A Conformational Restriction in the Influenza A Virus Neuraminidase Binding Site by R152 Results in a Combinational Effect of I222T and H274Y on Oseltamivir Resistance
Identifieur interne : 000144 ( PascalFrancis/Checkpoint ); précédent : 000143; suivant : 000145A Conformational Restriction in the Influenza A Virus Neuraminidase Binding Site by R152 Results in a Combinational Effect of I222T and H274Y on Oseltamivir Resistance
Auteurs : LAN HUANG [République populaire de Chine] ; YANG CAO [République populaire de Chine] ; JIANFANG ZHOU [République populaire de Chine] ; KUN QIN [République populaire de Chine] ; WENFEI ZHU [République populaire de Chine] ; YUN ZHU [République populaire de Chine] ; LEI YANG [République populaire de Chine] ; DAYAN WANG [République populaire de Chine] ; HONG WEI [République populaire de Chine] ; YUELONG SHU [République populaire de Chine]Source :
- Antimicrobial agents and chemotherapy [ 0066-4804 ] ; 2014.
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Abstract
The I222K, I222R, and I222T substitutions in neuraminidase (NA) have been found in clinically derived 2009 pandemic influenza A/H1N1 viruses with altered susceptibilities to NA inhibitors (NAIs). The effects of these substitutions, together with the most frequently observed resistance-related substitution, H274Y, on viral fitness and resistance mechanisms were further investigated in this study. Reduced sensitivities to oseltamivir were observed in all three mutants (I222K, I222R, and I222T). Furthermore, the I222K and I222T substitutions had a combinational effect of further increasing resistance in the presence of H274Y, which might result from a conformational restriction in the NA binding site. Of note, by using molecular dynamics simulations, R152, the neighbor of T222, was observed to translate to a position closer to T222, resulting in the narrowing of the binding pocket, which otherwise only subtends the residue substitution of H274Y. Moreover, significantly attenuated NA function and viral growth abilities were found in the I222K+H274Y double mutant, while the I222T+H274Y double mutant exhibited slightly delayed growth but had a peak viral titer similar to that of the wild-type virus in MDCK cells. The relative growth advantage of the I222T mutant versus the I222K mutant and the higher frequency of I222T emerging in N1 subtype influenza viruses raise concerns necessitating close monitoring of the dual substitutions I222T and H274Y.
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en" level="a">A Conformational Restriction in the Influenza A Virus Neuraminidase Binding Site by R152 Results in a Combinational Effect of I222T and H274Y on Oseltamivir Resistance</title><author><name sortKey="Lan Huang" sort="Lan Huang" uniqKey="Lan Huang" last="Lan Huang">LAN HUANG</name><affiliation wicri:level="3"><inist:fA14 i1="01"><s1>Chinese National Influenza Center, National Institute for Viral Disease Control and Prevention, China CDC</s1><s2>Beijing</s2><s3>CHN</s3><sZ>1 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>République populaire de Chine</country><placeName><settlement type="city">Pékin</settlement></placeName></affiliation><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Department of Neonatology, Children's Hospital of Chongqing Medical University</s1><s2>Chongqing</s2><s3>CHN</s3><sZ>1 aut.</sZ><sZ>9 aut.</sZ></inist:fA14><country>République populaire de Chine</country><wicri:noRegion>Chongqing</wicri:noRegion></affiliation></author><author><name sortKey="Yang Cao" sort="Yang Cao" uniqKey="Yang Cao" last="Yang Cao">YANG CAO</name><affiliation wicri:level="1"><inist:fA14 i1="03"><s1>Center of Growth, Metabolism, and Aging, Key Laboratory of Bio-resource and Eco-environment, Ministry of Education, College of Life Sciences, Sichuan University</s1><s2>Chengdu</s2><s3>CHN</s3><sZ>2 aut.</sZ></inist:fA14><country>République populaire de Chine</country><wicri:noRegion>Chengdu</wicri:noRegion></affiliation></author><author><name sortKey="Jianfang Zhou" sort="Jianfang Zhou" uniqKey="Jianfang Zhou" last="Jianfang Zhou">JIANFANG ZHOU</name><affiliation wicri:level="3"><inist:fA14 i1="01"><s1>Chinese National Influenza Center, National Institute for Viral Disease Control and Prevention, China CDC</s1><s2>Beijing</s2><s3>CHN</s3><sZ>1 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>République populaire de Chine</country><placeName><settlement type="city">Pékin</settlement></placeName></affiliation></author><author><name sortKey="Kun Qin" sort="Kun Qin" uniqKey="Kun Qin" last="Kun Qin">KUN QIN</name><affiliation wicri:level="3"><inist:fA14 i1="01"><s1>Chinese National Influenza Center, National Institute for Viral Disease Control and Prevention, China CDC</s1><s2>Beijing</s2><s3>CHN</s3><sZ>1 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>République populaire de Chine</country><placeName><settlement type="city">Pékin</settlement></placeName></affiliation></author><author><name sortKey="Wenfei Zhu" sort="Wenfei Zhu" uniqKey="Wenfei Zhu" last="Wenfei Zhu">WENFEI ZHU</name><affiliation wicri:level="3"><inist:fA14 i1="01"><s1>Chinese National Influenza Center, National Institute for Viral Disease Control and Prevention, China CDC</s1><s2>Beijing</s2><s3>CHN</s3><sZ>1 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>République populaire de Chine</country><placeName><settlement type="city">Pékin</settlement></placeName></affiliation></author><author><name sortKey="Yun Zhu" sort="Yun Zhu" uniqKey="Yun Zhu" last="Yun Zhu">YUN ZHU</name><affiliation wicri:level="3"><inist:fA14 i1="01"><s1>Chinese National Influenza Center, National Institute for Viral Disease Control and Prevention, China CDC</s1><s2>Beijing</s2><s3>CHN</s3><sZ>1 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>République populaire de Chine</country><placeName><settlement type="city">Pékin</settlement></placeName></affiliation></author><author><name sortKey="Lei Yang" sort="Lei Yang" uniqKey="Lei Yang" last="Lei Yang">LEI YANG</name><affiliation wicri:level="3"><inist:fA14 i1="01"><s1>Chinese National Influenza Center, National Institute for Viral Disease Control and Prevention, China CDC</s1><s2>Beijing</s2><s3>CHN</s3><sZ>1 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>République populaire de Chine</country><placeName><settlement type="city">Pékin</settlement></placeName></affiliation></author><author><name sortKey="Dayan Wang" sort="Dayan Wang" uniqKey="Dayan Wang" last="Dayan Wang">DAYAN WANG</name><affiliation wicri:level="3"><inist:fA14 i1="01"><s1>Chinese National Influenza Center, National Institute for Viral Disease Control and Prevention, China CDC</s1><s2>Beijing</s2><s3>CHN</s3><sZ>1 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>République populaire de Chine</country><placeName><settlement type="city">Pékin</settlement></placeName></affiliation></author><author><name sortKey="Hong Wei" sort="Hong Wei" uniqKey="Hong Wei" last="Hong Wei">HONG WEI</name><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Department of Neonatology, Children's Hospital of Chongqing Medical University</s1><s2>Chongqing</s2><s3>CHN</s3><sZ>1 aut.</sZ><sZ>9 aut.</sZ></inist:fA14><country>République populaire de Chine</country><wicri:noRegion>Chongqing</wicri:noRegion></affiliation></author><author><name sortKey="Yuelong Shu" sort="Yuelong Shu" uniqKey="Yuelong Shu" last="Yuelong Shu">YUELONG SHU</name><affiliation wicri:level="3"><inist:fA14 i1="01"><s1>Chinese National Influenza Center, National Institute for Viral Disease Control and Prevention, China CDC</s1><s2>Beijing</s2><s3>CHN</s3><sZ>1 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>République populaire de Chine</country><placeName><settlement type="city">Pékin</settlement></placeName></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">INIST</idno><idno type="inist">14-0080482</idno><date when="2014">2014</date><idno type="stanalyst">PASCAL 14-0080482 INIST</idno><idno type="RBID">Pascal:14-0080482</idno><idno type="wicri:Area/PascalFrancis/Corpus">000135</idno><idno type="wicri:Area/PascalFrancis/Curation">001C83</idno><idno type="wicri:Area/PascalFrancis/Checkpoint">000144</idno><idno type="wicri:explorRef" wicri:stream="PascalFrancis" wicri:step="Checkpoint">000144</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a">A Conformational Restriction in the Influenza A Virus Neuraminidase Binding Site by R152 Results in a Combinational Effect of I222T and H274Y on Oseltamivir Resistance</title><author><name sortKey="Lan Huang" sort="Lan Huang" uniqKey="Lan Huang" last="Lan Huang">LAN HUANG</name><affiliation wicri:level="3"><inist:fA14 i1="01"><s1>Chinese National Influenza Center, National Institute for Viral Disease Control and Prevention, China CDC</s1><s2>Beijing</s2><s3>CHN</s3><sZ>1 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>République populaire de Chine</country><placeName><settlement type="city">Pékin</settlement></placeName></affiliation><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Department of Neonatology, Children's Hospital of Chongqing Medical University</s1><s2>Chongqing</s2><s3>CHN</s3><sZ>1 aut.</sZ><sZ>9 aut.</sZ></inist:fA14><country>République populaire de Chine</country><wicri:noRegion>Chongqing</wicri:noRegion></affiliation></author><author><name sortKey="Yang Cao" sort="Yang Cao" uniqKey="Yang Cao" last="Yang Cao">YANG CAO</name><affiliation wicri:level="1"><inist:fA14 i1="03"><s1>Center of Growth, Metabolism, and Aging, Key Laboratory of Bio-resource and Eco-environment, Ministry of Education, College of Life Sciences, Sichuan University</s1><s2>Chengdu</s2><s3>CHN</s3><sZ>2 aut.</sZ></inist:fA14><country>République populaire de Chine</country><wicri:noRegion>Chengdu</wicri:noRegion></affiliation></author><author><name sortKey="Jianfang Zhou" sort="Jianfang Zhou" uniqKey="Jianfang Zhou" last="Jianfang Zhou">JIANFANG ZHOU</name><affiliation wicri:level="3"><inist:fA14 i1="01"><s1>Chinese National Influenza Center, National Institute for Viral Disease Control and Prevention, China CDC</s1><s2>Beijing</s2><s3>CHN</s3><sZ>1 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>République populaire de Chine</country><placeName><settlement type="city">Pékin</settlement></placeName></affiliation></author><author><name sortKey="Kun Qin" sort="Kun Qin" uniqKey="Kun Qin" last="Kun Qin">KUN QIN</name><affiliation wicri:level="3"><inist:fA14 i1="01"><s1>Chinese National Influenza Center, National Institute for Viral Disease Control and Prevention, China CDC</s1><s2>Beijing</s2><s3>CHN</s3><sZ>1 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>République populaire de Chine</country><placeName><settlement type="city">Pékin</settlement></placeName></affiliation></author><author><name sortKey="Wenfei Zhu" sort="Wenfei Zhu" uniqKey="Wenfei Zhu" last="Wenfei Zhu">WENFEI ZHU</name><affiliation wicri:level="3"><inist:fA14 i1="01"><s1>Chinese National Influenza Center, National Institute for Viral Disease Control and Prevention, China CDC</s1><s2>Beijing</s2><s3>CHN</s3><sZ>1 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>République populaire de Chine</country><placeName><settlement type="city">Pékin</settlement></placeName></affiliation></author><author><name sortKey="Yun Zhu" sort="Yun Zhu" uniqKey="Yun Zhu" last="Yun Zhu">YUN ZHU</name><affiliation wicri:level="3"><inist:fA14 i1="01"><s1>Chinese National Influenza Center, National Institute for Viral Disease Control and Prevention, China CDC</s1><s2>Beijing</s2><s3>CHN</s3><sZ>1 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>République populaire de Chine</country><placeName><settlement type="city">Pékin</settlement></placeName></affiliation></author><author><name sortKey="Lei Yang" sort="Lei Yang" uniqKey="Lei Yang" last="Lei Yang">LEI YANG</name><affiliation wicri:level="3"><inist:fA14 i1="01"><s1>Chinese National Influenza Center, National Institute for Viral Disease Control and Prevention, China CDC</s1><s2>Beijing</s2><s3>CHN</s3><sZ>1 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>République populaire de Chine</country><placeName><settlement type="city">Pékin</settlement></placeName></affiliation></author><author><name sortKey="Dayan Wang" sort="Dayan Wang" uniqKey="Dayan Wang" last="Dayan Wang">DAYAN WANG</name><affiliation wicri:level="3"><inist:fA14 i1="01"><s1>Chinese National Influenza Center, National Institute for Viral Disease Control and Prevention, China CDC</s1><s2>Beijing</s2><s3>CHN</s3><sZ>1 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>République populaire de Chine</country><placeName><settlement type="city">Pékin</settlement></placeName></affiliation></author><author><name sortKey="Hong Wei" sort="Hong Wei" uniqKey="Hong Wei" last="Hong Wei">HONG WEI</name><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Department of Neonatology, Children's Hospital of Chongqing Medical University</s1><s2>Chongqing</s2><s3>CHN</s3><sZ>1 aut.</sZ><sZ>9 aut.</sZ></inist:fA14><country>République populaire de Chine</country><wicri:noRegion>Chongqing</wicri:noRegion></affiliation></author><author><name sortKey="Yuelong Shu" sort="Yuelong Shu" uniqKey="Yuelong Shu" last="Yuelong Shu">YUELONG SHU</name><affiliation wicri:level="3"><inist:fA14 i1="01"><s1>Chinese National Influenza Center, National Institute for Viral Disease Control and Prevention, China CDC</s1><s2>Beijing</s2><s3>CHN</s3><sZ>1 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>République populaire de Chine</country><placeName><settlement type="city">Pékin</settlement></placeName></affiliation></author></analytic><series><title level="j" type="main">Antimicrobial agents and chemotherapy</title><title level="j" type="abbreviated">Antimicrob. agents chemother.</title><idno type="ISSN">0066-4804</idno><imprint><date when="2014">2014</date></imprint></series></biblStruct></sourceDesc><seriesStmt><title level="j" type="main">Antimicrobial agents and chemotherapy</title><title level="j" type="abbreviated">Antimicrob. agents chemother.</title><idno type="ISSN">0066-4804</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Antiviral</term><term>Binding site</term><term>Conformation</term><term>Exo-α-sialidase</term><term>Influenza A virus</term><term>Oseltamivir</term><term>Resistance</term><term>Result</term></keywords><keywords scheme="Pascal" xml:lang="fr"><term>Conformation</term><term>Virus grippal A</term><term>Exo-α-sialidase</term><term>Site fixation</term><term>Résultat</term><term>Oséltamivir</term><term>Résistance</term><term>Antiviral</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">The I222K, I222R, and I222T substitutions in neuraminidase (NA) have been found in clinically derived 2009 pandemic influenza A/H1N1 viruses with altered susceptibilities to NA inhibitors (NAIs). The effects of these substitutions, together with the most frequently observed resistance-related substitution, H274Y, on viral fitness and resistance mechanisms were further investigated in this study. Reduced sensitivities to oseltamivir were observed in all three mutants (I222K, I222R, and I222T). Furthermore, the I222K and I222T substitutions had a combinational effect of further increasing resistance in the presence of H274Y, which might result from a conformational restriction in the NA binding site. Of note, by using molecular dynamics simulations, R152, the neighbor of T222, was observed to translate to a position closer to T222, resulting in the narrowing of the binding pocket, which otherwise only subtends the residue substitution of H274Y. Moreover, significantly attenuated NA function and viral growth abilities were found in the I222K+H274Y double mutant, while the I222T+H274Y double mutant exhibited slightly delayed growth but had a peak viral titer similar to that of the wild-type virus in MDCK cells. The relative growth advantage of the I222T mutant versus the I222K mutant and the higher frequency of I222T emerging in N1 subtype influenza viruses raise concerns necessitating close monitoring of the dual substitutions I222T and H274Y.</div></front></TEI><inist><standard h6="B"><pA><fA01 i1="01" i2="1"><s0>0066-4804</s0></fA01><fA02 i1="01"><s0>AACHAX</s0></fA02><fA03 i2="1"><s0>Antimicrob. agents chemother.</s0></fA03><fA05><s2>58</s2></fA05><fA06><s2>3</s2></fA06><fA08 i1="01" i2="1" l="ENG"><s1>A Conformational Restriction in the Influenza A Virus Neuraminidase Binding Site by R152 Results in a Combinational Effect of I222T and H274Y on Oseltamivir Resistance</s1></fA08><fA11 i1="01" i2="1"><s1>LAN HUANG</s1></fA11><fA11 i1="02" i2="1"><s1>YANG CAO</s1></fA11><fA11 i1="03" i2="1"><s1>JIANFANG ZHOU</s1></fA11><fA11 i1="04" i2="1"><s1>KUN QIN</s1></fA11><fA11 i1="05" i2="1"><s1>WENFEI ZHU</s1></fA11><fA11 i1="06" i2="1"><s1>YUN ZHU</s1></fA11><fA11 i1="07" i2="1"><s1>LEI YANG</s1></fA11><fA11 i1="08" i2="1"><s1>DAYAN WANG</s1></fA11><fA11 i1="09" i2="1"><s1>HONG WEI</s1></fA11><fA11 i1="10" i2="1"><s1>YUELONG SHU</s1></fA11><fA14 i1="01"><s1>Chinese National Influenza Center, National Institute for Viral Disease Control and Prevention, China CDC</s1><s2>Beijing</s2><s3>CHN</s3><sZ>1 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ><sZ>10 aut.</sZ></fA14><fA14 i1="02"><s1>Department of Neonatology, Children's Hospital of Chongqing Medical University</s1><s2>Chongqing</s2><s3>CHN</s3><sZ>1 aut.</sZ><sZ>9 aut.</sZ></fA14><fA14 i1="03"><s1>Center of Growth, Metabolism, and Aging, Key Laboratory of Bio-resource and Eco-environment, Ministry of Education, College of Life Sciences, Sichuan University</s1><s2>Chengdu</s2><s3>CHN</s3><sZ>2 aut.</sZ></fA14><fA20><s1>1639-1645</s1></fA20><fA21><s1>2014</s1></fA21><fA23 i1="01"><s0>ENG</s0></fA23><fA43 i1="01"><s1>INIST</s1><s2>13334</s2><s5>354000505799120450</s5></fA43><fA44><s0>0000</s0><s1>© 2014 INIST-CNRS. All rights reserved.</s1></fA44><fA45><s0>41 ref.</s0></fA45><fA47 i1="01" i2="1"><s0>14-0080482</s0></fA47><fA60><s1>P</s1></fA60><fA61><s0>A</s0></fA61><fA64 i1="01" i2="1"><s0>Antimicrobial agents and chemotherapy</s0></fA64><fA66 i1="01"><s0>USA</s0></fA66><fC01 i1="01" l="ENG"><s0>The I222K, I222R, and I222T substitutions in neuraminidase (NA) have been found in clinically derived 2009 pandemic influenza A/H1N1 viruses with altered susceptibilities to NA inhibitors (NAIs). The effects of these substitutions, together with the most frequently observed resistance-related substitution, H274Y, on viral fitness and resistance mechanisms were further investigated in this study. Reduced sensitivities to oseltamivir were observed in all three mutants (I222K, I222R, and I222T). Furthermore, the I222K and I222T substitutions had a combinational effect of further increasing resistance in the presence of H274Y, which might result from a conformational restriction in the NA binding site. Of note, by using molecular dynamics simulations, R152, the neighbor of T222, was observed to translate to a position closer to T222, resulting in the narrowing of the binding pocket, which otherwise only subtends the residue substitution of H274Y. Moreover, significantly attenuated NA function and viral growth abilities were found in the I222K+H274Y double mutant, while the I222T+H274Y double mutant exhibited slightly delayed growth but had a peak viral titer similar to that of the wild-type virus in MDCK cells. The relative growth advantage of the I222T mutant versus the I222K mutant and the higher frequency of I222T emerging in N1 subtype influenza viruses raise concerns necessitating close monitoring of the dual substitutions I222T and H274Y.</s0></fC01><fC02 i1="01" i2="X"><s0>002B02S</s0></fC02><fC03 i1="01" i2="X" l="FRE"><s0>Conformation</s0><s5>01</s5></fC03><fC03 i1="01" i2="X" l="ENG"><s0>Conformation</s0><s5>01</s5></fC03><fC03 i1="01" i2="X" l="SPA"><s0>Conformación</s0><s5>01</s5></fC03><fC03 i1="02" i2="X" l="FRE"><s0>Virus grippal A</s0><s2>NW</s2><s5>02</s5></fC03><fC03 i1="02" i2="X" l="ENG"><s0>Influenza A virus</s0><s2>NW</s2><s5>02</s5></fC03><fC03 i1="02" i2="X" l="SPA"><s0>Influenza A virus</s0><s2>NW</s2><s5>02</s5></fC03><fC03 i1="03" i2="X" l="FRE"><s0>Exo-α-sialidase</s0><s2>FE</s2><s5>04</s5></fC03><fC03 i1="03" i2="X" l="ENG"><s0>Exo-α-sialidase</s0><s2>FE</s2><s5>04</s5></fC03><fC03 i1="03" i2="X" l="SPA"><s0>Exo-α-sialidase</s0><s2>FE</s2><s5>04</s5></fC03><fC03 i1="04" i2="X" l="FRE"><s0>Site fixation</s0><s5>05</s5></fC03><fC03 i1="04" i2="X" l="ENG"><s0>Binding site</s0><s5>05</s5></fC03><fC03 i1="04" i2="X" l="SPA"><s0>Sitio fijación</s0><s5>05</s5></fC03><fC03 i1="05" i2="X" l="FRE"><s0>Résultat</s0><s5>06</s5></fC03><fC03 i1="05" i2="X" l="ENG"><s0>Result</s0><s5>06</s5></fC03><fC03 i1="05" i2="X" l="SPA"><s0>Resultado</s0><s5>06</s5></fC03><fC03 i1="06" i2="X" l="FRE"><s0>Oséltamivir</s0><s2>NK</s2><s2>FR</s2><s5>07</s5></fC03><fC03 i1="06" i2="X" l="ENG"><s0>Oseltamivir</s0><s2>NK</s2><s2>FR</s2><s5>07</s5></fC03><fC03 i1="06" i2="X" l="SPA"><s0>Oseltamivir</s0><s2>NK</s2><s2>FR</s2><s5>07</s5></fC03><fC03 i1="07" i2="X" l="FRE"><s0>Résistance</s0><s5>08</s5></fC03><fC03 i1="07" i2="X" l="ENG"><s0>Resistance</s0><s5>08</s5></fC03><fC03 i1="07" i2="X" l="SPA"><s0>Resistencia</s0><s5>08</s5></fC03><fC03 i1="08" i2="X" l="FRE"><s0>Antiviral</s0><s5>23</s5></fC03><fC03 i1="08" i2="X" l="ENG"><s0>Antiviral</s0><s5>23</s5></fC03><fC03 i1="08" i2="X" l="SPA"><s0>Antiviral</s0><s5>23</s5></fC03><fC07 i1="01" i2="X" l="FRE"><s0>Influenzavirus A</s0><s2>NW</s2></fC07><fC07 i1="01" i2="X" l="ENG"><s0>Influenzavirus A</s0><s2>NW</s2></fC07><fC07 i1="01" i2="X" l="SPA"><s0>Influenzavirus A</s0><s2>NW</s2></fC07><fC07 i1="02" i2="X" l="FRE"><s0>Orthomyxoviridae</s0><s2>NW</s2></fC07><fC07 i1="02" i2="X" l="ENG"><s0>Orthomyxoviridae</s0><s2>NW</s2></fC07><fC07 i1="02" i2="X" l="SPA"><s0>Orthomyxoviridae</s0><s2>NW</s2></fC07><fC07 i1="03" i2="X" l="FRE"><s0>Virus</s0><s2>NW</s2></fC07><fC07 i1="03" i2="X" l="ENG"><s0>Virus</s0><s2>NW</s2></fC07><fC07 i1="03" i2="X" l="SPA"><s0>Virus</s0><s2>NW</s2></fC07><fC07 i1="04" i2="X" l="FRE"><s0>Glycosidases</s0><s2>FE</s2></fC07><fC07 i1="04" i2="X" l="ENG"><s0>Glycosidases</s0><s2>FE</s2></fC07><fC07 i1="04" i2="X" l="SPA"><s0>Glycosidases</s0><s2>FE</s2></fC07><fC07 i1="05" i2="X" l="FRE"><s0>Glycosylases</s0><s2>FE</s2></fC07><fC07 i1="05" i2="X" l="ENG"><s0>Glycosylases</s0><s2>FE</s2></fC07><fC07 i1="05" i2="X" l="SPA"><s0>Glycosylases</s0><s2>FE</s2></fC07><fC07 i1="06" i2="X" l="FRE"><s0>Hydrolases</s0><s2>FE</s2></fC07><fC07 i1="06" i2="X" l="ENG"><s0>Hydrolases</s0><s2>FE</s2></fC07><fC07 i1="06" i2="X" l="SPA"><s0>Hydrolases</s0><s2>FE</s2></fC07><fC07 i1="07" i2="X" l="FRE"><s0>Enzyme</s0><s2>FE</s2></fC07><fC07 i1="07" i2="X" l="ENG"><s0>Enzyme</s0><s2>FE</s2></fC07><fC07 i1="07" i2="X" l="SPA"><s0>Enzima</s0><s2>FE</s2></fC07><fC07 i1="08" i2="X" l="FRE"><s0>Inhibiteur enzyme</s0><s5>37</s5></fC07><fC07 i1="08" i2="X" l="ENG"><s0>Enzyme inhibitor</s0><s5>37</s5></fC07><fC07 i1="08" i2="X" l="SPA"><s0>Inhibidor enzima</s0><s5>37</s5></fC07><fC07 i1="09" i2="X" l="FRE"><s0>Inhibiteur neuraminidase</s0><s2>FR</s2><s5>38</s5></fC07><fC07 i1="09" i2="X" l="ENG"><s0>Neuraminidase inhibitor</s0><s2>FR</s2><s5>38</s5></fC07><fC07 i1="09" i2="X" l="SPA"><s0>Inhibidor neuraminidas</s0><s2>FR</s2><s5>38</s5></fC07><fN21><s1>111</s1></fN21><fN44 i1="01"><s1>OTO</s1></fN44><fN82><s1>OTO</s1></fN82></pA></standard></inist><affiliations><list><country><li>République populaire de Chine</li></country><settlement><li>Pékin</li></settlement></list><tree><country name="République populaire de Chine"><noRegion><name sortKey="Lan Huang" sort="Lan Huang" uniqKey="Lan Huang" last="Lan Huang">LAN HUANG</name></noRegion><name sortKey="Dayan Wang" sort="Dayan Wang" uniqKey="Dayan Wang" last="Dayan Wang">DAYAN WANG</name><name sortKey="Hong Wei" sort="Hong Wei" uniqKey="Hong Wei" last="Hong Wei">HONG WEI</name><name sortKey="Jianfang Zhou" sort="Jianfang Zhou" uniqKey="Jianfang Zhou" last="Jianfang Zhou">JIANFANG ZHOU</name><name sortKey="Kun Qin" sort="Kun Qin" uniqKey="Kun Qin" last="Kun Qin">KUN QIN</name><name sortKey="Lan Huang" sort="Lan Huang" uniqKey="Lan Huang" last="Lan Huang">LAN HUANG</name><name sortKey="Lei Yang" sort="Lei Yang" uniqKey="Lei Yang" 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|wiki= Sante
|area= PandemieGrippaleV1
|flux= PascalFrancis
|étape= Checkpoint
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|clé= Pascal:14-0080482
|texte= A Conformational Restriction in the Influenza A Virus Neuraminidase Binding Site by R152 Results in a Combinational Effect of I222T and H274Y on Oseltamivir Resistance
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