warrant exploring this combination in patients with severe HPIV-3 infections and possibly also against infections with other viruses that are susceptible in vitro to these two drugs.<\/jats:p>","DOI":"10.3390\/v17020172","type":"journal-article","created":{"date-parts":[[2025,1,27]],"date-time":"2025-01-27T04:59:10Z","timestamp":1737953950000},"page":"172","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["The Combination of GS-441524 (Remdesivir) and Ribavirin Results in a Potent Antiviral Effect Against Human Parainfluenza Virus 3 Infection in Human Airway Epithelial Cell Cultures and in a Mouse Infection Model"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7890-8030","authenticated-orcid":false,"given":"Yuxia","family":"Lin","sequence":"first","affiliation":[{"name":"KU Leuven Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Virology, Antiviral Drug & Vaccine Research Group, B-3000 Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Birgit","family":"Weynand","sequence":"additional","affiliation":[{"name":"KU Leuven Department of Imaging and Pathology, Division of Translational Cell and Tissue Research, B-3000 Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Zhang","sequence":"additional","affiliation":[{"name":"KU Leuven Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Virology, Antiviral Drug & Vaccine Research Group, B-3000 Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5708-1321","authenticated-orcid":false,"given":"Manon","family":"Laporte","sequence":"additional","affiliation":[{"name":"KU Leuven Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Virology, Antiviral Drug & Vaccine Research Group, B-3000 Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9265-6028","authenticated-orcid":false,"given":"Dirk","family":"Jochmans","sequence":"additional","affiliation":[{"name":"KU Leuven Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Virology, Antiviral Drug & Vaccine Research Group, B-3000 Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0033-7514","authenticated-orcid":false,"given":"Johan","family":"Neyts","sequence":"additional","affiliation":[{"name":"KU Leuven Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Virology, Antiviral Drug & Vaccine Research Group, B-3000 Leuven, Belgium"},{"name":"VirusBank Platform, KU Leuven, B-3000 Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,1,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"538","DOI":"10.1055\/s-0036-1584798","article-title":"Parainfluenza Virus Infection","volume":"37","author":"Branche","year":"2016","journal-title":"Semin. Respir. Crit. Care Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"564","DOI":"10.1111\/irv.12514","article-title":"Human parainfluenza virus infection in severe acute respiratory infection cases in Beijing, 2014\u20132016: A molecular epidemiological study","volume":"11","author":"Pan","year":"2017","journal-title":"Influenza Other Respir. Viruses"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"640","DOI":"10.1016\/S0022-3476(99)70064-8","article-title":"Viral infections in interferon-gamma receptor deficiency","volume":"135","author":"Dorman","year":"1999","journal-title":"J. Pediatr."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"11S","DOI":"10.1053\/bbmt.2001.v7.pm11777098","article-title":"Community-acquired respiratory syncytial virus and parainfluenza virus infections after hematopoietic stem cell transplantation: The Fred Hutchinson Cancer Research Center experience","volume":"7","author":"Nichols","year":"2001","journal-title":"Biol. Blood Marrow Transplant."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"121","DOI":"10.2147\/IDR.S25874","article-title":"Current management of parainfluenza pneumonitis in immunocompromised patients: A review","volume":"5","author":"Falsey","year":"2012","journal-title":"Infect. Drug Resist."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1038\/s41409-020-01022-x","article-title":"Oral ribavirin is a highly effective treatment for lower respiratory tract infections due to respiratory syncytial virus or parainfluenza after allogeneic stem cell transplantation","volume":"56","author":"Stamouli","year":"2021","journal-title":"Bone Marrow Transplant."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2252","DOI":"10.1093\/cid\/ciab969","article-title":"Respiratory Syncytial Virus, Human Metapneumovirus, and Parainfluenza Virus Infections in Lung Transplant Recipients: A Systematic Review of Outcomes and Treatment Strategies","volume":"74","author":"Lunter","year":"2022","journal-title":"Clin. Infect. Dis."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.jcv.2018.02.009","article-title":"In vitro sensitivity of human parainfluenza 3 clinical isolates to ribavirin, favipiravir and zanamivir","volume":"102","author":"Smielewska","year":"2018","journal-title":"J. Clin. Virol."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Bailly, B., Dirr, L., El-Deeb, I.M., Altmeyer, R., Guillon, P., and von Itzstein, M. (2016). A dual drug regimen synergistically blocks human parainfluenza virus infection. Sci. Rep., 6.","DOI":"10.1038\/srep24138"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1126\/science.177.4050.705","article-title":"Broad-spectrum antiviral activity of Virazole: 1-beta-D-ribofuranosyl-1,2,4-triazole-3-carboxamide","volume":"177","author":"Sidwell","year":"1972","journal-title":"Science"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1943","DOI":"10.1128\/JVI.79.3.1943-1947.2005","article-title":"The predominant mechanism by which ribavirin exerts its antiviral activity in vitro against flaviviruses and paramyxoviruses is mediated by inhibition of IMP dehydrogenase","volume":"79","author":"Leyssen","year":"2005","journal-title":"J. Virol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"S46","DOI":"10.1016\/j.healun.2020.01.1218","article-title":"Mycophenolic Acid Has Intrinsic Antiviral Properties and Potentiates the Antiviral Effect of Ribavirin on Parainfluenza Virus","volume":"39","author":"Verschuuren","year":"2020","journal-title":"J. Heart Lung Transplant."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1111\/liv.13212","article-title":"Ribavirin revisited in the era of direct-acting antiviral therapy for hepatitis C virus infection","volume":"37","author":"Feld","year":"2017","journal-title":"Liver Int."},{"key":"ref_14","first-page":"165","article-title":"Lassa Fever Natural History and Clinical Management","volume":"440","author":"Grant","year":"2023","journal-title":"Curr. Top. Microbiol. Immunol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1016\/j.healun.2004.01.003","article-title":"Treatment of parainfluenza virus 3 pneumonia in a cardiac transplant recipient with intravenous ribavirin and methylprednisolone","volume":"24","author":"Wright","year":"2005","journal-title":"J. Heart Lung Transplant."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1111\/j.1399-3046.2006.00607.x","article-title":"Long-term therapy with aerosolized ribavirin for parainfluenza 3 virus respiratory tract infection in an infant with severe combined immunodeficiency","volume":"11","author":"Stankova","year":"2007","journal-title":"Pediatr. Transplant."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"336","DOI":"10.1007\/s12185-008-0148-6","article-title":"Successful treatment of parainfluenza virus 3 pneumonia with oral ribavirin and methylprednisolone in a bone marrow transplant recipient","volume":"88","author":"Shima","year":"2008","journal-title":"Int. J. Hematol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1558","DOI":"10.1038\/bmt.2013.112","article-title":"Oral ribavirin for treatment of respiratory syncitial virus and parainfluenza 3 virus infections post allogeneic haematopoietic stem cell transplantation","volume":"48","author":"Casey","year":"2013","journal-title":"Bone Marrow Transplant."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1941","DOI":"10.1007\/s15010-024-02213-0","article-title":"Outcome of Human Parainfluenza Virus infection in allogeneic stem cell transplantation recipients: Possible impact of ribavirin therapy","volume":"52","author":"Montoro","year":"2024","journal-title":"Infection"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"13596535221082773","DOI":"10.1177\/13596535221082773","article-title":"Journey of remdesivir from the inhibition of hepatitis C virus to the treatment of COVID-19","volume":"27","author":"Cihlar","year":"2022","journal-title":"Antivir Ther."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"U.S. Food & Drug Administration (2020, October 22). FDA Approves First Treatment for COVID-19, Available online: https:\/\/www.fda.gov\/news-events\/press-announcements\/fda-approves-first-treatment-covid-19.","DOI":"10.1002\/cpu.30542"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"6415","DOI":"10.1038\/s41467-021-26760-4","article-title":"Oral prodrug of remdesivir parent GS-441524 is efficacious against SARS-CoV-2 in ferrets","volume":"12","author":"Cox","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Lo, M.K., Jordan, R., Arvey, A., Sudhamsu, J., Shrivastava-Ranjan, P., Hotard, A.L., Flint, M., McMullan, L.K., Siegel, D., and Clarke, M.O. (2017). GS-5734 and its parent nucleoside analog inhibit Filo-, Pneumo-, and Paramyxoviruses. Sci. Rep., 7.","DOI":"10.1038\/srep43395"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"eaau9242","DOI":"10.1126\/scitranslmed.aau9242","article-title":"Remdesivir (GS-5734) protects African green monkeys from Nipah virus challenge","volume":"11","author":"Lo","year":"2019","journal-title":"Sci. Transl. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"6771","DOI":"10.1073\/pnas.1922083117","article-title":"Prophylactic and therapeutic remdesivir (GS-5734) treatment in the rhesus macaque model of MERS-CoV infection","volume":"117","author":"Feldmann","year":"2020","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"5001","DOI":"10.1021\/acs.jmedchem.1c00071","article-title":"Prodrugs of a 1\u2019-CN-4-Aza-7,9-dideazaadenosine C-Nucleoside Leading to the Discovery of Remdesivir (GS-5734) as a Potent Inhibitor of Respiratory Syncytial Virus with Efficacy in the African Green Monkey Model of RSV","volume":"64","author":"Mackman","year":"2021","journal-title":"J. Med. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"7765","DOI":"10.1038\/s41467-024-52071-5","article-title":"A robust mouse model of HPIV-3 infection and efficacy of GS-441524 against virus-induced lung pathology","volume":"15","author":"Lin","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1485","DOI":"10.1056\/NEJM199811193392101","article-title":"Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. Hepatitis Interventional Therapy Group","volume":"339","author":"McHutchison","year":"1998","journal-title":"N. Engl. J. Med."},{"key":"ref_29","first-page":"31s","article-title":"Treatment Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents: An Update","volume":"33","author":"Gibert","year":"2016","journal-title":"Fed. Pract."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"534","DOI":"10.1111\/liv.13266","article-title":"Real life Egyptian experience of efficacy and safety of Simeprevir\/Sofosbuvir therapy in 6211 chronic HCV genotype IV infected patients","volume":"37","author":"Eletreby","year":"2017","journal-title":"Liver Int."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1038\/s41586-022-04797-9","article-title":"Combination anti-HIV antibodies provide sustained virological suppression","volume":"606","author":"Sneller","year":"2022","journal-title":"Nature"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"W739","DOI":"10.1093\/nar\/gkac382","article-title":"SynergyFinder 3.0: An interactive analysis and consensus interpretation of multi-drug synergies across multiple samples","volume":"50","author":"Ianevski","year":"2022","journal-title":"Nucleic Acids Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"856","DOI":"10.1165\/rcmb.2020-0280LE","article-title":"Standardization of Reporting Criteria for Lung Pathology in SARS-CoV-2-infected Hamsters: What Matters?","volume":"63","author":"Gruber","year":"2020","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1113","DOI":"10.1128\/JVI.79.2.1113-1124.2005","article-title":"Infection of ciliated cells by human parainfluenza virus type 3 in an in vitro model of human airway epithelium","volume":"79","author":"Zhang","year":"2005","journal-title":"J. Virol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"6785","DOI":"10.1074\/jbc.RA120.013679","article-title":"Remdesivir is a direct-acting antiviral that inhibits RNA-dependent RNA polymerase from severe acute respiratory syndrome coronavirus 2 with high potency","volume":"295","author":"Gordon","year":"2020","journal-title":"J. Biol. Chem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"16156","DOI":"10.1074\/jbc.AC120.015720","article-title":"Template-dependent inhibition of coronavirus RNA-dependent RNA polymerase by remdesivir reveals a second mechanism of action","volume":"295","author":"Tchesnokov","year":"2020","journal-title":"J. Biol. Chem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1002\/rmv.483","article-title":"Mechanisms of action of ribavirin against distinct viruses","volume":"16","author":"Graci","year":"2006","journal-title":"Rev. Med. Virol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/j.virusres.2011.02.005","article-title":"Mechanism of action of ribavirin in a novel hepatitis C virus replication cell system","volume":"157","author":"Mori","year":"2011","journal-title":"Virus Res."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Akram, T., Gul, I., Parveez Zia, M., Hassan, A., Khatun, A., Shah, R.A., Ahmad, S.M., Ganai, N.A., Chikan, N.A., and Kim, W.I. (2023). Ribavirin inhibits the replication of infectious bursal disease virus predominantly through depletion of cellular guanosine pool. Front. Vet. Sci., 10.","DOI":"10.3389\/fvets.2023.1192583"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1016\/S0021-9258(18)51782-8","article-title":"Nucleoside triphosphate-nucleoside diphosphate transphosphorylase (nucleoside diphosphokinase). I. Isolation of the Crystalline Enzyme from Brewers\u2019 Yeast","volume":"239","author":"Ratliff","year":"1964","journal-title":"J. Biol. Chem."},{"key":"ref_41","unstructured":"Berg, J., Tymoczko, J., and Stryer, L. (2002). Biochemistry, W.H. Freeman. [5th ed.]."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1016\/S0166-3542(00)00121-2","article-title":"Ribavirin and mycophenolic acid potentiate the activity of guanine- and diaminopurine-based nucleoside analogues against hepatitis B virus","volume":"48","author":"Ying","year":"2000","journal-title":"Antiviral Res."}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/17\/2\/172\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T10:36:19Z","timestamp":1759919779000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/17\/2\/172"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,1,26]]},"references-count":42,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2025,2]]}},"alternative-id":["v17020172"],"URL":"https:\/\/doi.org\/10.3390\/v17020172","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2025.01.06.631491","asserted-by":"object"}]},"ISSN":["1999-4915"],"issn-type":[{"value":"1999-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,1,26]]}}}