Phenotypic effects of substitutions within the receptor binding site of highly pathogenic avian influenza H5N1 observed during human infection.
Identifieur interne : 000172 ( Main/Exploration ); précédent : 000171; suivant : 000173Phenotypic effects of substitutions within the receptor binding site of highly pathogenic avian influenza H5N1 observed during human infection.
Auteurs : Dirk Eggink [Pays-Bas] ; Monique Spronken [Pays-Bas] ; Roosmarijn Van Der Woude [Pays-Bas] ; Jocynthe Buzink [Pays-Bas] ; Frederik Broszeit [Pays-Bas] ; Ryan Mcbride [États-Unis] ; Hana A. Pawestri [Indonésie] ; Vivi Setiawaty [Indonésie] ; James C. Paulson [États-Unis] ; Geert-Jan Boons [Pays-Bas] ; Ron A M. Fouchier [Pays-Bas] ; Colin A. Russell [Pays-Bas] ; Menno D. De Jong [Pays-Bas] ; Robert P. De Vries [Pays-Bas]Source :
- Journal of virology [ 1098-5514 ] ; 2020.
Abstract
Highly pathogenic avian influenza (HPAI) viruses are enzootic in wild birds and poultry and continue to cause human infections with high mortality. To date, more than 850 confirmed human cases of H5N1 virus infection have been reported, of which ∼60% were fatal. Global concern persists that these or similar avian influenza viruses will evolve into viruses that can transmit efficiently between humans, causing a severe influenza pandemic. It was shown previously that a change in receptor specificity is a hallmark for adaptation to humans and evolution towards a transmittable virus.Substantial genetic diversity was detected within the receptor binding site of hemagglutinin of HPAI A/H5N1 viruses, evolved during human infection, as detected by next generation sequencing. Here we investigated the functional impact of substitutions that were detected during these human infections. Upon rescue of 21 mutant viruses, most substitutions in the RBS resulted in viable virus, but virus replication, entry and stability were often impeded. None of the tested substitutions individually resulted in a clear switch in receptor preference as measured with modified red blood cells and glycan arrays. Although several combinations of the substitutions can lead to human-type receptor specificity, accumulation of multiple amino acid substitutions within a single hemagglutinin during human infection is rare, thus reducing the risk of virus adaptation to humans.IMPORTANCE H5 viruses continue to be a threat for public health. Because these viruses are immunologically novel to humans, they could spark a pandemic when adapted to transmit between humans. Avian influenza viruses need several adaptive mutations to bind to human-type receptors, increase HA stability, and replicate in human cells. However, knowledge on adaptive mutations during human infections is limited. A previous study showed substantial diversity within the receptor binding site of H5N1 during human infection. We therefore analyzed the observed amino acid changes phenotypically in a diverse set of assays, including virus replication, stability and receptor specificity. None of the tested substitutions resulted in a clear step towards a human adapted virus capable of aerosol transmission. It is notable that acquiring human-type receptor specificity needs multiple amino acid mutations, and that variability at key position 226 is not tolerated, reducing the risk of them being acquired naturally.
DOI: 10.1128/JVI.00195-20
PubMed: 32321815
Affiliations:
- Indonésie, Pays-Bas, États-Unis
- Californie, Hollande-Méridionale, Hollande-Septentrionale, Utrecht (province)
- Amsterdam, Rotterdam, Utrecht
- Université d'Utrecht
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Le document en format XML
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<front><div type="abstract" xml:lang="en">Highly pathogenic avian influenza (HPAI) viruses are enzootic in wild birds and poultry and continue to cause human infections with high mortality. To date, more than 850 confirmed human cases of H5N1 virus infection have been reported, of which ∼60% were fatal. Global concern persists that these or similar avian influenza viruses will evolve into viruses that can transmit efficiently between humans, causing a severe influenza pandemic. It was shown previously that a change in receptor specificity is a hallmark for adaptation to humans and evolution towards a transmittable virus.Substantial genetic diversity was detected within the receptor binding site of hemagglutinin of HPAI A/H5N1 viruses, evolved during human infection, as detected by next generation sequencing. Here we investigated the functional impact of substitutions that were detected during these human infections. Upon rescue of 21 mutant viruses, most substitutions in the RBS resulted in viable virus, but virus replication, entry and stability were often impeded. None of the tested substitutions individually resulted in a clear switch in receptor preference as measured with modified red blood cells and glycan arrays. Although several combinations of the substitutions can lead to human-type receptor specificity, accumulation of multiple amino acid substitutions within a single hemagglutinin during human infection is rare, thus reducing the risk of virus adaptation to humans.<b>IMPORTANCE</b>
H5 viruses continue to be a threat for public health. Because these viruses are immunologically novel to humans, they could spark a pandemic when adapted to transmit between humans. Avian influenza viruses need several adaptive mutations to bind to human-type receptors, increase HA stability, and replicate in human cells. However, knowledge on adaptive mutations during human infections is limited. A previous study showed substantial diversity within the receptor binding site of H5N1 during human infection. We therefore analyzed the observed amino acid changes phenotypically in a diverse set of assays, including virus replication, stability and receptor specificity. None of the tested substitutions resulted in a clear step towards a human adapted virus capable of aerosol transmission. It is notable that acquiring human-type receptor specificity needs multiple amino acid mutations, and that variability at key position 226 is not tolerated, reducing the risk of them being acquired naturally.</div>
</front>
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<affiliations><list><country><li>Indonésie</li>
<li>Pays-Bas</li>
<li>États-Unis</li>
</country>
<region><li>Californie</li>
<li>Hollande-Méridionale</li>
<li>Hollande-Septentrionale</li>
<li>Utrecht (province)</li>
</region>
<settlement><li>Amsterdam</li>
<li>Rotterdam</li>
<li>Utrecht</li>
</settlement>
<orgName><li>Université d'Utrecht</li>
</orgName>
</list>
<tree><country name="Pays-Bas"><region name="Hollande-Septentrionale"><name sortKey="Eggink, Dirk" sort="Eggink, Dirk" uniqKey="Eggink D" first="Dirk" last="Eggink">Dirk Eggink</name>
</region>
<name sortKey="Boons, Geert Jan" sort="Boons, Geert Jan" uniqKey="Boons G" first="Geert-Jan" last="Boons">Geert-Jan Boons</name>
<name sortKey="Broszeit, Frederik" sort="Broszeit, Frederik" uniqKey="Broszeit F" first="Frederik" last="Broszeit">Frederik Broszeit</name>
<name sortKey="Buzink, Jocynthe" sort="Buzink, Jocynthe" uniqKey="Buzink J" first="Jocynthe" last="Buzink">Jocynthe Buzink</name>
<name sortKey="De Jong, Menno D" sort="De Jong, Menno D" uniqKey="De Jong M" first="Menno D" last="De Jong">Menno D. De Jong</name>
<name sortKey="De Vries, Robert P" sort="De Vries, Robert P" uniqKey="De Vries R" first="Robert P" last="De Vries">Robert P. De Vries</name>
<name sortKey="Fouchier, Ron A M" sort="Fouchier, Ron A M" uniqKey="Fouchier R" first="Ron A M" last="Fouchier">Ron A M. Fouchier</name>
<name sortKey="Russell, Colin A" sort="Russell, Colin A" uniqKey="Russell C" first="Colin A" last="Russell">Colin A. Russell</name>
<name sortKey="Spronken, Monique" sort="Spronken, Monique" uniqKey="Spronken M" first="Monique" last="Spronken">Monique Spronken</name>
<name sortKey="Van Der Woude, Roosmarijn" sort="Van Der Woude, Roosmarijn" uniqKey="Van Der Woude R" first="Roosmarijn" last="Van Der Woude">Roosmarijn Van Der Woude</name>
</country>
<country name="États-Unis"><region name="Californie"><name sortKey="Mcbride, Ryan" sort="Mcbride, Ryan" uniqKey="Mcbride R" first="Ryan" last="Mcbride">Ryan Mcbride</name>
</region>
<name sortKey="Paulson, James C" sort="Paulson, James C" uniqKey="Paulson J" first="James C" last="Paulson">James C. Paulson</name>
</country>
<country name="Indonésie"><noRegion><name sortKey="Pawestri, Hana A" sort="Pawestri, Hana A" uniqKey="Pawestri H" first="Hana A" last="Pawestri">Hana A. Pawestri</name>
</noRegion>
<name sortKey="Setiawaty, Vivi" sort="Setiawaty, Vivi" uniqKey="Setiawaty V" first="Vivi" last="Setiawaty">Vivi Setiawaty</name>
</country>
</tree>
</affiliations>
</record>
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