{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T19:21:15Z","timestamp":1790536875530,"version":"4.1.0"},"reference-count":22,"publisher":"American Society for Microbiology","issue":"21","license":[{"start":{"date-parts":[[2014,11,1]],"date-time":"2014-11-01T00:00:00Z","timestamp":1414800000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["J Virol"],"published-print":{"date-parts":[[2014,11]]},"abstract":"ABSTRACT<\/jats:title>\n \n Live attenuated influenza vaccines in the United States are derived from a human virus that is temperature sensitive (\n ts<\/jats:italic>\n ), characterized by restricted (\u2265100-fold) replication at 39\u00b0C. The\n ts<\/jats:italic>\n genetic signature (\n ts<\/jats:italic>\n sig) has been mapped to 5 loci in 3 genes: PB1 (391E, 581G, and 661T), PB2 (265S), and NP (34G). However, when transferred into avian and swine influenza viruses, only partial\n ts<\/jats:italic>\n and attenuation phenotypes occur. To investigate the reason for this, we introduced the\n ts<\/jats:italic>\n sig into the human origin virus A\/WSN\/33 (WSN), the avian-origin virus A\/Vietnam\/1203\/04 (VN04), and the swine origin triple-reassortant 2009 pandemic H1N1 virus A\/California\/07\/2009 (CA07), which contains gene segments from human, avian, and swine viruses. The VN04\n \n ts<\/jats:italic>\n <\/jats:sup>\n sig<\/jats:sup>\n and CA07\n \n ts<\/jats:italic>\n <\/jats:sup>\n sig<\/jats:sup>\n viruses replicated efficiently in Madin-Darby canine kidney (MDCK) cells at 39\u00b0C, but the replication of WSN\n \n ts<\/jats:italic>\n <\/jats:sup>\n sig<\/jats:sup>\n was restricted \u2265100-fold compared to that at 33\u00b0C. Reassortant CA07\n \n ts<\/jats:italic>\n <\/jats:sup>\n sig<\/jats:sup>\n viruses were generated with individual polymerase gene segments from WSN, and vice versa. Only\n ts<\/jats:italic>\n sig viruses with a PB2 gene segment derived from WSN were restricted in replication \u2265100-fold at 39\u00b0C. In ferrets, the CA07\n \n ts<\/jats:italic>\n <\/jats:sup>\n sig<\/jats:sup>\n virus replicated in the upper and lower respiratory tract, but the replication of a reassortant CA07\n \n ts<\/jats:italic>\n <\/jats:sup>\n sig<\/jats:sup>\n virus with a WSN PB2 gene was severely restricted in the lungs. Taken together, these data suggest that the origin of the PB2 gene segment influences the\n ts<\/jats:italic>\n phenotype\n in vitro<\/jats:italic>\n and attenuation\n in vivo<\/jats:italic>\n . This could have implications for the design of novel live vaccines against animal origin influenza viruses.\n <\/jats:p>\n \n IMPORTANCE<\/jats:bold>\n Live attenuated influenza vaccines (LAIVs) on temperature-sensitive (\n ts<\/jats:italic>\n ) backbones derived from animal origin influenza viruses are being sought for use in the poultry and swine industries and to protect people against animal origin influenza. However, inserting the\n ts<\/jats:italic>\n genetic signature from a licensed LAIV backbone fails to fully attenuate these viruses. Our data indicate this is associated with the presence of a PB2 gene segment derived from an avian influenza virus. We show that a reassortant 2009 pandemic H1N1 virus with the\n ts<\/jats:italic>\n signature from a licensed LAIV donor virus is\n ts in vitro<\/jats:italic>\n and attenuated\n in vivo<\/jats:italic>\n when the PB2 gene is derived from a human origin virus but not from an avian virus. Our study provides information that could benefit the rational design of alternative LAIV backbones against animal origin influenza viruses.\n <\/jats:p>","DOI":"10.1128\/jvi.02142-14","type":"journal-article","created":{"date-parts":[[2014,8,14]],"date-time":"2014-08-14T07:06:05Z","timestamp":1407999965000},"page":"12339-12347","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":26,"title":["The Temperature-Sensitive and Attenuation Phenotypes Conferred by Mutations in the Influenza Virus PB2, PB1, and NP Genes Are Influenced by the Species of Origin of the PB2 Gene in Reassortant Viruses Derived from Influenza A\/California\/07\/2009 and A\/WSN\/33 Viruses"],"prefix":"10.1128","volume":"88","author":[{"given":"Andrew J.","family":"Broadbent","sequence":"first","affiliation":[{"name":"Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Celia P.","family":"Santos","sequence":"additional","affiliation":[{"name":"Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel A.","family":"Godbout","sequence":"additional","affiliation":[{"name":"Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kanta","family":"Subbarao","sequence":"additional","affiliation":[{"name":"Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"issue":"07","key":"e_1_3_2_2_2","first-page":"1","article-title":"Prevention and control of seasonal influenza with vaccines. 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