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Genomic diversity of oseltamivir-resistant influenza virus A (H1N1), Luxembourg, 2007-08.

Gerloff NA, Kremer JR, Mossong J, Opp M, Muller CP - Emerging Infect. Dis. (2009)

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The prevalence of oseltamivir-resistant influenza viruses A (H1N1) (ORVs) increased dramatically worldwide during the winter of 2007–08... On the PB2 amino acid level, all OSVs and the resistant outlier LNS-365 shared Pro453, whereas all ORV encoded serine at the same position (Ser453)... All published PB2 sequences for influenza virus (H1N1) strains collected since 1918 (n = 720) encoded either Pro453 or His453... There was no amino acid mutation in any of the other genes that segregated in the same way between ORVs and OSVs other than Ser453 (PB2)... Like many other subclade 2C strains, which were recently identified, this virus encoded the amantadine-resistance marker Asn31 in the matrix 2 protein... Although we did not identify any reassortments between ORVs and OSVs, double-resistant strains may result from co-circulation of amantadine-resistant and ORVs in the same region... In 98 clinical specimens (78 sensitive and 20 resistant strains) no minority alleles were reliably detected above the 3% threshold of the assay... Six OSVs with values between 2.1% and 2.9% were further analyzed by cloning of partial NA genes... No evidence of ORVs was found (Tyr275) in 227 clones... In summary, we have described amino acid markers in NA (Gly354) and PB2 (Ser453) proteins, which were present in ORVs but absent in all OSVs from Luxembourg in 2007–08... ORVs without this background did not spread as efficiently and were rarely found in Europe... We speculate that the unexpected fitness of the 2007–08 influenza viruses (H1N1) may be caused by a new genetic background that is most likely encoded in the PB2 gene.

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Phylogeny of A) neuraminidase (NA, complete gene) and B) polymerase complex 2 (C-terminal 1,300 nt) genes for selected influenza viruses A (H1N1) from Luxembourg and other countries. Subclades are identified to the right of each tree. The best-approximating model of nucleotide evolution was the general time reversible model with a gamma rate distribution and this model was used for the Bayesian analysis. Markov chain Monte Carlo sampling was implemented in MrBayes version 3 (8). In all cases, 6 chains with at least 4 million generations were calculated (10% burn-in removed). At least 2 independent runs of each analysis were performed. Posterior probabilities (indicated on important nodes) of the consensus tree topologies were estimated by sampling likelihood parameters every 125 generations. Boldface indicates sequences of oseltamivir-resistant influenza viruses A (H1N1) with the Tyr275 mutation in NA. In MEGA version 4, a neighbor-joining tree with 10,000 replicates was generated to calculate bootstrap values, shown in italics on the node dividing resistant and sensitive strains. Scale bars indicate nucleotide substitutions per site. The trees are rooted on A/New Caledonia/01/1999 and A/BrevigMission/1918 (indicated by arrows).
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Figure 1: Phylogeny of A) neuraminidase (NA, complete gene) and B) polymerase complex 2 (C-terminal 1,300 nt) genes for selected influenza viruses A (H1N1) from Luxembourg and other countries. Subclades are identified to the right of each tree. The best-approximating model of nucleotide evolution was the general time reversible model with a gamma rate distribution and this model was used for the Bayesian analysis. Markov chain Monte Carlo sampling was implemented in MrBayes version 3 (8). In all cases, 6 chains with at least 4 million generations were calculated (10% burn-in removed). At least 2 independent runs of each analysis were performed. Posterior probabilities (indicated on important nodes) of the consensus tree topologies were estimated by sampling likelihood parameters every 125 generations. Boldface indicates sequences of oseltamivir-resistant influenza viruses A (H1N1) with the Tyr275 mutation in NA. In MEGA version 4, a neighbor-joining tree with 10,000 replicates was generated to calculate bootstrap values, shown in italics on the node dividing resistant and sensitive strains. Scale bars indicate nucleotide substitutions per site. The trees are rooted on A/New Caledonia/01/1999 and A/BrevigMission/1918 (indicated by arrows).

Mentions: Among 140 viruses, 34 strains (24.3%) had the oseltamivir-resistant genotype (Tyr275) in the NA gene. Bayesian analyses of NA genes showed that ORVs formed a distinct cluster supported by high posterior probability (1.00) on the common node (Figure). One resistant strain (LNS-365) was more closely related to OSVs (minimal Kimura distance 0.3%, 4 nt) than to ORVs (minimal Kimura distance 0.5%, 6 nt). In NA protein, 33 ORVs showed the common Asp354Gly substitution in addition to the Tyr275 mutation. The resistant outlier LNS-365 encoded Asp354 like all other OSVs (n = 106). Similarly, only 4 other resistant strains from Europe from the same season shared Asp354 with all 2007–08 sensitive influenza virus (H1N1) strains (n = 251) available in public databases.


Genomic diversity of oseltamivir-resistant influenza virus A (H1N1), Luxembourg, 2007-08.

Gerloff NA, Kremer JR, Mossong J, Opp M, Muller CP - Emerging Infect. Dis. (2009)

Phylogeny of A) neuraminidase (NA, complete gene) and B) polymerase complex 2 (C-terminal 1,300 nt) genes for selected influenza viruses A (H1N1) from Luxembourg and other countries. Subclades are identified to the right of each tree. The best-approximating model of nucleotide evolution was the general time reversible model with a gamma rate distribution and this model was used for the Bayesian analysis. Markov chain Monte Carlo sampling was implemented in MrBayes version 3 (8). In all cases, 6 chains with at least 4 million generations were calculated (10% burn-in removed). At least 2 independent runs of each analysis were performed. Posterior probabilities (indicated on important nodes) of the consensus tree topologies were estimated by sampling likelihood parameters every 125 generations. Boldface indicates sequences of oseltamivir-resistant influenza viruses A (H1N1) with the Tyr275 mutation in NA. In MEGA version 4, a neighbor-joining tree with 10,000 replicates was generated to calculate bootstrap values, shown in italics on the node dividing resistant and sensitive strains. Scale bars indicate nucleotide substitutions per site. The trees are rooted on A/New Caledonia/01/1999 and A/BrevigMission/1918 (indicated by arrows).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2819849&req=5

Figure 1: Phylogeny of A) neuraminidase (NA, complete gene) and B) polymerase complex 2 (C-terminal 1,300 nt) genes for selected influenza viruses A (H1N1) from Luxembourg and other countries. Subclades are identified to the right of each tree. The best-approximating model of nucleotide evolution was the general time reversible model with a gamma rate distribution and this model was used for the Bayesian analysis. Markov chain Monte Carlo sampling was implemented in MrBayes version 3 (8). In all cases, 6 chains with at least 4 million generations were calculated (10% burn-in removed). At least 2 independent runs of each analysis were performed. Posterior probabilities (indicated on important nodes) of the consensus tree topologies were estimated by sampling likelihood parameters every 125 generations. Boldface indicates sequences of oseltamivir-resistant influenza viruses A (H1N1) with the Tyr275 mutation in NA. In MEGA version 4, a neighbor-joining tree with 10,000 replicates was generated to calculate bootstrap values, shown in italics on the node dividing resistant and sensitive strains. Scale bars indicate nucleotide substitutions per site. The trees are rooted on A/New Caledonia/01/1999 and A/BrevigMission/1918 (indicated by arrows).
Mentions: Among 140 viruses, 34 strains (24.3%) had the oseltamivir-resistant genotype (Tyr275) in the NA gene. Bayesian analyses of NA genes showed that ORVs formed a distinct cluster supported by high posterior probability (1.00) on the common node (Figure). One resistant strain (LNS-365) was more closely related to OSVs (minimal Kimura distance 0.3%, 4 nt) than to ORVs (minimal Kimura distance 0.5%, 6 nt). In NA protein, 33 ORVs showed the common Asp354Gly substitution in addition to the Tyr275 mutation. The resistant outlier LNS-365 encoded Asp354 like all other OSVs (n = 106). Similarly, only 4 other resistant strains from Europe from the same season shared Asp354 with all 2007–08 sensitive influenza virus (H1N1) strains (n = 251) available in public databases.

View Article: PubMed Central - PubMed

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

The prevalence of oseltamivir-resistant influenza viruses A (H1N1) (ORVs) increased dramatically worldwide during the winter of 2007–08... On the PB2 amino acid level, all OSVs and the resistant outlier LNS-365 shared Pro453, whereas all ORV encoded serine at the same position (Ser453)... All published PB2 sequences for influenza virus (H1N1) strains collected since 1918 (n = 720) encoded either Pro453 or His453... There was no amino acid mutation in any of the other genes that segregated in the same way between ORVs and OSVs other than Ser453 (PB2)... Like many other subclade 2C strains, which were recently identified, this virus encoded the amantadine-resistance marker Asn31 in the matrix 2 protein... Although we did not identify any reassortments between ORVs and OSVs, double-resistant strains may result from co-circulation of amantadine-resistant and ORVs in the same region... In 98 clinical specimens (78 sensitive and 20 resistant strains) no minority alleles were reliably detected above the 3% threshold of the assay... Six OSVs with values between 2.1% and 2.9% were further analyzed by cloning of partial NA genes... No evidence of ORVs was found (Tyr275) in 227 clones... In summary, we have described amino acid markers in NA (Gly354) and PB2 (Ser453) proteins, which were present in ORVs but absent in all OSVs from Luxembourg in 2007–08... ORVs without this background did not spread as efficiently and were rarely found in Europe... We speculate that the unexpected fitness of the 2007–08 influenza viruses (H1N1) may be caused by a new genetic background that is most likely encoded in the PB2 gene.

Show MeSH
Related in: MedlinePlus