A novel I117T substitution in neuraminidase of highly pathogenic avian influenza H5N1 virus conferring reduced susceptibility to oseltamivir and zanamivir

•NA gene sequencing of 67 HPAI H5N1 viruses revealed NA mutations in nine viruses.•A novel NA I117T mutation of HPAI H5N1 virus conferred resistance to NA inhibitors.•NAI susceptibility studied using fluorometric MUNANA assays and in ovo assays.•The I117T and I117V variants showed different levels o...

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Published in:Veterinary microbiology 2019-08, Vol.235, p.21-24
Main Authors: Kode, Sadhana S., Pawar, Shailesh D., Tare, Deeksha S., Keng, Sachin S., Hurt, Aeron C., Mullick, Jayati
Format: Article
Language:English
Subjects:
Amino acid substitution
Antiviral drugs
Antiviral resistance
Assaying
Avian flu
Cross-resistance
Disease resistance
Exo-a-sialidase
Fluorescence
H5N1
I117T substitution
In ovo assay
Inhibition
Mutation
Oseltamivir
Viruses
Zanamivir
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Summary:•NA gene sequencing of 67 HPAI H5N1 viruses revealed NA mutations in nine viruses.•A novel NA I117T mutation of HPAI H5N1 virus conferred resistance to NA inhibitors.•NAI susceptibility studied using fluorometric MUNANA assays and in ovo assays.•The I117T and I117V variants showed different levels of NAI susceptibility.•Natural occurrence of NAI-resistant I117T-mutant H5N1 virus is a cause of concern. Occurrence of avian influenza (AI) with Neuraminidase (NA) mutations which confer reduced neuraminidase inhibitor (NAI) susceptibility has remained a cause of concern. The susceptibility to NAIs of 67 highly pathogenic avian influenza H5N1 viruses isolated during 2006–2012 in India was tested in phenotypic fluorescence-based NA inhibition assay, sequence analysis and in ovo. One isolate showed a novel NA I117T amino acid substitution (N2 numbering) and eight isolates showed previously known NAI-resistance marker mutations (I117V, E119D, N294S, total 9/67). The overall incidence of resistant variants was 13.4%. The novel I117T substitution reduced oseltamivir susceptibility by 18.6-fold and zanamivir susceptibility by 11.8-fold, compared to the wild type AI H5N1virus, thus showed cross-resistance to both oseltamivir and zanamivir in NA inhibition assays. However, the other two isolates with I117V substitution were sensitive to both the NAIs. In addition, the comparison of growth of the I117T and I117V variants in presence of NAI’s in the in ovo assays exhibited difference in growth levels. The present study reports the natural occurrence of a novel I117T mutation in AI H5N1 virus conferring cross-resistance to oseltamivir and zanamivir highlighting the urgent need of antiviral surveillance of AI viruses.
ISSN:0378-1135
1873-2542
DOI:10.1016/j.vetmic.2019.06.005