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J Infect Dis. 2014 Oct 15;210(8):1260-9. doi: 10.1093/infdis/jiu244. Epub 2014 May 3.

A novel I221L substitution in neuraminidase confers high-level resistance to oseltamivir in influenza B viruses.

Author information

1
Laboratoire de Virologie et Centre National de Référence virus influenzae Laboratoire Virpath EA4610, Faculté de Médecine Lyon Est, Université Claude Bernard Lyon 1, Université de Lyon, and.
2
Division of Virology.
3
Division of Virology Division of Molecular Structure.
4
WHO Collaborating Centre for Reference and Research on Influenza, Division of Virology, Medical Research Council National Institute for Medical Research, London, United Kingdom.
5
Laboratoire Virpath EA4610, Faculté de Médecine Lyon Est, Université Claude Bernard Lyon 1, Université de Lyon, and.
6
Genotyping of Pathogens and Public Health Platform, Institut Pasteur, Paris, France.
7
Division of Molecular Structure.
8
Service de Réanimation Pédiatrique, Hôpital Femme Mère Enfant, Groupement Hospitalier Est, Hospices Civils de Lyon, Bron.
9
Laboratoire de Virologie et Centre National de Référence virus influenzae.

Abstract

Influenza B viruses with a novel I221L substitution in neuraminidase (NA) conferring high-level resistance to oseltamivir were isolated from an immunocompromised patient after prolonged oseltamivir treatment.

METHODS:

Enzymatic characterization of the NAs (Km, Ki) and the in vitro fitness of viruses carrying wild-type or mutated (I221L) NA genes were evaluated. Proportions of wild-type and mutated NA genes were directly quantified in the patient samples. Structural characterizations by X-ray crystallography of a wild-type and I221L variant NA were performed.

RESULTS:

The Km and Ki revealed that the I221L variant NA had approximately 84 and 51 times lower affinity for oseltamivir carboxylate and zanamivir, respectively, compared with wild-type NA. Viruses with a wild-type or I221L variant NA had similar growth kinetics in Madin-Darby canine kidney (MDCK) cells, and 5 passages in MDCK cells revealed no reversion of the I221L substitution. The crystal structure of the I221L NA and oseltamivir complex showed that the leucine side chain protrudes into the hydrophobic pocket of the active site that accommodates the pentyloxy substituent of oseltamivir.

CONCLUSIONS:

Enzyme kinetic and NA structural analyses provide an explanation for the high level of resistance to oseltamivir while retaining good fitness of viruses carrying I221L variant NA.

KEYWORDS:

influenza B virus; neuraminidase substitution I221L; oseltamivir resistance

PMID:
24795482
PMCID:
PMC4176448
DOI:
10.1093/infdis/jiu244
[Indexed for MEDLINE]
Free PMC Article

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