{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T19:15:34Z","timestamp":1791486934734,"version":"4.3.4"},"reference-count":55,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2018,2,9]],"date-time":"2018-02-09T00:00:00Z","timestamp":1518134400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["R21NS099838"],"award-info":[{"award-number":["R21NS099838"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000052","name":"NIH Office of the Director","doi-asserted-by":"publisher","award":["OD024896"],"award-info":[{"award-number":["OD024896"]}],"id":[{"id":"10.13039\/100000052","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Zika virus (ZIKV) has recently emerged as a new public health threat. ZIKV infections have caused a wide spectrum of neurological diseases, such as Guillain\u2013Barr\u00e9 syndrome, myelitis, meningoencephalitis, and congenital microcephaly. No effective therapies currently exist for treating patients infected with ZIKV. Herein, we evaluated the anti-viral activity of favipiravir (T-705) and ribavirin against Asian and African strains of ZIKV using different cell models, including human neuronal progenitor cells (hNPCs), human dermal fibroblasts (HDFs), human lung adenocarcinoma cells (A549) and Vero cells. Cells were treated with favipiravir or ribavirin and effects on ZIKV replication were determined using quantitative real-time PCR and plaque assay. Our results demonstrate that favipiravir or ribavirin treatment significantly inhibited ZIKV replication in a dose-dependent manner. Moreover, favipiravir treatment of ZIKV-infected hNPCs led to reduced cell death, enhanced AKT pathway phosphorylation, and increased expression of anti-apoptotic factor B cell lymphoma 2. In conclusion, our results demonstrate conclusively that favipiravir inhibits ZIKV replication and prevents cell death, and can be a promising intervention for ZIKV-associated disease.<\/jats:p>","DOI":"10.3390\/v10020072","type":"journal-article","created":{"date-parts":[[2018,2,9]],"date-time":"2018-02-09T12:46:27Z","timestamp":1518180387000},"page":"72","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":82,"title":["Favipiravir and Ribavirin Inhibit Replication of Asian and African Strains of Zika Virus in Different Cell Models"],"prefix":"10.3390","volume":"10","author":[{"given":"Ji-Ae","family":"Kim","sequence":"first","affiliation":[{"name":"Department of Biomedical Sciences, College of Medicine, Korea University Guro Hospital, Seoul 08308, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rak-Kyun","family":"Seong","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, College of Medicine, Korea University Guro Hospital, Seoul 08308, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0970-4875","authenticated-orcid":false,"given":"Mukesh","family":"Kumar","sequence":"additional","affiliation":[{"name":"Department of Tropical Medicine, Medical Microbiology and Pharmacology, Pacific Center for Emerging Infectious Diseases Research, John A. Burns School of Medicine, University of Hawaii at Manoa, Honolulu, HI 96813, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ok","family":"Shin","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, College of Medicine, Korea University Guro Hospital, Seoul 08308, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2018,2,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1016\/0035-9203(52)90042-4","article-title":"Zika virus. I. Isolations and serological specificity","volume":"46","author":"Dick","year":"1952","journal-title":"Trans. R. Soc. Trop. Med. Hyg."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Haddow, A.D., Schuh, A.J., Yasuda, C.Y., Kasper, M.R., Heang, V., Huy, R., Guzman, H., Tesh, R.B., and Weaver, S.C. (2012). Genetic characterization of Zika virus strains: Geographic expansion of the Asian lineage. PLoS Negl. Trop. Dis., 6.","DOI":"10.1371\/journal.pntd.0001477"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Yun, S.I., Song, B.H., Frank, J.C., Julander, J.G., Polejaeva, I.A., Davies, C.J., White, K.L., and Lee, Y.M. (2016). Complete genome sequences of three historically important, spatiotemporally distinct, and genetically divergent strains of Zika virus: MR-766, P6-740, and PRVABC-59. Genome Announc., 4.","DOI":"10.1128\/genomeA.00800-16"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2536","DOI":"10.1056\/NEJMoa0805715","article-title":"Zika virus outbreak on Yap Island, Federated States of Micronesia","volume":"360","author":"Duffy","year":"2009","journal-title":"N. Engl. J. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"917","DOI":"10.15585\/mmwr.mm6534e3","article-title":"Hearing loss in infants with microcephaly and evidence of congenital Zika virus infection\u2014Brazil, November 2015\u2013May 2016","volume":"65","author":"Leal","year":"2016","journal-title":"MMWR Morb. Mortal. Wkly. Rep."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1531","DOI":"10.1016\/S0140-6736(16)00562-6","article-title":"Guillain-Barre syndrome outbreak associated with Zika virus infection in French polynesia: A case-control study","volume":"387","author":"Blake","year":"2016","journal-title":"Lancet"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1993","DOI":"10.1016\/S0140-6736(16)30428-7","article-title":"International Society of Blood Transfusion Working Party on Transfusion-Transmitted Infectious Deases. Zika virus: A new challenge for blood transfusion","volume":"387","author":"Musso","year":"2016","journal-title":"Lancet"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1590\/0004-282X20160035","article-title":"Guillain-Barre syndrome associated with the Zika virus outbreak in Brazil","volume":"74","author":"Araujo","year":"2016","journal-title":"Arq. Neuropsiquiatr."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"4864","DOI":"10.1128\/JVI.00252-16","article-title":"Zika virus: New clinical syndromes and its emergence in the western hemisphere","volume":"90","author":"Lazear","year":"2016","journal-title":"J. Virol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1469","DOI":"10.3389\/fmicb.2017.01469","article-title":"Advances in developing therapies to combat Zika virus: Current knowledge and future perspectives","volume":"8","author":"Munjal","year":"2017","journal-title":"Front. Microbiol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"690","DOI":"10.1016\/j.stem.2016.11.014","article-title":"Advances in Zika virus research: Stem cell models, challenges, and opportunities","volume":"19","author":"Ming","year":"2016","journal-title":"Cell Stem Cell"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"17006","DOI":"10.1038\/celldisc.2017.6","article-title":"Zika virus evades interferon-mediated Antivir. Res.ponse through the co-operation of multiple nonstructural proteins in vitro","volume":"3","author":"Wu","year":"2017","journal-title":"Cell Discov."},{"key":"ref_13","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":"Furuta","year":"2013","journal-title":"Antivir. Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/j.antiviral.2009.02.198","article-title":"T-705 (favipiravir) and related compounds: Novel broad-spectrum inhibitors of RNA viral infections","volume":"82","author":"Furuta","year":"2009","journal-title":"Antivir. Res."},{"key":"ref_15","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":"Furuta","year":"2002","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_16","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_17","doi-asserted-by":"crossref","first-page":"695","DOI":"10.1128\/CMR.00102-15","article-title":"Approved antiviral drugs over the past 50 years","volume":"29","author":"Li","year":"2016","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2101","DOI":"10.1016\/j.jid.2017.03.041","article-title":"Sting is involved in antiviral immune response against VZV infection via the induction of type I and III IFN pathways","volume":"137","author":"Kim","year":"2017","journal-title":"J. Investig. Dermatol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1186\/s12985-017-0750-4","article-title":"A guinea pig model of Zika virus infection","volume":"14","author":"Kumar","year":"2017","journal-title":"Virol. J."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1186\/1742-2094-7-73","article-title":"Pro-inflammatory cytokines derived from West Nile virus (WNV)-infected SK-N-SH cells mediate neuroinflammatory markers and neuronal death","volume":"7","author":"Kumar","year":"2010","journal-title":"J. Neuroinflamm."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"3655","DOI":"10.1128\/JVI.02667-12","article-title":"Inflammasome adaptor protein Apoptosis-associated speck-like protein containing CARD (ASC) is critical for the immune response and survival in west Nile virus encephalitis","volume":"87","author":"Kumar","year":"2013","journal-title":"J. Virol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1186\/1742-2094-11-80","article-title":"Reduced immune cell infiltration and increased pro-inflammatory mediators in the brain of type 2 diabetic mouse model infected with West Nile virus","volume":"11","author":"Kumar","year":"2014","journal-title":"J. Neuroinflamm."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Barr, K.L., Anderson, B.D., Prakoso, D., and Long, M.T. (2016). Working with Zika and Usutu viruses in vitro. PLoS Negl. Trop. Dis., 10.","DOI":"10.1371\/journal.pntd.0004931"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1501","DOI":"10.1002\/jmv.23241","article-title":"A diagnostic polymerase chain reaction assay for Zika virus","volume":"84","author":"Balm","year":"2012","journal-title":"J. Med. Virol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"979","DOI":"10.1016\/j.imbio.2017.07.002","article-title":"Schlafen 14 (SLFN14) is a novel antiviral factor involved in the control of viral replication","volume":"222","author":"Seong","year":"2017","journal-title":"Immunobiology"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1016\/j.stem.2016.04.014","article-title":"Zika virus depletes neural progenitors in human cerebral organoids through activation of the innate immune receptor TLR3","volume":"19","author":"Dang","year":"2016","journal-title":"Cell Stem Cell"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"816","DOI":"10.1126\/science.aaf6116","article-title":"Zika virus impairs growth in human neurospheres and brain organoids","volume":"352","author":"Garcez","year":"2016","journal-title":"Science"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1238","DOI":"10.1016\/j.cell.2016.04.032","article-title":"Brain-region-specific organoids using mini-bioreactors for modeling ZIKV exposure","volume":"165","author":"Qian","year":"2016","journal-title":"Cell"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1016\/j.stem.2016.02.016","article-title":"Zika virus infects human cortical neural progenitors and attenuates their growth","volume":"18","author":"Tang","year":"2016","journal-title":"Cell Stem Cell"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Anfasa, F., Siegers, J.Y., van der Kroeg, M., Mumtaz, N., Stalin Raj, V., de Vrij, F.M.S., Widagdo, W., Gabriel, G., Salinas, S., and Simonin, Y. (2017). Phenotypic differences between Asian and African lineage Zika viruses in human neural progenitor cells. mSphere, 2.","DOI":"10.1128\/mSphere.00292-17"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Tripathi, S., Balasubramaniam, V.R., Brown, J.A., Mena, I., Grant, A., Bardina, S.V., Maringer, K., Schwarz, M.C., Maestre, A.M., and Sourisseau, M. (2017). A novel Zika virus mouse model reveals strain specific differences in virus pathogenesis and host inflammatory immune responses. PLoS Pathog., 13.","DOI":"10.1371\/journal.ppat.1006258"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"E1587","DOI":"10.1073\/pnas.1616097114","article-title":"Vulnerability of primitive human placental trophoblast to Zika virus","volume":"114","author":"Sheridan","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1016\/j.meegid.2017.01.015","article-title":"African and Asian Zika virus strains differentially induce early Antiviral Responses in primary human astrocytes","volume":"49","author":"Hamel","year":"2017","journal-title":"Infect. Genet. Evol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"613","DOI":"10.3851\/IMP3180","article-title":"In vitro susceptibility of geographically and temporally distinct Zika viruses to favipiravir and ribavirin","volume":"22","author":"Baz","year":"2017","journal-title":"Antivir. Ther."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2847","DOI":"10.1007\/s00705-017-3436-8","article-title":"Viral polymerase inhibitors T-705 and T-1105 are potential inhibitors of Zika virus replication","volume":"162","author":"Cai","year":"2017","journal-title":"Arch. Virol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1016\/j.antiviral.2017.07.010","article-title":"Replication of the Zika virus in different iPSC-derived neuronal cells and implications to assess efficacy of antivirals","volume":"145","author":"Lanko","year":"2017","journal-title":"Antivir. Res."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Pires de Mello, C.P., Tao, X., Kim, T.H., Bulitta, J.B., Rodriquez, J.L., Pomeroy, J.J., and Brown, A.N. (2018). Zika virus replication is substantially inhibited by novel favipiravir and interferon alpha combination regimens. Antimicrob. Agents Chemother., 62.","DOI":"10.1128\/AAC.01983-17"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1128\/AAC.01051-06","article-title":"Efficacy of orally administered T-705 on lethal avian influenza A (H5N1) virus infections in mice","volume":"51","author":"Sidwell","year":"2007","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1177\/095632020301400502","article-title":"In vitro and in vivo activities of T-705 and oseltamivir against influenza virus","volume":"14","author":"Takahashi","year":"2003","journal-title":"Antivir. Chem. Chemother."},{"key":"ref_40","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":"Gowen","year":"2007","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1016\/j.antiviral.2017.04.016","article-title":"Suramin inhibits Zika virus replication by interfering with virus attachment and release of infectious particles","volume":"143","author":"Albulescu","year":"2017","journal-title":"Antivir. Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1016\/j.antiviral.2017.04.017","article-title":"Polysulfonate suramin inhibits Zika virus infection","volume":"143","author":"Tan","year":"2017","journal-title":"Antivir. Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1016\/j.antiviral.2016.11.023","article-title":"The FDA-approved drug sofosbuvir inhibits Zika virus infection","volume":"137","author":"Govero","year":"2017","journal-title":"Antivir. Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/j.ijid.2016.12.011","article-title":"Sofosbuvir: An antiviral drug with potential efficacy against Zika infection","volume":"55","author":"Reznik","year":"2017","journal-title":"Int. J. Infect. Dis."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"40920","DOI":"10.1038\/srep40920","article-title":"The clinically approved antiviral drug sofosbuvir inhibits Zika virus replication","volume":"7","author":"Sacramento","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"396","DOI":"10.3389\/fncel.2014.00396","article-title":"Neurogenesis in the embryonic and adult brain: Same regulators, different roles","volume":"8","author":"Urban","year":"2014","journal-title":"Front. Cell Neurosci."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"849","DOI":"10.1101\/gad.298216.117","article-title":"How does Zika virus cause microcephaly?","volume":"31","author":"Wen","year":"2017","journal-title":"Genes Dev."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1111\/jnc.12718","article-title":"PI3K-p110-alpha-subtype signalling mediates survival, proliferation and neurogenesis of cortical progenitor cells via activation of mTORC2","volume":"130","author":"Wahane","year":"2014","journal-title":"J. Neurochem."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1016\/j.stem.2016.07.019","article-title":"Zika virus NS4A and NS4B proteins deregulate Akt-mTOR signaling in human fetal neural stem cells to inhibit neurogenesis and induce autophagy","volume":"19","author":"Liang","year":"2016","journal-title":"Cell Stem Cell"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1016\/j.stem.2016.04.017","article-title":"Zika virus disrupts neural progenitor development and leads to microcephaly in mice","volume":"19","author":"Li","year":"2016","journal-title":"Cell Stem Cell"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"3225","DOI":"10.1038\/sj.onc.1202591","article-title":"Bcl-2 family proteins","volume":"17","author":"Reed","year":"1998","journal-title":"Oncogene"},{"key":"ref_52","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":"Baranovich","year":"2013","journal-title":"J. Virol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"e03679","DOI":"10.7554\/eLife.03679","article-title":"Favipiravir elicits antiviral mutagenesis during virus replication in vivo","volume":"3","author":"Arias","year":"2014","journal-title":"eLife"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"S27","DOI":"10.1093\/infdis\/jiv280","article-title":"Advances toward a norovirus antiviral: From classical inhibitors to lethal mutagenesis","volume":"213","author":"Thorne","year":"2016","journal-title":"J. Infect. Dis."},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Escribano-Romero, E., Jimenez de Oya, N., Domingo, E., and Saiz, J.C. (2017). Extinction of West Nile virus by favipiravir through lethal mutagenesis. Antimicrob. Agents Chemother., 61.","DOI":"10.1128\/AAC.01400-17"}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/10\/2\/72\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T14:54:29Z","timestamp":1760194469000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/10\/2\/72"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,2,9]]},"references-count":55,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2018,2]]}},"alternative-id":["v10020072"],"URL":"https:\/\/doi.org\/10.3390\/v10020072","relation":{},"ISSN":["1999-4915"],"issn-type":[{"value":"1999-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,2,9]]}}}