Study of the Influenza A virus susceptibility to neuraminidase inhibitors
Identifieur interne : 000007 ( Hal/Checkpoint ); précédent : 000006; suivant : 000008Study of the Influenza A virus susceptibility to neuraminidase inhibitors
Auteurs : Alexandre Gaymard [France]Source :
Descripteurs français
- mix :
English descriptors
- mix :
Abstract
Influenza viruses are important human pathogens that are responsible for flu, whether seasonal, pandemic or zoonotic. Very few therapeutic options are available against these pathogens and neuraminidase inhibitors (NAI) are the only antiviral agents recommended by the WHO for treatment and prophylaxis of influenza virus infections. NAI resistance has already been described and the H274Y, E119V and R292K neuraminidase substitutions are the most frequently encountered substitutions responsible for oseltamivir resistance. During this work, we focused the NAI resistance study around two main objectives: first, we monitored clinical and biological resistance in treated patients and then we studied the impact of substitutions responsible for NAI resistance using avian neuraminidases. For NAI resistance monitoring, viral genomic diversity of a child's influenza A(H1N1)pdm09 was characterized in the context of a severe combined immunodeficiency and a chronic viral excretion despite antiviral treatment. For a better detection of H274Y substitution in A(H1N1) influenza viruses, a digital droplet PCR was developed and evaluated. At a more fundamental level, resistance substitutions (H274Y, R292K, E119V ± I222L) were analysed using all neuraminidase subtypes of influenza A viruses. To summarize, H274Y substitution is preferentially isolated in N1 but also decreases oseltamivir susceptibility in all group 1 neuraminidases (N1, N4, N5 and N8). The E119V substitution impact on oseltamivir susceptibility depends on the neuraminidase and decreases oseltamivir susceptibility especially within N2, N7, N9 and N5. Moreover, the E119V+I222L substitutions has a synergistic effect on oseltamivir resistance profile. The R292K substitution decreases all NAI susceptibility for all group 2 neuraminidases (N2, N3, N6, N7 and N9). The production of a recombinant N9 bearing the R292K substitution allows to highlight the substitution impact on the sialidasic activity. Development of new technological tools are still in progress to allow a more accurate analysis of the mechanisms that underlie the NAI resistance
Url:
Links toward previous steps (curation, corpus...)
Links to Exploration step
Hal:tel-02356404Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Study of the Influenza A virus susceptibility to neuraminidase inhibitors</title><title xml:lang="fr">Étude et suivi de la résistance des virus influenzae A aux inhibiteurs de la neuraminidase</title><author><name sortKey="Gaymard, Alexandre" sort="Gaymard, Alexandre" uniqKey="Gaymard A" first="Alexandre" last="Gaymard">Alexandre Gaymard</name><affiliation wicri:level="1"><hal:affiliation type="regrouplaboratory" xml:id="struct-222995" status="VALID"> <idno type="IdRef">17825696X</idno> <idno type="RNSR">201320572J</idno> <orgName>Centre International de Recherche en Infectiologie - UMR</orgName> <orgName type="acronym">CIRI</orgName> <date type="start">2013-01-01</date> <desc> <address> <addrLine>21 avenue Tony Garnier 69365 Lyon Cedex 07</addrLine> <country key="FR"></country> </address> <ref type="url">http://ciri.inserm.fr/</ref> </desc> <listRelation> <relation name="U1111" active="#struct-303623" type="direct"></relation> <relation active="#struct-6818" type="direct"></relation> <relation active="#struct-194495" type="direct"></relation> <relation active="#struct-301088" type="indirect"></relation> <relation name="UMR5308" active="#struct-441569" type="direct"></relation> </listRelation> <tutelles><tutelle name="U1111" active="#struct-303623" type="direct"><org type="institution" xml:id="struct-303623" status="VALID"> <idno type="IdRef">026388278</idno> <orgName>Institut National de la Santé et de la Recherche Médicale</orgName> <orgName type="acronym">INSERM</orgName> <desc> <address> <addrLine>101, rue de Tolbiac, 75013 Paris </addrLine> <country key="FR"></country> </address> <ref type="url">http://www.inserm.fr</ref> </desc> </org></tutelle><tutelle active="#struct-6818" type="direct"><org type="institution" xml:id="struct-6818" status="VALID"> <idno type="IdRef">149154992</idno> <orgName>École normale supérieure - Lyon</orgName> <orgName type="acronym">ENS Lyon</orgName> <desc> <address> <addrLine>15 parvis René Descartes - BP 7000 - 69342 Lyon Cedex 07</addrLine> <country key="FR"></country> </address> <ref type="url">http://www.ens-lyon.eu/</ref> </desc> </org></tutelle><tutelle active="#struct-194495" type="direct"><org type="institution" xml:id="struct-194495" status="VALID"> <idno type="IdRef">026402823</idno> <idno type="ISNI">0000000121686185</idno> <orgName>Université Claude Bernard Lyon 1</orgName> <orgName type="acronym">UCBL</orgName> <desc> <address> <addrLine>43, boulevard du 11 novembre 1918, 69622 Villeurbanne cedex</addrLine> <country key="FR"></country> </address> <ref type="url">http://www.univ-lyon1.fr/</ref> </desc> <listRelation> <relation active="#struct-301088" type="direct"></relation> </listRelation> </org></tutelle><tutelle active="#struct-301088" type="indirect"><org type="regroupinstitution" xml:id="struct-301088" status="VALID"> <orgName>Université de Lyon</orgName> <desc> <address> <addrLine>92 rue Pasteur - CS 30122, 69361 Lyon Cedex 07</addrLine> <country key="FR"></country> </address> <ref type="url">https://www.universite-lyon.fr/</ref> </desc> </org></tutelle><tutelle name="UMR5308" active="#struct-441569" type="direct"><org type="institution" xml:id="struct-441569" status="VALID"> <idno type="IdRef">02636817X</idno> <idno type="ISNI">0000000122597504</idno> <orgName>Centre National de la Recherche Scientifique</orgName> <orgName type="acronym">CNRS</orgName> <date type="start">1939-10-19</date> <desc> <address> <country key="FR"></country> </address> <ref type="url">http://www.cnrs.fr/</ref> </desc> </org></tutelle></tutelles></hal:affiliation><country>France</country><placeName><settlement type="city">Lyon</settlement><region type="region" nuts="2">Auvergne-Rhône-Alpes</region><region type="old region" nuts="2">Rhône-Alpes</region></placeName><orgName type="university">Université Claude Bernard Lyon 1</orgName><orgName type="institution" wicri:auto="newGroup">Université de Lyon</orgName></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">HAL</idno><idno type="RBID">Hal:tel-02356404</idno><idno type="halId">tel-02356404</idno><idno type="halUri">https://tel.archives-ouvertes.fr/tel-02356404</idno><idno type="url">https://tel.archives-ouvertes.fr/tel-02356404</idno><date when="2019-09-25">2019-09-25</date><idno type="wicri:Area/Hal/Corpus">000273</idno><idno type="wicri:Area/Hal/Curation">000273</idno><idno type="wicri:Area/Hal/Checkpoint">000007</idno><idno type="wicri:explorRef" wicri:stream="Hal" wicri:step="Checkpoint">000007</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Study of the Influenza A virus susceptibility to neuraminidase inhibitors</title><title xml:lang="fr">Étude et suivi de la résistance des virus influenzae A aux inhibiteurs de la neuraminidase</title><author><name sortKey="Gaymard, Alexandre" sort="Gaymard, Alexandre" uniqKey="Gaymard A" first="Alexandre" last="Gaymard">Alexandre Gaymard</name><affiliation wicri:level="1"><hal:affiliation type="regrouplaboratory" xml:id="struct-222995" status="VALID"> <idno type="IdRef">17825696X</idno> <idno type="RNSR">201320572J</idno> <orgName>Centre International de Recherche en Infectiologie - UMR</orgName> <orgName type="acronym">CIRI</orgName> <date type="start">2013-01-01</date> <desc> <address> <addrLine>21 avenue Tony Garnier 69365 Lyon Cedex 07</addrLine> <country key="FR"></country> </address> <ref type="url">http://ciri.inserm.fr/</ref> </desc> <listRelation> <relation name="U1111" active="#struct-303623" type="direct"></relation> <relation active="#struct-6818" type="direct"></relation> <relation active="#struct-194495" type="direct"></relation> <relation active="#struct-301088" type="indirect"></relation> <relation name="UMR5308" active="#struct-441569" type="direct"></relation> </listRelation> <tutelles><tutelle name="U1111" active="#struct-303623" type="direct"><org type="institution" xml:id="struct-303623" status="VALID"> <idno type="IdRef">026388278</idno> <orgName>Institut National de la Santé et de la Recherche Médicale</orgName> <orgName type="acronym">INSERM</orgName> <desc> <address> <addrLine>101, rue de Tolbiac, 75013 Paris </addrLine> <country key="FR"></country> </address> <ref type="url">http://www.inserm.fr</ref> </desc> </org></tutelle><tutelle active="#struct-6818" type="direct"><org type="institution" xml:id="struct-6818" status="VALID"> <idno type="IdRef">149154992</idno> <orgName>École normale supérieure - Lyon</orgName> <orgName type="acronym">ENS Lyon</orgName> <desc> <address> <addrLine>15 parvis René Descartes - BP 7000 - 69342 Lyon Cedex 07</addrLine> <country key="FR"></country> </address> <ref type="url">http://www.ens-lyon.eu/</ref> </desc> </org></tutelle><tutelle active="#struct-194495" type="direct"><org type="institution" xml:id="struct-194495" status="VALID"> <idno type="IdRef">026402823</idno> <idno type="ISNI">0000000121686185</idno> <orgName>Université Claude Bernard Lyon 1</orgName> <orgName type="acronym">UCBL</orgName> <desc> <address> <addrLine>43, boulevard du 11 novembre 1918, 69622 Villeurbanne cedex</addrLine> <country key="FR"></country> </address> <ref type="url">http://www.univ-lyon1.fr/</ref> </desc> <listRelation> <relation active="#struct-301088" type="direct"></relation> </listRelation> </org></tutelle><tutelle active="#struct-301088" type="indirect"><org type="regroupinstitution" xml:id="struct-301088" status="VALID"> <orgName>Université de Lyon</orgName> <desc> <address> <addrLine>92 rue Pasteur - CS 30122, 69361 Lyon Cedex 07</addrLine> <country key="FR"></country> </address> <ref type="url">https://www.universite-lyon.fr/</ref> </desc> </org></tutelle><tutelle name="UMR5308" active="#struct-441569" type="direct"><org type="institution" xml:id="struct-441569" status="VALID"> <idno type="IdRef">02636817X</idno> <idno type="ISNI">0000000122597504</idno> <orgName>Centre National de la Recherche Scientifique</orgName> <orgName type="acronym">CNRS</orgName> <date type="start">1939-10-19</date> <desc> <address> <country key="FR"></country> </address> <ref type="url">http://www.cnrs.fr/</ref> </desc> </org></tutelle></tutelles></hal:affiliation><country>France</country><placeName><settlement type="city">Lyon</settlement><region type="region" nuts="2">Auvergne-Rhône-Alpes</region><region type="old region" nuts="2">Rhône-Alpes</region></placeName><orgName type="university">Université Claude Bernard Lyon 1</orgName><orgName type="institution" wicri:auto="newGroup">Université de Lyon</orgName></affiliation></author></analytic></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="mix" xml:lang="en"><term>E119V substitution</term><term>E119V+I222L substitution</term><term>H274Y substitution</term><term>Influenza A virus</term><term>Oseltamivir susceptibility</term><term>R292K substitution</term></keywords><keywords scheme="mix" xml:lang="fr"><term>Résistance à l’oseltamivir</term><term>Substitution E119V</term><term>Substitution E119V+I222L</term><term>Substitution H274Y</term><term>Substitution R292K</term><term>Virus influenza A</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"> <p>Influenza viruses are important human pathogens that are responsible for flu, whether seasonal, pandemic or zoonotic. Very few therapeutic options are available against these pathogens and neuraminidase inhibitors (NAI) are the only antiviral agents recommended by the WHO for treatment and prophylaxis of influenza virus infections. NAI resistance has already been described and the H274Y, E119V and R292K neuraminidase substitutions are the most frequently encountered substitutions responsible for oseltamivir resistance. During this work, we focused the NAI resistance study around two main objectives: first, we monitored clinical and biological resistance in treated patients and then we studied the impact of substitutions responsible for NAI resistance using avian neuraminidases. For NAI resistance monitoring, viral genomic diversity of a child's influenza A(H1N1)pdm09 was characterized in the context of a severe combined immunodeficiency and a chronic viral excretion despite antiviral treatment. For a better detection of H274Y substitution in A(H1N1) influenza viruses, a digital droplet PCR was developed and evaluated. At a more fundamental level, resistance substitutions (H274Y, R292K, E119V ± I222L) were analysed using all neuraminidase subtypes of influenza A viruses. To summarize, H274Y substitution is preferentially isolated in N1 but also decreases oseltamivir susceptibility in all group 1 neuraminidases (N1, N4, N5 and N8). The E119V substitution impact on oseltamivir susceptibility depends on the neuraminidase and decreases oseltamivir susceptibility especially within N2, N7, N9 and N5. Moreover, the E119V+I222L substitutions has a synergistic effect on oseltamivir resistance profile. The R292K substitution decreases all NAI susceptibility for all group 2 neuraminidases (N2, N3, N6, N7 and N9). The production of a recombinant N9 bearing the R292K substitution allows to highlight the substitution impact on the sialidasic activity. Development of new technological tools are still in progress to allow a more accurate analysis of the mechanisms that underlie the NAI resistance</p> </div></front></TEI><hal api="V3"> <titleStmt> <title xml:lang="en">Study of the Influenza A virus susceptibility to neuraminidase inhibitors</title> <title xml:lang="fr">Étude et suivi de la résistance des virus influenzae A aux inhibiteurs de la neuraminidase</title> <author role="aut"> <persName> <forename type="first">Alexandre</forename> <surname>Gaymard</surname> </persName> <idno type="halauthorid">11306990</idno> <affiliation ref="#struct-222995"></affiliation> </author> <editor role="depositor"> <persName> <forename>ABES</forename> <surname>STAR</surname> </persName> <email type="md5">f5aa7f563b02bb6adbba7496989af39a</email> <email type="domain">abes.fr</email> </editor> </titleStmt> <editionStmt> <edition n="v1" type="current"> <date type="whenSubmitted">2019-11-08 17:02:42</date> <date type="whenModified">2019-11-19 18:18:59</date> <date type="whenReleased">2019-11-08 17:02:47</date> <date type="whenProduced">2019-09-25</date> <date type="whenEndEmbargoed">2019-11-08</date> <ref type="file" target="https://tel.archives-ouvertes.fr/tel-02356404/document"> <date notBefore="2019-11-08"></date> </ref> <ref type="file" subtype="author" n="1" target="https://tel.archives-ouvertes.fr/tel-02356404/file/TH2019GAYMARDALEXANDRE.pdf"> <date notBefore="2019-11-08"></date> </ref> </edition> <respStmt> <resp>contributor</resp> <name key="131274"> <persName> <forename>ABES</forename> <surname>STAR</surname> </persName> <email type="md5">f5aa7f563b02bb6adbba7496989af39a</email> <email type="domain">abes.fr</email> </name> </respStmt> </editionStmt> <publicationStmt> <distributor>CCSD</distributor> <idno type="halId">tel-02356404</idno> <idno type="halUri">https://tel.archives-ouvertes.fr/tel-02356404</idno> <idno type="halBibtex">gaymard:tel-02356404</idno> <idno type="halRefHtml">Virologie. Université de Lyon, 2019. Français. ⟨NNT : 2019LYSE1135⟩</idno> <idno type="halRef">Virologie. Université de Lyon, 2019. Français. ⟨NNT : 2019LYSE1135⟩</idno> </publicationStmt> <seriesStmt> <idno type="stamp" n="STAR">STAR - Dépôt national des thèses électroniques</idno> <idno type="stamp" n="ENS-LYON">École Normale Supérieure de Lyon</idno> <idno type="stamp" n="CNRS">CNRS - Centre national de la recherche scientifique</idno> <idno type="stamp" n="UNIV-LYON1">Université Claude Bernard - Lyon I</idno> <idno type="stamp" n="THESES_LYON1" corresp="UNIV-LYON1">Thèses Université Claude Bernard Lyon 1</idno> <idno type="stamp" n="CIRI-THESES" corresp="CIRI">CIRI-Thèses</idno> <idno type="stamp" n="CIRI" corresp="UNIV-LYON1">Centre International de Recherche en Infectiologie</idno> <idno type="stamp" n="UDL">UDL</idno> <idno type="stamp" n="UNIV-LYON">Université de Lyon</idno> <idno type="stamp" n="INSERM">INSERM - Institut national de la santé et de la recherche médicale</idno> </seriesStmt> <notesStmt></notesStmt> <sourceDesc> <biblStruct> <analytic> <title xml:lang="en">Study of the Influenza A virus susceptibility to neuraminidase inhibitors</title> <title xml:lang="fr">Étude et suivi de la résistance des virus influenzae A aux inhibiteurs de la neuraminidase</title> <author role="aut"> <persName> <forename type="first">Alexandre</forename> <surname>Gaymard</surname> </persName> <idno type="halauthorid">11306990</idno> <affiliation ref="#struct-222995"></affiliation> </author> </analytic> <monogr> <idno type="nnt">2019LYSE1135</idno> <imprint> <date type="dateDefended">2019-09-25</date> </imprint> <authority type="institution">Université de Lyon</authority> <authority type="school">École Doctorale Evolution Ecosystèmes Microbiologie Modélisation</authority> <authority type="supervisor">Vanessa Escuret</authority> <authority type="supervisor">Émilie Frobert</authority> <authority type="jury">Bruno Lina [Président]</authority> <authority type="jury">Jean-Luc Guérin [Rapporteur]</authority> <authority type="jury">Marie-Anne Rameix-Welti [Rapporteur]</authority> <authority type="jury">Florence Ader</authority> <authority type="jury">Jacques Gaillat</authority> </monogr> </biblStruct> </sourceDesc> <profileDesc> <langUsage> <language ident="fr">French</language> </langUsage> <textClass> <keywords scheme="author"> <term xml:lang="en">Influenza A virus</term> <term xml:lang="en">Oseltamivir susceptibility</term> <term xml:lang="en">H274Y substitution</term> <term xml:lang="en">E119V substitution</term> <term xml:lang="en">E119V+I222L substitution</term> <term xml:lang="en">R292K substitution</term> <term xml:lang="fr">Virus influenza A</term> <term xml:lang="fr">Résistance à l’oseltamivir</term> <term xml:lang="fr">Substitution H274Y</term> <term xml:lang="fr">Substitution E119V</term> <term xml:lang="fr">Substitution E119V+I222L</term> <term xml:lang="fr">Substitution R292K</term> </keywords> <classCode scheme="halDomain" n="sdv.mp.vir">Life Sciences [q-bio]/Microbiology and Parasitology/Virology</classCode> <classCode scheme="halTypology" n="THESE">Theses</classCode> </textClass> <abstract xml:lang="en"> <p>Influenza viruses are important human pathogens that are responsible for flu, whether seasonal, pandemic or zoonotic. Very few therapeutic options are available against these pathogens and neuraminidase inhibitors (NAI) are the only antiviral agents recommended by the WHO for treatment and prophylaxis of influenza virus infections. NAI resistance has already been described and the H274Y, E119V and R292K neuraminidase substitutions are the most frequently encountered substitutions responsible for oseltamivir resistance. During this work, we focused the NAI resistance study around two main objectives: first, we monitored clinical and biological resistance in treated patients and then we studied the impact of substitutions responsible for NAI resistance using avian neuraminidases. For NAI resistance monitoring, viral genomic diversity of a child's influenza A(H1N1)pdm09 was characterized in the context of a severe combined immunodeficiency and a chronic viral excretion despite antiviral treatment. For a better detection of H274Y substitution in A(H1N1) influenza viruses, a digital droplet PCR was developed and evaluated. At a more fundamental level, resistance substitutions (H274Y, R292K, E119V ± I222L) were analysed using all neuraminidase subtypes of influenza A viruses. To summarize, H274Y substitution is preferentially isolated in N1 but also decreases oseltamivir susceptibility in all group 1 neuraminidases (N1, N4, N5 and N8). The E119V substitution impact on oseltamivir susceptibility depends on the neuraminidase and decreases oseltamivir susceptibility especially within N2, N7, N9 and N5. Moreover, the E119V+I222L substitutions has a synergistic effect on oseltamivir resistance profile. The R292K substitution decreases all NAI susceptibility for all group 2 neuraminidases (N2, N3, N6, N7 and N9). The production of a recombinant N9 bearing the R292K substitution allows to highlight the substitution impact on the sialidasic activity. Development of new technological tools are still in progress to allow a more accurate analysis of the mechanisms that underlie the NAI resistance</p> </abstract> <abstract xml:lang="fr"> <p>Les virus influenzae sont des pathogènes importants ayant un impact à la fois écologique et en santé publique humaine. En effet chez l’Homme, ces virus sont responsables de la grippe, qu’elle soit saisonnière, pandémique ou zoonotique. Face à ces infections très peu d’options thérapeutiques sont disponibles : seuls les inhibiteurs de neuraminidases (INA) sont recommandés par l’OMS mais des résistances ont été décrites. Les substitutions H274Y, E119V et R292K sont les substitutions de résistance retrouvées le plus fréquemment dans les neuraminidases des virus influenzae humains. Dans notre travail, l’étude des résistances aux INA a été organisée autour de deux axes, d’une part via le suivi clinique et biologique de la résistance chez les patients et d’autre part via l’étude de l’impact des substitutions de résistance dans des neuraminidases aviaires. La surveillance de ces résistances au sein du CNR des virus des infections respiratoires a permis la caractérisation du génome de virus influenza A(H1N1)pdm09 dans un contexte d’excrétion chronique en présence d’un traitement par INA chez un patient atteint de déficit immunitaire combiné sévère mais aussi le développement et l’évaluation de la PCR digitale pour le diagnostic de la substitution H274Y des virus A(H1N1). Au niveau mécanistique, notre travail a permis l’analyse des substitutions (H274Y, R292K, E119V±I222L) sur l’ensemble des sous-types de neuraminidases des virus influenzae A. La substitution H274Y se retrouve préférentiellement dans les N1 mais est responsable d’une diminution de la sensibilité à l’oseltamivir pour toutes les neuraminidases du groupe 1 (N1, N4, N5 et N8). La substitution E119V entraine une diminution de la sensibilité à l’oseltamivir variable en fonction des neuraminidases avec un impact plus important pour les N2, N7, N9 et N5. De plus l’association des substitutions E119V+I222L entraine un effet synergique sur le phénotype de résistance à l’oseltamivir. Enfin la substitution R292K entraine une diminution de la sensibilité à tous les INA dans toutes les neuraminidases du groupe 2 (N2, N3, N6, N7 et N9). La production d’une N9 recombinante portant la substitution R292K a montré un impact majeur de la substitution sur l’activité enzymatique. Un développement technologique toujours en cours au laboratoire va nous permettre d’aller plus loin dans l’analyse des mécanismes qui sous-tendent l’apparition de ces résistances</p> </abstract> </profileDesc> </hal></record>Pour manipuler ce document sous Unix (Dilib)
EXPLOR_STEP=$WICRI_ROOT/Sante/explor/H2N2V1/Data/Hal/Checkpoint
HfdSelect -h $EXPLOR_STEP/biblio.hfd -nk 000007 | SxmlIndent | more
Ou
HfdSelect -h $EXPLOR_AREA/Data/Hal/Checkpoint/biblio.hfd -nk 000007 | SxmlIndent | more
Pour mettre un lien sur cette page dans le réseau Wicri
{{Explor lien
|wiki= Sante
|area= H2N2V1
|flux= Hal
|étape= Checkpoint
|type= RBID
|clé= Hal:tel-02356404
|texte= Study of the Influenza A virus susceptibility to neuraminidase inhibitors
}}
| This area was generated with Dilib version V0.6.33. |  |