{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T21:09:11Z","timestamp":1793740151559,"version":"4.6.1"},"reference-count":130,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2015,4,1]],"date-time":"2015-04-01T00:00:00Z","timestamp":1427846400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"EUVIRNA Marie Curie Initial Training Network","award":["264286"],"award-info":[{"award-number":["264286"]}]},{"name":"Welcome Trust Seeding Drug Initiative","award":["100405"],"award-info":[{"award-number":["100405"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Reviews in Medical Virology"],"published-print":{"date-parts":[[2015,7]]},"abstract":"<jats:title>Summary<\/jats:title><jats:p>Dengue virus and other flaviviruses such as the yellow fever, West Nile, and Japanese encephalitis viruses are emerging vector\u2010borne human pathogens that affect annually more than 100 million individuals and that may cause debilitating and potentially fatal hemorrhagic and encephalitic diseases. Currently, there are no specific antiviral drugs for the treatment of flavivirus\u2010associated disease. A better understanding of the flavivirus\u2013host interactions during the different events of the flaviviral life cycle may be essential when developing novel antiviral strategies. The flaviviral non\u2010structural protein 4b (NS4b) appears to play an important role in flaviviral replication by facilitating the formation of the viral replication complexes and in counteracting innate immune responses such as the following: (i) type I IFN signaling; (ii) RNA interference; (iii) formation of stress granules; and (iv) the unfolded protein response. Intriguingly, NS4b has recently been shown to constitute an excellent target for the selective inhibition of flavivirus replication. We here review the current knowledge on NS4b. \u00a9 2015 The Authors. <jats:italic>Reviews in Medical Virology<\/jats:italic> published by John Wiley &amp; Sons Ltd.<\/jats:p>","DOI":"10.1002\/rmv.1835","type":"journal-article","created":{"date-parts":[[2015,4,2]],"date-time":"2015-04-02T20:04:51Z","timestamp":1428005091000},"page":"205-223","source":"Crossref","is-referenced-by-count":107,"title":["Flaviviral NS4b, chameleon and jack\u2010in\u2010the\u2010box roles in viral replication and pathogenesis, and a molecular target for antiviral intervention"],"prefix":"10.1002","volume":"25","author":[{"given":"Joanna","family":"Zmurko","sequence":"first","affiliation":[{"name":"KU Leuven, Rega Institute for Medical Research, Department of Microbiology and Immunology Laboratory of Virology and Chemotherapy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johan","family":"Neyts","sequence":"additional","affiliation":[{"name":"KU Leuven, Rega Institute for Medical Research, Department of Microbiology and Immunology Laboratory of Virology and Chemotherapy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Dallmeier","sequence":"additional","affiliation":[{"name":"KU Leuven, Rega Institute for Medical Research, Department of Microbiology and Immunology Laboratory of Virology and Chemotherapy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2015,4]]},"reference":[{"key":"e_1_2_9_2_1","article-title":"Dengue: guidelines for diagnosis, treatment, prevention, and control","author":"WHO","year":"2009","journal-title":"Special Programme for Research and Training in Tropical Diseases"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature12060"},{"key":"e_1_2_9_4_1","unstructured":"PaperWP.Weekly epidemiological recordRelev\u00e9 \u00e9pid\u00e9miologique hebdomadaire.2013;27(88):269\u2013284.http:\/\/www.who.int\/wer"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/rmv1752"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/nri2629"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.antiviral.2012.12.002"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(07)70030-3"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrmicro2950"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1051\/vetres\/2010039"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.2471\/BLT.10.085233"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.4161\/hv.26902"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.7774\/cevr.2014.3.1.58"},{"key":"e_1_2_9_14_1","first-page":"362","article-title":"Pharmaceutical approval update","volume":"33","author":"Goldenberg MM","year":"2008","journal-title":"Pharmacy and Therapeutics"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1128\/CMR.13.1.67-82.2000"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.coviro.2013.03.001"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.antiviral.2013.09.013"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.05431-11"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0065-3527(03)59002-9"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.antiviral.2008.08.004"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrmicro1890"},{"key":"e_1_2_9_22_1","doi-asserted-by":"crossref","first-page":"2034","DOI":"10.1128\/jvi.67.4.2034-2042.1993","article-title":"Deletion analysis of dengue virus type 4 nonstructural protein NS2b: identification of a domain required for NS2b\u2013NS3 protease activity","volume":"67","author":"Falgout B","year":"1993","journal-title":"Journal of Virology"},{"key":"e_1_2_9_23_1","doi-asserted-by":"crossref","first-page":"989","DOI":"10.1128\/jvi.67.2.989-996.1993","article-title":"RNA\u2010Stimulated NTPase Activity Associated with Yellow Fever Virus NS3 Protein Expressed in Bacteria","volume":"67","author":"Warrener P","year":"1993","journal-title":"Journal of Virology"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/0042-6822(91)90440-M"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M104248200\/jbc"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/21.11.2757"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0166-0934(00)00270-6"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1006\/viro.1996.0067"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.antiviral.2008.06.007"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.antiviral.2013.03.008"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.05468-11"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M512697200"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2009.03.007"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.79.13.8004"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2009.03.007"},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-61779-882-5_3"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.1006\/viro.1997.8629"},{"key":"e_1_2_9_38_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00157-12"},{"key":"e_1_2_9_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.virol.2013.08.006"},{"key":"e_1_2_9_40_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.03454-14"},{"key":"e_1_2_9_41_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.03453-14"},{"key":"e_1_2_9_42_1","doi-asserted-by":"publisher","DOI":"10.1099\/vir.0.000044"},{"key":"e_1_2_9_43_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.02782-13"},{"key":"e_1_2_9_44_1","doi-asserted-by":"crossref","first-page":"10272","DOI":"10.1128\/JVI.73.12.10272-10280.1999","article-title":"Efficient trans\u2010complementation of the flavivirus Kunjin NS5 protein but not of the NS1 protein requires its coexpression with other components of the viral replicase","volume":"73","author":"Khromykh AA","year":"1999","journal-title":"Journal of Virology"},{"key":"e_1_2_9_45_1","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-7-S5-S4"},{"key":"e_1_2_9_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.antiviral.2011.05.001"},{"key":"e_1_2_9_47_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0042-6822(03)00197-1"},{"key":"e_1_2_9_48_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0264-410X(03)00487-0"},{"key":"e_1_2_9_49_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.022652799"},{"key":"e_1_2_9_50_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00665-11"},{"key":"e_1_2_9_51_1","doi-asserted-by":"publisher","DOI":"10.1099\/vir.0.045088-0"},{"key":"e_1_2_9_52_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.virusres.2013.04.003"},{"key":"e_1_2_9_53_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.77.2.1462-1468.2003"},{"key":"e_1_2_9_54_1","doi-asserted-by":"publisher","DOI":"10.1006\/viro.1999.9873"},{"key":"e_1_2_9_55_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biologicals.2013.04.005"},{"key":"e_1_2_9_56_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.78.14.7418"},{"key":"e_1_2_9_57_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.virol.2006.03.007"},{"key":"e_1_2_9_58_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.virol.2011.11.022"},{"key":"e_1_2_9_59_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.virol.2006.11.012"},{"key":"e_1_2_9_60_1","doi-asserted-by":"publisher","DOI":"10.1099\/0022-1317-76-2-409"},{"key":"e_1_2_9_61_1","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2180-11-234"},{"key":"e_1_2_9_62_1","doi-asserted-by":"publisher","DOI":"10.1074\/mcp.M111.012187"},{"key":"e_1_2_9_63_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature07207"},{"key":"e_1_2_9_64_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.coviro.2012.09.003"},{"key":"e_1_2_9_65_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2008.02.005"},{"key":"e_1_2_9_66_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0053535"},{"key":"e_1_2_9_67_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm3011"},{"key":"e_1_2_9_68_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11373-007-9151-9"},{"key":"e_1_2_9_69_1","doi-asserted-by":"publisher","DOI":"10.3390\/biom2020203"},{"key":"e_1_2_9_70_1","doi-asserted-by":"publisher","DOI":"10.1002\/iub.1240"},{"key":"e_1_2_9_71_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.78.14.7803-7812.2004"},{"key":"e_1_2_9_72_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.01145-12"},{"key":"e_1_2_9_73_1","doi-asserted-by":"publisher","DOI":"10.1093\/embo-reports\/kvf213"},{"key":"e_1_2_9_74_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.220398297"},{"key":"e_1_2_9_75_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111.254896"},{"key":"e_1_2_9_76_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10549-014-2897-7"},{"key":"e_1_2_9_77_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature07960"},{"key":"e_1_2_9_78_1","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(95)90420-4"},{"key":"e_1_2_9_79_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature08476"},{"key":"e_1_2_9_80_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1002934"},{"key":"e_1_2_9_81_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-immunol-032713-120231"},{"key":"e_1_2_9_82_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature09907"},{"key":"e_1_2_9_83_1","doi-asserted-by":"crossref","unstructured":"MunJL.Subversion of Interferon by Dengue Virus.2010;338:35\u201344.","DOI":"10.1007\/978-3-642-02215-9_3"},{"key":"e_1_2_9_84_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2335168100"},{"key":"e_1_2_9_85_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00791-07"},{"key":"e_1_2_9_86_1","doi-asserted-by":"publisher","DOI":"10.1099\/vir.0.2008\/001594-0"},{"key":"e_1_2_9_87_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2013.11.023"},{"key":"e_1_2_9_88_1","first-page":"932","article-title":"NS4A and NS4B proteins from dengue virus: membranotropic regions. [Internet]","volume":"1818","author":"Nem\u00e9sio H","year":"2012","journal-title":"Biochimica et Biophysica Acta"},{"key":"e_1_2_9_89_1","doi-asserted-by":"publisher","DOI":"10.1002\/pmic.201300001"},{"key":"e_1_2_9_90_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M301344200"},{"key":"e_1_2_9_91_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.95.18.10626"},{"key":"e_1_2_9_92_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111.235978"},{"key":"e_1_2_9_93_1","doi-asserted-by":"publisher","DOI":"10.1038\/nri2824"},{"key":"e_1_2_9_94_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.coviro.2014.04.002"},{"key":"e_1_2_9_95_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0027551"},{"key":"e_1_2_9_96_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.02774-12"},{"key":"e_1_2_9_97_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-61779-882-5_3"},{"key":"e_1_2_9_98_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-61779-037-9_12"},{"key":"e_1_2_9_99_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.virol.2012.11.017"},{"key":"e_1_2_9_100_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2009.11.020"},{"key":"e_1_2_9_101_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1002741"},{"key":"e_1_2_9_102_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.06549-11"},{"key":"e_1_2_9_103_1","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2014.00266"},{"key":"e_1_2_9_104_1","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2014.00222"},{"key":"e_1_2_9_105_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00879-06"},{"key":"e_1_2_9_106_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.23.21.7448-7459.2003"},{"key":"e_1_2_9_107_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.02050-10"},{"key":"e_1_2_9_108_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111.222703"},{"key":"e_1_2_9_109_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.74.1.564-572.2000"},{"key":"e_1_2_9_110_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.79.14.8698"},{"key":"e_1_2_9_111_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.76.8.3596-3604.2002"},{"key":"e_1_2_9_112_1","doi-asserted-by":"publisher","DOI":"10.1086\/511310"},{"key":"e_1_2_9_113_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.antiviral.2010.11.002"},{"key":"e_1_2_9_114_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01457-08"},{"key":"e_1_2_9_115_1","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jiu319"},{"key":"e_1_2_9_116_1","doi-asserted-by":"publisher","DOI":"10.3851\/IMP1884"},{"key":"e_1_2_9_117_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00074-09"},{"key":"e_1_2_9_118_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.antiviral.2013.05.011"},{"key":"e_1_2_9_119_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11262-013-0956-5"},{"key":"e_1_2_9_120_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00632-13"},{"key":"e_1_2_9_121_1","doi-asserted-by":"publisher","DOI":"10.1002\/rmv.640"},{"key":"e_1_2_9_122_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.02663-08"},{"key":"e_1_2_9_123_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00053-06"},{"key":"e_1_2_9_124_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.78.20.11288"},{"key":"e_1_2_9_125_1","first-page":"511","article-title":"Biochemical characterization of recombinant hepatitis C virus nonstructural protein 4B: evidence for ATP\/GTP hydrolysis and adenylate kinase activity","volume":"38","author":"Thompson A","year":"2005","journal-title":"Biotechniques"},{"key":"e_1_2_9_126_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.03523-12"},{"key":"e_1_2_9_127_1","doi-asserted-by":"publisher","DOI":"10.1002\/jmv.20123"},{"key":"e_1_2_9_128_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.virol.2009.06.039"},{"key":"e_1_2_9_129_1","doi-asserted-by":"publisher","DOI":"10.1086\/653080"},{"key":"e_1_2_9_130_1","first-page":"41","article-title":"Approaches to hepatitis C treatment and cure using NS5A inhibitors","volume":"7","author":"Kohler JJ","year":"2014","journal-title":"Infection and Drug Resistance"},{"key":"e_1_2_9_131_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-642-27340-7_5.131"}],"container-title":["Reviews in Medical Virology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Frmv.1835","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Frmv.1835","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/rmv.1835","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/rmv.1835","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/rmv.1835","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,5]],"date-time":"2023-10-05T10:32:20Z","timestamp":1696501940000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/rmv.1835"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,4]]},"references-count":130,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2015,7]]}},"alternative-id":["10.1002\/rmv.1835"],"URL":"https:\/\/doi.org\/10.1002\/rmv.1835","archive":["Portico"],"relation":{},"ISSN":["1052-9276","1099-1654"],"issn-type":[{"value":"1052-9276","type":"print"},{"value":"1099-1654","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,4]]}}}