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. 2014 Feb 18;9(2):e89306.
doi: 10.1371/journal.pone.0089306. eCollection 2014.

Study of oseltamivir and zanamivir resistance-related mutations in influenza viruses isolated from wild mallards in Sweden

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Study of oseltamivir and zanamivir resistance-related mutations in influenza viruses isolated from wild mallards in Sweden

Goran Orozovic et al. PLoS One. .

Abstract

Resistance to neuraminidase inhibitors (NAIs) is a growing problem in battle against influenza A virus. However, little is known about the resistance of viruses isolated from dabbling ducks, the natural reservoir of the influenza virus. To our knowledge, no low-pathogenic avian influenza (LPAI) virus resistant to NAIs has been detected. The aim of this study was to investigate mallard isolates of influenza A virus previously identified to carry oseltamivir carboxylate (OC) or zanamivir (ZA) resistance-related mutations. In this work, 21 viruses belonging to the N1, N3, N6 and N9 subtypes were analyzed using a colorimetric NA inhibition assay. The results of assay showed no NAIs-resistant phenotype for any of the viruses. The R118K mutation was the most recurrent, as it was observed in all subtypes except for N6. IC50 values confirmed the differences in sensitivity to OC or ZA observed in the N1 and N2 groups of NAs. Furthermore, both wild types (WTs) in the N6 and one WT in the N9 subtype were less sensitive to ZA than were genotypically related mutants with R152K and R118K change in the respective subtypes. This may indicate that these and probably even other NAIs resistance-related mutations found in our virus collection were not induced by NAIs residuals in the environment and that the impact of such mutations in an avian influenza could be dependent on subtype, strain and host species.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Sequence alignment of N2 reference, and three N1 sensitive mutants.
The sequence interval between the 121th and 149th amino acid (marked with - - - ; N2 reference numbering) is excluded from alignment for practical reasons. The relevant mutation sites are indicated in red. (r) - reference sequence; Number within the parenthesis indicate code for virus isolates according Table 2. (3) - H1N1 R118K mutant; (4) - H1N1 R118K/D151N mutant; (14) - H6N1 R118K/D151N/D198N mutant. Cl.Co- ClustalW consensus sequence, “*” is used to indicate identical residues, “:” is used to indicate conserved substitution, “.” is used to indicate semi-conserved substitution, “ ” (empty space) is used to indicate dissimilar residues.
Figure 2
Figure 2. IC50 values of viral isolates analyzed by CM.
Each bar shows mean ± SE IC50 of three replicates. The x-axis shows the viral isolates. NxI and NxII represent wild types (WTs) and 1–14 represent mutants. For codes of enumeration, see Table 2. z – inhibition by ZA; o – inhibition by OC. On the y-axis, the IC50 values are expressed as concentration of inhibitor in nM. All means were tested by one-way ANOVA and post-hoc Tukey tests. A) N1 subtype; B) N3 subtype; C) N6 subtype and D) N9 subtype.

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