PandemieGrippaleV1, PascalFrancis, Corpus, bibRecord, 000135

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 : 000135 ( PascalFrancis/Corpus ); précédent : 000134; suivant : 000136

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

Auteurs : LAN HUANG ; YANG CAO ; JIANFANG ZHOU ; KUN QIN ; WENFEI ZHU ; YUN ZHU ; LEI YANG ; DAYAN WANG ; HONG WEI ; YUELONG SHU

Source :

Antimicrobial agents and chemotherapy [ 0066-4804 ] ; 2014.

RBID : Pascal:14-0080482

Descripteurs français

Pascal (Inist)
- Conformation, Virus grippal A, Exo-α-sialidase, Site fixation, Résultat, Oséltamivir, Résistance, Antiviral.

English descriptors

KwdEn :
- Antiviral, Binding site, Conformation, Exo-α-sialidase, Influenza A virus, Oseltamivir, Resistance, Result.

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.

Notice en format standard (ISO 2709)

Pour connaître la documentation sur le format Inist Standard.

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A02	`01`			`@0 AACHAX`
A03		`1`		`@0 Antimicrob. agents chemother.`
A05				`@2 58`
A06				`@2 3`
A08	`01`	`1`	`ENG`	`@1 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`
A11	`01`	`1`		`@1 LAN HUANG`
A11	`02`	`1`		`@1 YANG CAO`
A11	`03`	`1`		`@1 JIANFANG ZHOU`
A11	`04`	`1`		`@1 KUN QIN`
A11	`05`	`1`		`@1 WENFEI ZHU`
A11	`06`	`1`		`@1 YUN ZHU`
A11	`07`	`1`		`@1 LEI YANG`
A11	`08`	`1`		`@1 DAYAN WANG`
A11	`09`	`1`		`@1 HONG WEI`
A11	`10`	`1`		`@1 YUELONG SHU`
A14	`01`			`@1 Chinese National Influenza Center, National Institute for Viral Disease Control and Prevention, China CDC @2 Beijing @3 CHN @Z 1 aut. @Z 3 aut. @Z 4 aut. @Z 5 aut. @Z 6 aut. @Z 7 aut. @Z 8 aut. @Z 10 aut.`
A14	`02`			`@1 Department of Neonatology, Children's Hospital of Chongqing Medical University @2 Chongqing @3 CHN @Z 1 aut. @Z 9 aut.`
A14	`03`			`@1 Center of Growth, Metabolism, and Aging, Key Laboratory of Bio-resource and Eco-environment, Ministry of Education, College of Life Sciences, Sichuan University @2 Chengdu @3 CHN @Z 2 aut.`
A20				`@1 1639-1645`
A21				`@1 2014`
A23	`01`			`@0 ENG`
A43	`01`			`@1 INIST @2 13334 @5 354000505799120450`
A44				`@0 0000 @1 © 2014 INIST-CNRS. All rights reserved.`
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A64	`01`	`1`		`@0 Antimicrobial agents and chemotherapy`
A66	`01`			`@0 USA`
C01	`01`		`ENG`	@0 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.
C02	`01`	`X`		`@0 002B02S`
C03	`01`	`X`	`FRE`	`@0 Conformation @5 01`
C03	`01`	`X`	`ENG`	`@0 Conformation @5 01`
C03	`01`	`X`	`SPA`	`@0 Conformación @5 01`
C03	`02`	`X`	`FRE`	`@0 Virus grippal A @2 NW @5 02`
C03	`02`	`X`	`ENG`	`@0 Influenza A virus @2 NW @5 02`
C03	`02`	`X`	`SPA`	`@0 Influenza A virus @2 NW @5 02`
C03	`03`	`X`	`FRE`	`@0 Exo-α-sialidase @2 FE @5 04`
C03	`03`	`X`	`ENG`	`@0 Exo-α-sialidase @2 FE @5 04`
C03	`03`	`X`	`SPA`	`@0 Exo-α-sialidase @2 FE @5 04`
C03	`04`	`X`	`FRE`	`@0 Site fixation @5 05`
C03	`04`	`X`	`ENG`	`@0 Binding site @5 05`
C03	`04`	`X`	`SPA`	`@0 Sitio fijación @5 05`
C03	`05`	`X`	`FRE`	`@0 Résultat @5 06`
C03	`05`	`X`	`ENG`	`@0 Result @5 06`
C03	`05`	`X`	`SPA`	`@0 Resultado @5 06`
C03	`06`	`X`	`FRE`	`@0 Oséltamivir @2 NK @2 FR @5 07`
C03	`06`	`X`	`ENG`	`@0 Oseltamivir @2 NK @2 FR @5 07`
C03	`06`	`X`	`SPA`	`@0 Oseltamivir @2 NK @2 FR @5 07`
C03	`07`	`X`	`FRE`	`@0 Résistance @5 08`
C03	`07`	`X`	`ENG`	`@0 Resistance @5 08`
C03	`07`	`X`	`SPA`	`@0 Resistencia @5 08`
C03	`08`	`X`	`FRE`	`@0 Antiviral @5 23`
C03	`08`	`X`	`ENG`	`@0 Antiviral @5 23`
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C07	`01`	`X`	`FRE`	`@0 Influenzavirus A @2 NW`
C07	`01`	`X`	`ENG`	`@0 Influenzavirus A @2 NW`
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C07	`02`	`X`	`FRE`	`@0 Orthomyxoviridae @2 NW`
C07	`02`	`X`	`ENG`	`@0 Orthomyxoviridae @2 NW`
C07	`02`	`X`	`SPA`	`@0 Orthomyxoviridae @2 NW`
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C07	`03`	`X`	`SPA`	`@0 Virus @2 NW`
C07	`04`	`X`	`FRE`	`@0 Glycosidases @2 FE`
C07	`04`	`X`	`ENG`	`@0 Glycosidases @2 FE`
C07	`04`	`X`	`SPA`	`@0 Glycosidases @2 FE`
C07	`05`	`X`	`FRE`	`@0 Glycosylases @2 FE`
C07	`05`	`X`	`ENG`	`@0 Glycosylases @2 FE`
C07	`05`	`X`	`SPA`	`@0 Glycosylases @2 FE`
C07	`06`	`X`	`FRE`	`@0 Hydrolases @2 FE`
C07	`06`	`X`	`ENG`	`@0 Hydrolases @2 FE`
C07	`06`	`X`	`SPA`	`@0 Hydrolases @2 FE`
C07	`07`	`X`	`FRE`	`@0 Enzyme @2 FE`
C07	`07`	`X`	`ENG`	`@0 Enzyme @2 FE`
C07	`07`	`X`	`SPA`	`@0 Enzima @2 FE`
C07	`08`	`X`	`FRE`	`@0 Inhibiteur enzyme @5 37`
C07	`08`	`X`	`ENG`	`@0 Enzyme inhibitor @5 37`
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C07	`09`	`X`	`FRE`	`@0 Inhibiteur neuraminidase @2 FR @5 38`
C07	`09`	`X`	`ENG`	`@0 Neuraminidase inhibitor @2 FR @5 38`
C07	`09`	`X`	`SPA`	`@0 Inhibidor neuraminidas @2 FR @5 38`
N21				`@1 111`
N44	`01`			`@1 OTO`
N82				`@1 OTO`

Format Inist (serveur)

NO :	PASCAL 14-0080482 INIST
ET :	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
AU :	LAN HUANG; YANG CAO; JIANFANG ZHOU; KUN QIN; WENFEI ZHU; YUN ZHU; LEI YANG; DAYAN WANG; HONG WEI; YUELONG SHU
AF :	Chinese National Influenza Center, National Institute for Viral Disease Control and Prevention, China CDC/Beijing/Chine (1 aut., 3 aut., 4 aut., 5 aut., 6 aut., 7 aut., 8 aut., 10 aut.); Department of Neonatology, Children's Hospital of Chongqing Medical University/Chongqing/Chine (1 aut., 9 aut.); Center of Growth, Metabolism, and Aging, Key Laboratory of Bio-resource and Eco-environment, Ministry of Education, College of Life Sciences, Sichuan University/Chengdu/Chine (2 aut.)
DT :	Publication en série; Niveau analytique
SO :	Antimicrobial agents and chemotherapy; ISSN 0066-4804; Coden AACHAX; Etats-Unis; Da. 2014; Vol. 58; No. 3; Pp. 1639-1645; Bibl. 41 ref.
LA :	Anglais
EA :	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.
CC :	002B02S
FD :	Conformation; Virus grippal A; Exo-α-sialidase; Site fixation; Résultat; Oséltamivir; Résistance; Antiviral
FG :	Influenzavirus A; Orthomyxoviridae; Virus; Glycosidases; Glycosylases; Hydrolases; Enzyme; Inhibiteur enzyme; Inhibiteur neuraminidase
ED :	Conformation; Influenza A virus; Exo-α-sialidase; Binding site; Result; Oseltamivir; Resistance; Antiviral
EG :	Influenzavirus A; Orthomyxoviridae; Virus; Glycosidases; Glycosylases; Hydrolases; Enzyme; Enzyme inhibitor; Neuraminidase inhibitor
SD :	Conformación; Influenza A virus; Exo-α-sialidase; Sitio fijación; Resultado; Oseltamivir; Resistencia; Antiviral
LO :	INIST-13334.354000505799120450
ID :	14-0080482

Links to Exploration step

Pascal:14-0080482

Le document en format XML

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<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>
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<author><name sortKey="Wenfei Zhu" sort="Wenfei Zhu" uniqKey="Wenfei Zhu" last="Wenfei Zhu">WENFEI ZHU</name>
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<author><name sortKey="Yun Zhu" sort="Yun Zhu" uniqKey="Yun Zhu" last="Yun Zhu">YUN ZHU</name>
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<author><name sortKey="Lei Yang" sort="Lei Yang" uniqKey="Lei Yang" last="Lei Yang">LEI YANG</name>
<affiliation><inist:fA14 i1="01"><s1>Chinese National Influenza Center, National Institute for Viral Disease Control and Prevention, China CDC</s1>
<s2>Beijing</s2>
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<sZ>3 aut.</sZ>
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<author><name sortKey="Dayan Wang" sort="Dayan Wang" uniqKey="Dayan Wang" last="Dayan Wang">DAYAN WANG</name>
<affiliation><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>
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<author><name sortKey="Hong Wei" sort="Hong Wei" uniqKey="Hong Wei" last="Hong Wei">HONG WEI</name>
<affiliation><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>
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<author><name sortKey="Yuelong Shu" sort="Yuelong Shu" uniqKey="Yuelong Shu" last="Yuelong Shu">YUELONG SHU</name>
<affiliation><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>
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<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>
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<term>Conformation</term>
<term>Exo-α-sialidase</term>
<term>Influenza A virus</term>
<term>Oseltamivir</term>
<term>Resistance</term>
<term>Result</term>
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<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>
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<sZ>9 aut.</sZ>
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<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>
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<server><NO>PASCAL 14-0080482 INIST</NO>
<ET>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</ET>
<AU>LAN HUANG; YANG CAO; JIANFANG ZHOU; KUN QIN; WENFEI ZHU; YUN ZHU; LEI YANG; DAYAN WANG; HONG WEI; YUELONG SHU</AU>
<AF>Chinese National Influenza Center, National Institute for Viral Disease Control and Prevention, China CDC/Beijing/Chine (1 aut., 3 aut., 4 aut., 5 aut., 6 aut., 7 aut., 8 aut., 10 aut.); Department of Neonatology, Children's Hospital of Chongqing Medical University/Chongqing/Chine (1 aut., 9 aut.); Center of Growth, Metabolism, and Aging, Key Laboratory of Bio-resource and Eco-environment, Ministry of Education, College of Life Sciences, Sichuan University/Chengdu/Chine (2 aut.)</AF>
<DT>Publication en série; Niveau analytique</DT>
<SO>Antimicrobial agents and chemotherapy; ISSN 0066-4804; Coden AACHAX; Etats-Unis; Da. 2014; Vol. 58; No. 3; Pp. 1639-1645; Bibl. 41 ref.</SO>
<LA>Anglais</LA>
<EA>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.</EA>
<CC>002B02S</CC>
<FD>Conformation; Virus grippal A; Exo-α-sialidase; Site fixation; Résultat; Oséltamivir; Résistance; Antiviral</FD>
<FG>Influenzavirus A; Orthomyxoviridae; Virus; Glycosidases; Glycosylases; Hydrolases; Enzyme; Inhibiteur enzyme; Inhibiteur neuraminidase</FG>
<ED>Conformation; Influenza A virus; Exo-α-sialidase; Binding site; Result; Oseltamivir; Resistance; Antiviral</ED>
<EG>Influenzavirus A; Orthomyxoviridae; Virus; Glycosidases; Glycosylases; Hydrolases; Enzyme; Enzyme inhibitor; Neuraminidase inhibitor</EG>
<SD>Conformación; Influenza A virus; Exo-α-sialidase; Sitio fijación; Resultado; Oseltamivir; Resistencia; Antiviral</SD>
<LO>INIST-13334.354000505799120450</LO>
<ID>14-0080482</ID>
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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

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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