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Molecular Mechanisms Underlying Oseltamivir Resistance Mediated by an I117V Substitution in the Neuraminidase of Subtype H5N1 Avian Influenza A Viruses.
- Source :
- Journal of Infectious Diseases; Jan2013, Vol. 207 Issue 1, p89-97, 9p
- Publication Year :
- 2013
-
Abstract
- Background. The neuraminidase (NA) inhibitor oseltamivir is widely used to treat patients infected with influenza viruses. An Ile-to-Val change at position 117 in influenza A virus subtype H5N1 NA (NA-I117V) confers a reduction in susceptibility to oseltamivir carboxylate. However, the in vivo relevance and molecular basis of the decreased sensitivity mediated by this mutation are poorly understood.Methods. We created single-point-mutant viruses with 3 genetically different backgrounds (ie, 1 belonging to clade 1 and 2 belonging to clade 2.3.4) and evaluated the effects of the I117V mutation on oseltamivir susceptibility in vitro, in vivo, and in silico.Results. The NA-I117V mutation conferred a slight reduction in susceptibility to oseltamivir in vitro (1.3- to 6.3-fold changes), although it did not substantially compromise NA enzymatic activity. Mice infected with I117V virus exhibited reduced susceptibility to oseltamivir and decreased survival in 2 of 3 virus pairs tested. Molecular dynamics simulations revealed that I117V caused the loss of hydrogen bonds between an arginine at position 118 and the carboxyl group of oseltamivir, leading to a lower binding affinity for oseltamivir.Conclusions. Our findings provide new insight into the mechanism of NA-I117V–mediated oseltamivir resistance in highly pathogenic H5N1 avian influenza viruses. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 00221899
- Volume :
- 207
- Issue :
- 1
- Database :
- Complementary Index
- Journal :
- Journal of Infectious Diseases
- Publication Type :
- Academic Journal
- Accession number :
- 84556337
- Full Text :
- https://doi.org/10.1093/infdis/jis633