{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T15:07:11Z","timestamp":1791299231958,"version":"4.1.0"},"reference-count":59,"publisher":"Public Library of Science (PLoS)","issue":"5","license":[{"start":{"date-parts":[[2014,5,1]],"date-time":"2014-05-01T00:00:00Z","timestamp":1398902400000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosntds.org"],"crossmark-restriction":false},"short-container-title":["PLoS Negl Trop Dis"],"DOI":"10.1371\/journal.pntd.0002804","type":"journal-article","created":{"date-parts":[[2014,5,1]],"date-time":"2014-05-01T20:39:50Z","timestamp":1398976790000},"page":"e2804","update-policy":"https:\/\/doi.org\/10.1371\/journal.pntd.corrections_policy","source":"Crossref","is-referenced-by-count":175,"title":["Evaluation of Antiviral Efficacy of Ribavirin, Arbidol, and T-705 (Favipiravir) in a Mouse Model for Crimean-Congo Hemorrhagic Fever"],"prefix":"10.1371","volume":"8","author":[{"given":"Lisa","family":"Oestereich","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toni","family":"Rieger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melanie","family":"Neumann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Bernreuther","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Lehmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susanne","family":"Krasemann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie","family":"Wurr","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Petra","family":"Emmerich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xavier","family":"de Lamballerie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephan","family":"\u00d6lschl\u00e4ger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephan","family":"G\u00fcnther","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2014,5,1]]},"reference":[{"key":"ref1","first-page":"722","article-title":"A nosocomial outbreak of Crimean-Congo haemorrhagic fever at Tygerberg Hospital. Part III. Clinical pathology and pathogenesis","volume":"68","author":"JR Joubert","year":"1985","journal-title":"S Afr Med J"},{"key":"ref2","doi-asserted-by":"crossref","first-page":"S794","DOI":"10.1093\/clinids\/11.Supplement_4.S794","article-title":"The clinical pathology of Crimean-Congo hemorrhagic fever","volume":"11 Suppl 4","author":"R Swanepoel","year":"1989","journal-title":"Rev Infect Dis"},{"key":"ref3","first-page":"839","article-title":"Immunohistochemical and in situ localization of Crimean-Congo hemorrhagic fever (CCHF) virus in human tissues and implications for CCHF pathogenesis","volume":"121","author":"FJ Burt","year":"1997","journal-title":"Arch Pathol Lab Med"},{"key":"ref4","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1016\/S0166-3542(04)00163-9","article-title":"Crimean-Congo hemorrhagic fever","volume":"64","author":"CA Whitehouse","year":"2004","journal-title":"Antiviral Res"},{"key":"ref5","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1016\/S1473-3099(06)70435-2","article-title":"Crimean-Congo haemorrhagic fever","volume":"6","author":"O Ergonul","year":"2006","journal-title":"Lancet Infect Dis"},{"key":"ref6","doi-asserted-by":"crossref","first-page":"941","DOI":"10.1086\/500836","article-title":"Evaluation of serum levels of interleukin (IL)-6, IL-10, and tumor necrosis factor-alpha in patients with Crimean-Congo hemorrhagic fever","volume":"193","author":"O Ergonul","year":"2006","journal-title":"J Infect Dis"},{"key":"ref7","doi-asserted-by":"crossref","first-page":"1086","DOI":"10.1128\/CVI.00530-09","article-title":"Interacting roles of immune mechanisms and viral load in the pathogenesis of crimean-congo hemorrhagic fever","volume":"17","author":"A Saksida","year":"2010","journal-title":"Clin Vaccine Immunol"},{"key":"ref8","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1016\/j.jcv.2006.04.007","article-title":"Cytokine levels in Crimean-Congo hemorrhagic fever","volume":"36","author":"A Papa","year":"2006","journal-title":"J Clin Virol"},{"key":"ref9","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1016\/0166-3542(93)90040-P","article-title":"Ribavirin efficacy in an in vivo model of Crimean-Congo hemorrhagic fever virus (CCHF) infection","volume":"22","author":"GH Tignor","year":"1993","journal-title":"Antiviral Res"},{"key":"ref10","doi-asserted-by":"crossref","first-page":"11089","DOI":"10.1128\/JVI.01383-10","article-title":"Pathogenesis and immune response of Crimean-Congo hemorrhagic fever virus in a STAT-1 knockout mouse model","volume":"84","author":"DA Bente","year":"2010","journal-title":"J Virol"},{"key":"ref11","doi-asserted-by":"crossref","first-page":"1473","DOI":"10.1099\/vir.0.019034-0","article-title":"Crimean-Congo hemorrhagic fever virus infection is lethal for adult type I interferon receptor-knockout mice","volume":"91","author":"S Bereczky","year":"2010","journal-title":"J Gen Virol"},{"key":"ref12","doi-asserted-by":"crossref","first-page":"1909","DOI":"10.1093\/infdis\/jit061","article-title":"Lethal Crimean-Congo hemorrhagic fever virus infection in interferon alpha\/beta receptor knockout mice is associated with high viral loads, proinflammatory responses, and coagulopathy","volume":"207","author":"M Zivcec","year":"2013","journal-title":"J Infect Dis"},{"key":"ref13","doi-asserted-by":"crossref","first-page":"2005","DOI":"10.1099\/vir.0.81767-0","article-title":"Pathogenesis of Dugbe virus infection in wild-type and interferon-deficient mice","volume":"87","author":"A Boyd","year":"2006","journal-title":"J Gen Virol"},{"key":"ref14","doi-asserted-by":"crossref","first-page":"560","DOI":"10.1099\/vir.0.038455-0","article-title":"Hazara virus infection is lethal for adult type I interferon receptor-knockout mice and may act as a surrogate for infection with the human-pathogenic Crimean-Congo hemorrhagic fever virus","volume":"93","author":"SD Dowall","year":"2012","journal-title":"J Gen Virol"},{"key":"ref15","doi-asserted-by":"crossref","first-page":"581","DOI":"10.4269\/ajtmh.1989.41.581","article-title":"Inhibition of Crimean-Congo hemorrhagic fever viral infectivity yields in vitro by ribavirin","volume":"41","author":"DM Watts","year":"1989","journal-title":"Am J Trop Med Hyg"},{"key":"ref16","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1016\/S0140-6736(95)91323-8","article-title":"Crimean Congo-haemorrhagic fever treated with oral ribavirin","volume":"346","author":"SP Fisher-Hoch","year":"1995","journal-title":"Lancet"},{"key":"ref17","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1016\/j.jinf.2009.01.014","article-title":"Efficacy of oral ribavirin treatment in Crimean-Congo haemorrhagic fever: a quasi-experimental study from Turkey","volume":"58","author":"N Elaldi","year":"2009","journal-title":"J Infect"},{"key":"ref18","doi-asserted-by":"crossref","first-page":"1215","DOI":"10.1093\/jac\/dkr136","article-title":"Ribavirin for patients with Crimean-Congo haemorrhagic fever: a systematic review and meta-analysis","volume":"66","author":"S Ascioglu","year":"2011","journal-title":"J Antimicrob Chemother"},{"key":"ref19","doi-asserted-by":"crossref","first-page":"812","DOI":"10.1089\/vbz.2011.0694","article-title":"Re-evaluation of 400 Crimean-Congo hemorrhagic fever cases in an endemic area: is ribavirin treatment suitable?","volume":"12","author":"F Duygu","year":"2012","journal-title":"Vector Borne Zoonotic Dis"},{"key":"ref20","doi-asserted-by":"crossref","first-page":"1447","DOI":"10.1007\/s00705-007-0974-5","article-title":"Antiviral activity of arbidol against influenza A virus, respiratory syncytial virus, rhinovirus, coxsackie virus and adenovirus in vitro and in vivo","volume":"152","author":"L Shi","year":"2007","journal-title":"Arch Virol"},{"key":"ref21","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1007\/s00705-009-0346-4","article-title":"Antiviral activity of Arbidol against Coxsackie virus B5 in vitro and in vivo","volume":"154","author":"Q Zhong","year":"2009","journal-title":"Arch Virol"},{"key":"ref22","doi-asserted-by":"crossref","first-page":"1015","DOI":"10.1038\/aps.2009.53","article-title":"Efficacy of arbidol on lethal hantaan virus infections in suckling mice and in vitro","volume":"30","author":"HY Deng","year":"2009","journal-title":"Acta Pharmacol Sin"},{"key":"ref23","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/j.antiviral.2011.03.182","article-title":"In vitro antiviral activity of arbidol against Chikungunya virus and characteristics of a selected resistant mutant","volume":"90","author":"I Delogu","year":"2011","journal-title":"Antiviral Res"},{"key":"ref24","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1002\/jmv.22234","article-title":"Antiviral activity of arbidol, a broad-spectrum drug for use against respiratory viruses, varies according to test conditions","volume":"84","author":"MJ Brooks","year":"2012","journal-title":"J Med Virol"},{"key":"ref25","doi-asserted-by":"crossref","first-page":"997","DOI":"10.2174\/092986708784049658","article-title":"Arbidol: a broad-spectrum antiviral compound that blocks viral fusion","volume":"15","author":"YS Boriskin","year":"2008","journal-title":"Curr Med Chem"},{"key":"ref26","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1016\/j.antiviral.2008.10.009","article-title":"Characteristics of arbidol-resistant mutants of influenza virus: implications for the mechanism of anti-influenza action of arbidol","volume":"81","author":"IA Leneva","year":"2009","journal-title":"Antiviral Res"},{"key":"ref27","doi-asserted-by":"crossref","first-page":"e15874","DOI":"10.1371\/journal.pone.0015874","article-title":"Mechanism of inhibition of enveloped virus membrane fusion by the antiviral drug arbidol","volume":"6","author":"E Teissier","year":"2011","journal-title":"PLoS One"},{"key":"ref28","doi-asserted-by":"crossref","first-page":"977","DOI":"10.1128\/AAC.46.4.977-981.2002","article-title":"In vitro and in vivo activities of anti-influenza virus compound T-705","volume":"46","author":"Y Furuta","year":"2002","journal-title":"Antimicrob Agents Chemother"},{"key":"ref29","doi-asserted-by":"crossref","first-page":"3168","DOI":"10.1128\/AAC.00356-07","article-title":"In vitro and in vivo activities of T-705 against arenavirus and bunyavirus infections","volume":"51","author":"BB Gowen","year":"2007","journal-title":"Antimicrob Agents Chemother"},{"key":"ref30","doi-asserted-by":"crossref","first-page":"e3725","DOI":"10.1371\/journal.pone.0003725","article-title":"Treatment of late stage disease in a model of arenaviral hemorrhagic fever: T-705 efficacy and reduced toxicity suggests an alternative to ribavirin","volume":"3","author":"BB Gowen","year":"2008","journal-title":"PLoS One"},{"key":"ref31","doi-asserted-by":"crossref","first-page":"882","DOI":"10.1073\/pnas.0909603107","article-title":"T-705 (favipiravir) activity against lethal H5N1 influenza A viruses","volume":"107","author":"M Kiso","year":"2010","journal-title":"Proc Natl Acad Sci U S A"},{"key":"ref32","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/j.antiviral.2009.10.015","article-title":"Efficacy of favipiravir (T-705) and T-1106 pyrazine derivatives in phlebovirus disease models","volume":"86","author":"BB Gowen","year":"2010","journal-title":"Antiviral Res"},{"key":"ref33","doi-asserted-by":"crossref","first-page":"e1342","DOI":"10.1371\/journal.pntd.0001342","article-title":"Effective oral favipiravir (T-705) therapy initiated after the onset of clinical disease in a model of arenavirus hemorrhagic Fever","volume":"5","author":"M Mendenhall","year":"2011","journal-title":"PLoS Negl Trop Dis"},{"key":"ref34","doi-asserted-by":"crossref","first-page":"4673","DOI":"10.1128\/AAC.00886-13","article-title":"Antiviral efficacy of favipiravir against two prominent etiological agents of hantavirus pulmonary syndrome","volume":"57","author":"D Safronetz","year":"2013","journal-title":"Antimicrob Agents Chemother"},{"key":"ref35","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1016\/j.antiviral.2013.09.015","article-title":"Favipiravir (T-705), a novel viral RNA polymerase inhibitor","volume":"100","author":"Y Furuta","year":"2013","journal-title":"Antiviral Res"},{"key":"ref36","doi-asserted-by":"crossref","first-page":"3741","DOI":"10.1128\/JVI.02346-12","article-title":"T-705 (favipiravir) induces lethal mutagenesis in influenza A H1N1 viruses in vitro","volume":"87","author":"T Baranovich","year":"2013","journal-title":"J Virol"},{"key":"ref37","doi-asserted-by":"crossref","first-page":"e68347","DOI":"10.1371\/journal.pone.0068347","article-title":"The Ambiguous Base-Pairing and High Substrate Efficiency of T-705 (Favipiravir) Ribofuranosyl 5\u2032-Triphosphate towards Influenza A Virus Polymerase","volume":"8","author":"Z Jin","year":"2013","journal-title":"PLoS One"},{"key":"ref38","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1124\/mol.113.087247","article-title":"Role of human hypoxanthine guanine phosphoribosyltransferase in activation of the antiviral agent T-705 (favipiravir)","volume":"84","author":"L Naesens","year":"2013","journal-title":"Mol Pharmacol"},{"key":"ref39","doi-asserted-by":"crossref","first-page":"741","DOI":"10.1093\/jac\/dkp274","article-title":"Intracellular metabolism of favipiravir (T-705) in uninfected and influenza A (H5N1) virus-infected cells","volume":"64","author":"DF Smee","year":"2009","journal-title":"J Antimicrob Chemother"},{"key":"ref40","doi-asserted-by":"crossref","first-page":"981","DOI":"10.1128\/AAC.49.3.981-986.2005","article-title":"Mechanism of action of T-705 against influenza virus","volume":"49","author":"Y Furuta","year":"2005","journal-title":"Antimicrob Agents Chemother"},{"key":"ref41","doi-asserted-by":"crossref","first-page":"e1000412","DOI":"10.1371\/journal.pbio.1000412","article-title":"Improving bioscience research reporting: the ARRIVE guidelines for reporting animal research","volume":"8","author":"C Kilkenny","year":"2010","journal-title":"PLoS Biol"},{"key":"ref42","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1016\/j.jcv.2010.09.018","article-title":"Complete sequence and phylogenetic characterisation of Crimean-Congo hemorrhagic fever virus from Afghanistan","volume":"50","author":"S \u00d6lschl\u00e4ger","year":"2011","journal-title":"J Clin Virol"},{"key":"ref43","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1016\/j.antiviral.2004.05.001","article-title":"Application of real-time PCR for testing antiviral compounds against Lassa virus, SARS coronavirus and Ebola virus in vitro","volume":"63","author":"S G\u00fcnther","year":"2004","journal-title":"Antiviral Res"},{"key":"ref44","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1016\/S0031-6997(25)06847-4","article-title":"The search for synergy: a critical review from a response surface perspective","volume":"47","author":"WR Greco","year":"1995","journal-title":"Pharmacol Rev"},{"key":"ref45","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1016\/0166-3542(90)90001-N","article-title":"A three-dimensional model to analyze drug-drug interactions","volume":"14","author":"MN Prichard","year":"1990","journal-title":"Antiviral Res"},{"key":"ref46","doi-asserted-by":"crossref","first-page":"1918","DOI":"10.1126\/science.8009221","article-title":"Functional role of type I and type II interferons in antiviral defense","volume":"264","author":"U Muller","year":"1994","journal-title":"Science"},{"key":"ref47","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.antiviral.2005.06.003","article-title":"In vitro and in vivo influenza virus-inhibitory effects of viramidine","volume":"68","author":"RW Sidwell","year":"2005","journal-title":"Antiviral Res"},{"key":"ref48","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1016\/j.jcv.2010.05.002","article-title":"Early serodiagnosis of acute human Crimean-Congo hemorrhagic fever virus infections by novel capture assays","volume":"48","author":"P Emmerich","year":"2010","journal-title":"J Clin Virol"},{"key":"ref49","doi-asserted-by":"crossref","first-page":"11964","DOI":"10.1073\/pnas.96.21.11964","article-title":"Persistence of lymphocytic choriomeningitis virus at very low levels in immune mice","volume":"96","author":"A Ciurea","year":"1999","journal-title":"Proc Natl Acad Sci U S A"},{"key":"ref50","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1503\/cmaj.1040752","article-title":"Liver enzyme alteration: a guide for clinicians","volume":"172","author":"EG Giannini","year":"2005","journal-title":"Cmaj"},{"key":"ref51","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1007\/s11094-010-0351-7","article-title":"Synthesis and biological activity of water-soluble polymer complexes of arbidol","volume":"43","author":"MY Eropkin","year":"2009","journal-title":"Pharm Chem J"},{"key":"ref52","doi-asserted-by":"crossref","first-page":"1375","DOI":"10.1038\/82191","article-title":"The broad-spectrum antiviral ribonucleoside ribavirin is an RNA virus mutagen","volume":"6","author":"S Crotty","year":"2000","journal-title":"Nat Med"},{"key":"ref53","doi-asserted-by":"crossref","first-page":"830","DOI":"10.1016\/0006-291X(79)91853-9","article-title":"The broad spectrum antiviral agent ribavirin inhibits capping of mRNA","volume":"89","author":"BB Goswami","year":"1979","journal-title":"Biochem Biophys Res Commun"},{"key":"ref54","doi-asserted-by":"crossref","first-page":"946","DOI":"10.1128\/AAC.11.6.946","article-title":"Inhibition of influenza virus ribonucleic acid polymerase by ribavirin triphosphate","volume":"11","author":"B Eriksson","year":"1977","journal-title":"Antimicrob Agents Chemother"},{"key":"ref55","doi-asserted-by":"crossref","first-page":"1668","DOI":"10.1128\/AAC.33.10.1668","article-title":"Molecular analysis of the inhibitory effect of phosphorylated ribavirin on the vesicular stomatitis virus in vitro polymerase reaction","volume":"33","author":"R Fernandez-Larsson","year":"1989","journal-title":"Antimicrob Agents Chemother"},{"key":"ref56","doi-asserted-by":"crossref","first-page":"1174","DOI":"10.1073\/pnas.70.4.1174","article-title":"Mechanism of action of 1-beta-D-ribofuranosyl-1,2,4-triazole-3-carboxamide (Virazole), a new broad-spectrum antiviral agent","volume":"70","author":"DG Streeter","year":"1973","journal-title":"Proc Natl Acad Sci U S A"},{"key":"ref57","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":"P Leyssen","year":"2005","journal-title":"J Virol"},{"key":"ref58","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1177\/095632020101200602","article-title":"Antiviral activity and mode of action studies of ribavirin and mycophenolic acid against orthopoxviruses in vitro","volume":"12","author":"DF Smee","year":"2001","journal-title":"Antivir Chem Chemother"},{"key":"ref59","first-page":"176","article-title":"Effect of sex and age on serum biochemical reference ranges in C57BL\/6J mice","volume":"54","author":"X Zhou","year":"2004","journal-title":"Comp Med"}],"container-title":["PLoS Neglected Tropical Diseases"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/dx.plos.org\/10.1371\/journal.pntd.0002804","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,5,2]],"date-time":"2025-05-02T17:02:30Z","timestamp":1746205350000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pntd.0002804"}},"subtitle":[],"editor":[{"given":"Sunit Kumar","family":"Singh","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2014,5,1]]},"references-count":59,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2014,5,1]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pntd.0002804","relation":{},"ISSN":["1935-2735"],"issn-type":[{"value":"1935-2735","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,5,1]]}}}