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 : 001135 ( Main/Exploration ); précédent : 001134; suivant : 001136A 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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- Pascal (Inist)
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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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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 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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><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" last="Lei Yang">LEI YANG</name><name sortKey="Wenfei Zhu" sort="Wenfei Zhu" uniqKey="Wenfei Zhu" last="Wenfei Zhu">WENFEI ZHU</name><name sortKey="Yang Cao" sort="Yang Cao" uniqKey="Yang Cao" last="Yang Cao">YANG CAO</name><name sortKey="Yuelong Shu" sort="Yuelong Shu" uniqKey="Yuelong Shu" last="Yuelong Shu">YUELONG SHU</name><name sortKey="Yun Zhu" sort="Yun Zhu" uniqKey="Yun Zhu" last="Yun Zhu">YUN ZHU</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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