I222 Neuraminidase mutations further reduce oseltamivir susceptibility of Indonesian Clade 2.1 highly pathogenic Avian Influenza A(H5N1) viruses.
We have tested the susceptibility to neuraminidase inhibitors of 155 clade 2.1 H5N1 viruses from Indonesia, isolated between 2006-2008 as well as 12 clade 1 isolates from Thailand and Cambodia from 2004-2007 using a fluorometric MUNANA-based enzyme inhibition assay. The Thailand and Cambodian clade...
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2013-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3679007?pdf=render |
| _version_ | 1819021728975683584 |
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| author | Jennifer L McKimm-Breschkin Susan Barrett Pudjiatmoko Muhammad Azhar Frank Y K Wong Paul Selleck Peter G Mohr James McGrane Mia Kim |
| author_facet | Jennifer L McKimm-Breschkin Susan Barrett Pudjiatmoko Muhammad Azhar Frank Y K Wong Paul Selleck Peter G Mohr James McGrane Mia Kim |
| author_sort | Jennifer L McKimm-Breschkin |
| collection | DOAJ |
| description | We have tested the susceptibility to neuraminidase inhibitors of 155 clade 2.1 H5N1 viruses from Indonesia, isolated between 2006-2008 as well as 12 clade 1 isolates from Thailand and Cambodia from 2004-2007 using a fluorometric MUNANA-based enzyme inhibition assay. The Thailand and Cambodian clade 1 isolates tested here were all susceptible to oseltamivir and zanamivir, and sequence comparison indicated that reduced oseltamivir susceptibility we observed previously with clade 1 Cambodian isolates correlated with an S246G neuraminidase mutation. Eight Indonesian viruses (5%), all bearing I222 neuraminidase mutations, were identified as mild to extreme outliers for oseltamivir based on statistical analysis by box plots. IC50s were from 50 to 500-fold higher than the reference clade 1 virus from Viet Nam, ranging from 43-75 nM for I222T/V mutants and from 268-349 nM for I222M mutants. All eight viruses were from different geographic locales; all I222M variants were from central Sumatra. None of the H5N1 isolates tested demonstrated reduced susceptibility to zanamivir (IC50s all <5 nM). All I222 mutants showed loss of slow binding specifically for oseltamivir in an IC50 kinetics assay. We identified four other Indonesian isolates with higher IC50s which also demonstrated loss of slow binding, including one virus with an I117V mutation. There was a minimal effect on the binding of zanamivir and peramivir for all isolates tested. As H5N1 remains a potential pandemic threat, the incidence of mutations conferring reduced oseltamivir susceptibility is concerning and emphasizes the need for greater surveillance of drug susceptibility. |
| first_indexed | 2024-12-21T04:11:43Z |
| format | Article |
| id | doaj.art-765dc59d6ec147399eda427731667790 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-21T04:11:43Z |
| publishDate | 2013-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-765dc59d6ec147399eda4277316677902022-12-21T19:16:26ZengPublic Library of Science (PLoS)PLoS ONE1932-62032013-01-0186e6610510.1371/journal.pone.0066105I222 Neuraminidase mutations further reduce oseltamivir susceptibility of Indonesian Clade 2.1 highly pathogenic Avian Influenza A(H5N1) viruses.Jennifer L McKimm-BreschkinSusan BarrettPudjiatmokoMuhammad AzharFrank Y K WongPaul SelleckPeter G MohrJames McGraneMia KimWe have tested the susceptibility to neuraminidase inhibitors of 155 clade 2.1 H5N1 viruses from Indonesia, isolated between 2006-2008 as well as 12 clade 1 isolates from Thailand and Cambodia from 2004-2007 using a fluorometric MUNANA-based enzyme inhibition assay. The Thailand and Cambodian clade 1 isolates tested here were all susceptible to oseltamivir and zanamivir, and sequence comparison indicated that reduced oseltamivir susceptibility we observed previously with clade 1 Cambodian isolates correlated with an S246G neuraminidase mutation. Eight Indonesian viruses (5%), all bearing I222 neuraminidase mutations, were identified as mild to extreme outliers for oseltamivir based on statistical analysis by box plots. IC50s were from 50 to 500-fold higher than the reference clade 1 virus from Viet Nam, ranging from 43-75 nM for I222T/V mutants and from 268-349 nM for I222M mutants. All eight viruses were from different geographic locales; all I222M variants were from central Sumatra. None of the H5N1 isolates tested demonstrated reduced susceptibility to zanamivir (IC50s all <5 nM). All I222 mutants showed loss of slow binding specifically for oseltamivir in an IC50 kinetics assay. We identified four other Indonesian isolates with higher IC50s which also demonstrated loss of slow binding, including one virus with an I117V mutation. There was a minimal effect on the binding of zanamivir and peramivir for all isolates tested. As H5N1 remains a potential pandemic threat, the incidence of mutations conferring reduced oseltamivir susceptibility is concerning and emphasizes the need for greater surveillance of drug susceptibility.http://europepmc.org/articles/PMC3679007?pdf=render |
| spellingShingle | Jennifer L McKimm-Breschkin Susan Barrett Pudjiatmoko Muhammad Azhar Frank Y K Wong Paul Selleck Peter G Mohr James McGrane Mia Kim I222 Neuraminidase mutations further reduce oseltamivir susceptibility of Indonesian Clade 2.1 highly pathogenic Avian Influenza A(H5N1) viruses. PLoS ONE |
| title | I222 Neuraminidase mutations further reduce oseltamivir susceptibility of Indonesian Clade 2.1 highly pathogenic Avian Influenza A(H5N1) viruses. |
| title_full | I222 Neuraminidase mutations further reduce oseltamivir susceptibility of Indonesian Clade 2.1 highly pathogenic Avian Influenza A(H5N1) viruses. |
| title_fullStr | I222 Neuraminidase mutations further reduce oseltamivir susceptibility of Indonesian Clade 2.1 highly pathogenic Avian Influenza A(H5N1) viruses. |
| title_full_unstemmed | I222 Neuraminidase mutations further reduce oseltamivir susceptibility of Indonesian Clade 2.1 highly pathogenic Avian Influenza A(H5N1) viruses. |
| title_short | I222 Neuraminidase mutations further reduce oseltamivir susceptibility of Indonesian Clade 2.1 highly pathogenic Avian Influenza A(H5N1) viruses. |
| title_sort | i222 neuraminidase mutations further reduce oseltamivir susceptibility of indonesian clade 2 1 highly pathogenic avian influenza a h5n1 viruses |
| url | http://europepmc.org/articles/PMC3679007?pdf=render |
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