An influenza A live attenuated reassortant virus possessing three temperature-sensitive mutations in the PB2 polymerase gene rapidly loses temperature sensitivity following replication in hamsters
Identifieur interne : 001B55 ( Main/Curation ); précédent : 001B54; suivant : 001B56An influenza A live attenuated reassortant virus possessing three temperature-sensitive mutations in the PB2 polymerase gene rapidly loses temperature sensitivity following replication in hamsters
Auteurs : Brian R. Murphy [États-Unis] ; Eun Ju Park [États-Unis] ; Paul Gottlieb [États-Unis] ; Kanta Subbarao [États-Unis]Source :
- Vaccine [ 0264-410X ] ; 1997.
Descripteurs français
- Pascal (Inist)
- Wicri :
- topic : Vaccin.
English descriptors
- KwdEn :
- Teeft :
- Agmk, Agmk cells, Allantoic cavity, Amino acids, Attenuated, Attenuated influenza, Attenuating, Attenuating mutations, Attenuation, Clone, Constellation, Donor virus, Gene, Gene constellation, Greater degree, Hamster, High level, Infectious diseases, Influenza, Influenza virus, Input virus, Mdck, Mdck cells, Monolayer, Mutant, Mutation, Nasal turbinates, Parental, Parental origin, Parental viruses, Permissive temperature, Phenotype, Phenotypic stability, Plaque, Plaque formation, Present study, Progeny, Reassortant, Reassortant clone, Reassortant virus, Reassortant viruses, Reassortants, Replication, Restrictive temperatures, Significant loss, Temperature sensitivity, Transfectant, Transfectant virus, Vaccine, Viral genes, Virology, Virus, Wild type, Wild type virus.
Abstract
Abstract: The purpose of the present study was to produce an influenza A H2N2 donor virus from which an attenuating PB2 gene bearing three discrete temperature sensitive (ts) mutations could be readily transferred to currently epidemic influenza A H1N1 and H3N2 viruses via genetic reassortment. An influenza A transfectant virus was first produced that contained site-directed ts mutations at amino acids 112, 265, and 556 in the PB2 gene of influenza A/AA/60 virus origin in a background of the other seven RNA segments from the influenza A/LA/87 (H3N2) virus. The A/LA/87 PB2 ts transfectant virus (clone 22B1) was mated with the A/AA/60 (H2N2) wild type virus, and six H2N2 ts reassortants were obtained. One reassortant virus, clone 25A1, possessed the triple ts PB2 gene in the context of all seven other genes of homologous A/AA/60 origin. Isolation of this reassortant permitted an examination of the contribution of the ts mutations present in a triple ts PB2 transfectant virus to its attenuation and phenotypic stability indenpendent from an effect of the A/AA/60-A/LA/87 gene constellation on attenuation. It was found that the A/AA/60 triple ts reassortant virus was less ts, less attenuated, and less phenotypically stable than the A/LA/87 triple ts transfectant virus from which it was derived. The A/AA/60 reassortant possessing the PB2 gene containing three introduced ts mutations underwent rapid and significant loss of its temperature sensitivity following replication in the lungs of immunocompetent hamsters. This indicated that the A/AA/60-A/LA/87 gene constellation contributed significantly to the overall level of temperature-sensitivity, attenuation, and stability of the A/LA/87 triple ts transfectant virus. It is likely that the instability of the ts phenotype exhibited by the A/AA/60 triple ts reassortant virus would not be acceptable for a vaccine to be used in humans. The implications of these findings for the usefulness of ts mutations as the sole attenuating mutation in influenza virus vaccines is discussed.
Url:
DOI: 10.1016/S0264-410X(97)00031-5
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An influenza A transfectant virus was first produced that contained site-directed ts mutations at amino acids 112, 265, and 556 in the PB2 gene of influenza A/AA/60 virus origin in a background of the other seven RNA segments from the influenza A/LA/87 (H3N2) virus. The A/LA/87 PB2 ts transfectant virus (clone 22B1) was mated with the A/AA/60 (H2N2) wild type virus, and six H2N2 ts reassortants were obtained. One reassortant virus, clone 25A1, possessed the triple ts PB2 gene in the context of all seven other genes of homologous A/AA/60 origin. Isolation of this reassortant permitted an examination of the contribution of the ts mutations present in a triple ts PB2 transfectant virus to its attenuation and phenotypic stability indenpendent from an effect of the A/AA/60-A/LA/87 gene constellation on attenuation. It was found that the A/AA/60 triple ts reassortant virus was less ts, less attenuated, and less phenotypically stable than the A/LA/87 triple ts transfectant virus from which it was derived. The A/AA/60 reassortant possessing the PB2 gene containing three introduced ts mutations underwent rapid and significant loss of its temperature sensitivity following replication in the lungs of immunocompetent hamsters. This indicated that the A/AA/60-A/LA/87 gene constellation contributed significantly to the overall level of temperature-sensitivity, attenuation, and stability of the A/LA/87 triple ts transfectant virus. It is likely that the instability of the ts phenotype exhibited by the A/AA/60 triple ts reassortant virus would not be acceptable for a vaccine to be used in humans. The implications of these findings for the usefulness of ts mutations as the sole attenuating mutation in influenza virus vaccines is discussed.</div></front></TEI><double idat="0264-410X:1997:Murphy B:an:influenza:a"><INIST><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en" level="a">An influenza A live attenuated reassortant virus possessing three temperature-sensitive mutations in the PB2 polymerase gene rapidly loses temperature sensitivity following replication in hamsters</title><author><name sortKey="Murphy, B R" sort="Murphy, B R" uniqKey="Murphy B" first="B. R." last="Murphy">B. R. Murphy</name><affiliation wicri:level="2"><inist:fA14 i1="01"><s1>Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, NIH, 7 Center Drive, MSC 0720</s1><s2>Bethesda, MD 20892-0720</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Maryland</region></placeName></affiliation></author><author><name sortKey="Eun Ju Park" sort="Eun Ju Park" uniqKey="Eun Ju Park" last="Eun Ju Park">EUN JU PARK</name><affiliation wicri:level="2"><inist:fA14 i1="01"><s1>Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, NIH, 7 Center Drive, MSC 0720</s1><s2>Bethesda, MD 20892-0720</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Maryland</region></placeName></affiliation></author><author><name sortKey="Gottlieb, P" sort="Gottlieb, P" uniqKey="Gottlieb P" first="P." last="Gottlieb">P. Gottlieb</name><affiliation wicri:level="2"><inist:fA14 i1="01"><s1>Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, NIH, 7 Center Drive, MSC 0720</s1><s2>Bethesda, MD 20892-0720</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Maryland</region></placeName></affiliation></author><author><name sortKey="Subbarao, K" sort="Subbarao, K" uniqKey="Subbarao K" first="K." last="Subbarao">K. Subbarao</name><affiliation wicri:level="2"><inist:fA14 i1="01"><s1>Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, NIH, 7 Center Drive, MSC 0720</s1><s2>Bethesda, MD 20892-0720</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Maryland</region></placeName></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">INIST</idno><idno type="inist">97-0483720</idno><date when="1997">1997</date><idno type="stanalyst">PASCAL 97-0483720 INIST</idno><idno type="RBID">Pascal:97-0483720</idno><idno type="wicri:Area/PascalFrancis/Corpus">000083</idno><idno type="wicri:Area/PascalFrancis/Curation">000131</idno><idno type="wicri:Area/PascalFrancis/Checkpoint">000085</idno><idno type="wicri:explorRef" wicri:stream="PascalFrancis" wicri:step="Checkpoint">000085</idno><idno type="wicri:doubleKey">0264-410X:1997:Murphy B:an:influenza:a</idno><idno type="wicri:Area/Main/Merge">001C62</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a">An influenza A live attenuated reassortant virus possessing three temperature-sensitive mutations in the PB2 polymerase gene rapidly loses temperature sensitivity following replication in hamsters</title><author><name sortKey="Murphy, B R" sort="Murphy, B R" uniqKey="Murphy B" first="B. R." last="Murphy">B. R. Murphy</name><affiliation wicri:level="2"><inist:fA14 i1="01"><s1>Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, NIH, 7 Center Drive, MSC 0720</s1><s2>Bethesda, MD 20892-0720</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Maryland</region></placeName></affiliation></author><author><name sortKey="Eun Ju Park" sort="Eun Ju Park" uniqKey="Eun Ju Park" last="Eun Ju Park">EUN JU PARK</name><affiliation wicri:level="2"><inist:fA14 i1="01"><s1>Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, NIH, 7 Center Drive, MSC 0720</s1><s2>Bethesda, MD 20892-0720</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Maryland</region></placeName></affiliation></author><author><name sortKey="Gottlieb, P" sort="Gottlieb, P" uniqKey="Gottlieb P" first="P." last="Gottlieb">P. Gottlieb</name><affiliation wicri:level="2"><inist:fA14 i1="01"><s1>Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, NIH, 7 Center Drive, MSC 0720</s1><s2>Bethesda, MD 20892-0720</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Maryland</region></placeName></affiliation></author><author><name sortKey="Subbarao, K" sort="Subbarao, K" uniqKey="Subbarao K" first="K." last="Subbarao">K. Subbarao</name><affiliation wicri:level="2"><inist:fA14 i1="01"><s1>Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, NIH, 7 Center Drive, MSC 0720</s1><s2>Bethesda, MD 20892-0720</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Maryland</region></placeName></affiliation></author></analytic><series><title level="j" type="main">Vaccine</title><title level="j" type="abbreviated">Vaccine</title><idno type="ISSN">0264-410X</idno><imprint><date when="1997">1997</date></imprint></series></biblStruct></sourceDesc><seriesStmt><title level="j" type="main">Vaccine</title><title level="j" type="abbreviated">Vaccine</title><idno type="ISSN">0264-410X</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Attenuated strain</term><term>Genetic reassortment</term><term>Influenzavirus A</term><term>RNA-directed RNA polymerase</term><term>Reversion</term><term>Stability</term><term>Temperature sensitive mutation</term><term>Vaccine</term></keywords><keywords scheme="Pascal" xml:lang="fr"><term>Influenzavirus A</term><term>Vaccin</term><term>Souche atténuée</term><term>Mutation thermosensible</term><term>RNA-directed RNA polymerase</term><term>Stabilité</term><term>Réversion</term><term>Gène PB2</term><term>Réassortiment génétique</term></keywords><keywords scheme="Wicri" type="topic" xml:lang="fr"><term>Vaccin</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">The purpose of the present study was to produce an influenz A H2N2 donor virus from which an attenuating PB2 gene bearing three discrete temperature sensitive (ts) mutations could be readily transferred to currently epidemic influenza A HIN1 and H3N2 viruses via genetic reassortment. An influenza A transfectant virus was first produced that contained site-directed ts mutations at mino acids 112, 265, and 556 in the PB2 gene of influenza A/AA/60 virus origin in background of the other seven RNA segments from the influenza A/LA/87 (H3N2) virus. The A/LA/87 PB2 ts trans- fectant virus (clone 22Bl) was mated with the A/AA/60 (H2N2) wild type virus, and six H2N2 ts reassortants were obtained. One reassortant virus, clone 25A1, possessed the triple ts PB2 gene in the context of all seven other genes of homologus A/AA/60 virus origin in a background of the other seven RNA segments from the influenza A/LA/87 (H3N2) virus. The A/LA/87 PB2 ts transfectant virus (clone 22B1) was mated with the A/AA/60 (N2H2) wild type virus, and six H2N2 ts reassortants were obtained. One reassortant virus, clone 25A1, possessed the triplets PB2 gene in the context of all seven other genes of homologous A/AA/60 origin. Isolation of this reassortant permitted an examination of the contribution of the ts mutations present in a triple ts PB2 transfectant virus to its attenuation and phenotypic stability independent from an effect of the A/AA/60-A/LA/87 gene constellation on attenuation. It was found that the A/AA/60 triple ts reassortant virus was less ts, less attenuated, and less phenotypically stable than the A/ALA/87 triple ts transfectant virus from which it was derived. The A/AA/60 reassortant possessing the PB2 gene containing three introduced ts mutations underwent rapid and significant loss of its temperature sensitivity following replictaion in the lungs of immunocompetent hamsteers. This indicated that the A/AA/87 triple ts transfectant virus. It is likely that the instability of the ts phenotype exhibited by the A/AA/60 triple ts reassortant virus would not be acceptable for a vaccine to be used in humans. The implications of these findings for the usefulness of ts mutations as the sole attenuating mutation in influenza virus vaccines is discussed.</div></front></TEI></INIST><ISTEX><TEI wicri:istexFullTextTei="biblStruct"><teiHeader><fileDesc><titleStmt><title>An influenza A live attenuated reassortant virus possessing three temperature-sensitive mutations in the PB2 polymerase gene rapidly loses temperature sensitivity following replication in hamsters</title><author><name sortKey="Murphy, Brian R" sort="Murphy, Brian R" uniqKey="Murphy B" first="Brian R." last="Murphy">Brian R. Murphy</name></author><author><name sortKey="Park, Eun Ju" sort="Park, Eun Ju" uniqKey="Park E" first="Eun Ju" last="Park">Eun Ju Park</name></author><author><name sortKey="Gottlieb, Paul" sort="Gottlieb, Paul" uniqKey="Gottlieb P" first="Paul" last="Gottlieb">Paul Gottlieb</name></author><author><name sortKey="Subbarao, Kanta" sort="Subbarao, Kanta" uniqKey="Subbarao K" first="Kanta" last="Subbarao">Kanta Subbarao</name></author></titleStmt><publicationStmt><idno type="wicri:source">ISTEX</idno><idno type="RBID">ISTEX:2DFA746B001D1397B01365D1F84B196D11B97722</idno><date when="1997" year="1997">1997</date><idno type="doi">10.1016/S0264-410X(97)00031-5</idno><idno type="url">https://api.istex.fr/ark:/67375/6H6-M4L1G2TH-K/fulltext.pdf</idno><idno type="wicri:Area/Istex/Corpus">000070</idno><idno type="wicri:explorRef" wicri:stream="Istex" wicri:step="Corpus" wicri:corpus="ISTEX">000070</idno><idno type="wicri:Area/Istex/Curation">000070</idno><idno type="wicri:Area/Istex/Checkpoint">000941</idno><idno type="wicri:explorRef" wicri:stream="Istex" wicri:step="Checkpoint">000941</idno><idno type="wicri:doubleKey">0264-410X:1997:Murphy B:an:influenza:a</idno><idno type="wicri:Area/Main/Merge">001C17</idno></publicationStmt><sourceDesc><biblStruct><analytic><title level="a">An influenza A live attenuated reassortant virus possessing three temperature-sensitive mutations in the PB2 polymerase gene rapidly loses temperature sensitivity following replication in hamsters</title><author><name sortKey="Murphy, Brian R" sort="Murphy, Brian R" uniqKey="Murphy B" first="Brian R." last="Murphy">Brian R. Murphy</name><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><wicri:regionArea>Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, NIH, 7 Center Drive, MSC 0720, Bethesda, MD 20892-0720</wicri:regionArea><placeName><region type="state">Maryland</region></placeName></affiliation></author><author><name sortKey="Park, Eun Ju" sort="Park, Eun Ju" uniqKey="Park E" first="Eun Ju" last="Park">Eun Ju Park</name><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><wicri:regionArea>Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, NIH, 7 Center Drive, MSC 0720, Bethesda, MD 20892-0720</wicri:regionArea><placeName><region type="state">Maryland</region></placeName></affiliation></author><author><name sortKey="Gottlieb, Paul" sort="Gottlieb, Paul" uniqKey="Gottlieb P" first="Paul" last="Gottlieb">Paul Gottlieb</name><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><wicri:regionArea>Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, NIH, 7 Center Drive, MSC 0720, Bethesda, MD 20892-0720</wicri:regionArea><placeName><region type="state">Maryland</region></placeName></affiliation></author><author><name sortKey="Subbarao, Kanta" sort="Subbarao, Kanta" uniqKey="Subbarao K" first="Kanta" last="Subbarao">Kanta Subbarao</name><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><wicri:regionArea>Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, NIH, 7 Center Drive, MSC 0720, Bethesda, MD 20892-0720</wicri:regionArea><placeName><region type="state">Maryland</region></placeName></affiliation></author></analytic><monogr></monogr><series><title level="j">Vaccine</title><title level="j" type="abbrev">JVAC</title><idno type="ISSN">0264-410X</idno><imprint><publisher>ELSEVIER</publisher><date type="published" when="1997">1997</date><biblScope unit="volume">15</biblScope><biblScope unit="issue">12–13</biblScope><biblScope unit="page" from="1372">1372</biblScope><biblScope unit="page" to="1378">1378</biblScope></imprint><idno type="ISSN">0264-410X</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0264-410X</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="Teeft" xml:lang="en"><term>Agmk</term><term>Agmk cells</term><term>Allantoic cavity</term><term>Amino acids</term><term>Attenuated</term><term>Attenuated influenza</term><term>Attenuating</term><term>Attenuating mutations</term><term>Attenuation</term><term>Clone</term><term>Constellation</term><term>Donor virus</term><term>Gene</term><term>Gene constellation</term><term>Greater degree</term><term>Hamster</term><term>High level</term><term>Infectious diseases</term><term>Influenza</term><term>Influenza virus</term><term>Input virus</term><term>Mdck</term><term>Mdck cells</term><term>Monolayer</term><term>Mutant</term><term>Mutation</term><term>Nasal turbinates</term><term>Parental</term><term>Parental origin</term><term>Parental viruses</term><term>Permissive temperature</term><term>Phenotype</term><term>Phenotypic stability</term><term>Plaque</term><term>Plaque formation</term><term>Present study</term><term>Progeny</term><term>Reassortant</term><term>Reassortant clone</term><term>Reassortant virus</term><term>Reassortant viruses</term><term>Reassortants</term><term>Replication</term><term>Restrictive temperatures</term><term>Significant loss</term><term>Temperature sensitivity</term><term>Transfectant</term><term>Transfectant virus</term><term>Vaccine</term><term>Viral genes</term><term>Virology</term><term>Virus</term><term>Wild type</term><term>Wild type virus</term></keywords></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Abstract: The purpose of the present study was to produce an influenza A H2N2 donor virus from which an attenuating PB2 gene bearing three discrete temperature sensitive (ts) mutations could be readily transferred to currently epidemic influenza A H1N1 and H3N2 viruses via genetic reassortment. An influenza A transfectant virus was first produced that contained site-directed ts mutations at amino acids 112, 265, and 556 in the PB2 gene of influenza A/AA/60 virus origin in a background of the other seven RNA segments from the influenza A/LA/87 (H3N2) virus. The A/LA/87 PB2 ts transfectant virus (clone 22B1) was mated with the A/AA/60 (H2N2) wild type virus, and six H2N2 ts reassortants were obtained. One reassortant virus, clone 25A1, possessed the triple ts PB2 gene in the context of all seven other genes of homologous A/AA/60 origin. Isolation of this reassortant permitted an examination of the contribution of the ts mutations present in a triple ts PB2 transfectant virus to its attenuation and phenotypic stability indenpendent from an effect of the A/AA/60-A/LA/87 gene constellation on attenuation. It was found that the A/AA/60 triple ts reassortant virus was less ts, less attenuated, and less phenotypically stable than the A/LA/87 triple ts transfectant virus from which it was derived. The A/AA/60 reassortant possessing the PB2 gene containing three introduced ts mutations underwent rapid and significant loss of its temperature sensitivity following replication in the lungs of immunocompetent hamsters. This indicated that the A/AA/60-A/LA/87 gene constellation contributed significantly to the overall level of temperature-sensitivity, attenuation, and stability of the A/LA/87 triple ts transfectant virus. It is likely that the instability of the ts phenotype exhibited by the A/AA/60 triple ts reassortant virus would not be acceptable for a vaccine to be used in humans. The implications of these findings for the usefulness of ts mutations as the sole attenuating mutation in influenza virus vaccines is discussed.</div></front></TEI></ISTEX></double></record>Pour manipuler ce document sous Unix (Dilib)
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