The I222V Neuraminidase Mutation Has a Compensatory Role in Replication of an Oseltamivir-Resistant Influenza Virus A/H3N2 E119V Mutant

Simon, Philippe; Holder, Benjamin P.; Bouhy, Xavier; Abed, Yacine; Beauchemin, C.; Boivin, Guy

doi:10.1128/jcm.01732-10

Cited by 40 publications

(35 citation statements)

References 17 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Moreover, our group has previously described the recovery of an oseltamivir-resistant influenza A/H3N2 virus harboring the I222V (I223V in N1 numbering) mutation in combination with E119V from an immunocompromised patient undergoing oseltamivir therapy (3). In these studies, the I223V substitution was found to alter the resistance phenotype, with a negative effect on replication kinetics of A/H5N1 viruses but improved viral fitness in the A/H3N2 subtype (3,16,32,36). The impact of amino acid changes at residue I223 has FIG 2 Seroconversion rates in ferrets infected with recombinant wild-type (WT), H275Y, and I223V-H275Y pH1N1 viruses.…”

Section: Discussionmentioning

confidence: 99%

Impact of Mutations at Residue I223 of the Neuraminidase Protein on the Resistance Profile, Replication Level, and Virulence of the 2009 Pandemic Influenza Virus

Pizzorno

Abed

Bouhy

et al. 2012

Antimicrob Agents Chemother

Self Cite

View full text Add to dashboard Cite

Amino acid substitutions at residue I223 of the neuraminidase (NA) protein have been identified in 2009 pandemic influenza (pH1N1) variants with altered susceptibilities to NA inhibitors (NAIs). We used reverse genetics and site-directed mutagenesis to generate the recombinant A/Québec/144147/09 pH1N1 wild-type virus (WT) and five (I223R, I223V, H275Y, I223V-H275Y, and I223R-H275Y) NA mutants. A fluorimetry-based assay was used to determine 50% inhibitory concentrations (IC 50 s) of oseltamivir, zanamivir, and peramivir. Replicative capacity was analyzed by viral yield assays in ST6GalI-MDCK cells. Infectivity and transmission of the WT, H275Y, and I223V-H275Y recombinant viruses were evaluated in ferrets. As expected, the H275Y mutation conferred resistance to oseltamivir (982-fold) and peramivir (661-fold) compared to the drug-susceptible recombinant WT. The single I223R mutant was associated with reduced susceptibility to oseltamivir (53-fold), zanamivir (7-fold) and peramivir (10-fold), whereas the I223V virus had reduced susceptibility to oseltamivir (6-fold) only. Interestingly, enhanced levels of resistance to oseltamivir and peramivir and reduced susceptibility to zanamivir (1,647-, 17,347-, and 16-fold increases in IC 50 s, respectively) were observed for the I223R-H275Y recombinant, while the I223V-H275Y mutant exhibited 1,733-, 2,707-, and 2-fold increases in respective IC 50 s. The I223R and I223V changes were associated with equivalent or higher viral titers in vitro compared to the recombinant WT. Infectivity and transmissibility in ferrets were comparable between the recombinant WT and the H275Y or I223V-H275Y recombinants. In conclusion, amino acid changes at residue I223 may alter the NAI susceptibilities of pH1N1 variants without compromising fitness. Consequently, I223R and I223V mutations, alone or with H275Y, need to be thoroughly monitored.

show abstract

Section: Discussionmentioning

confidence: 99%

Impact of Mutations at Residue I223 of the Neuraminidase Protein on the Resistance Profile, Replication Level, and Virulence of the 2009 Pandemic Influenza Virus

Pizzorno

Abed

Bouhy

et al. 2012

Antimicrob Agents Chemother

Self Cite

View full text Add to dashboard Cite

show abstract

“…For example, the altered receptor-binding avidity and lower replication resulting from the antigenic escape mutation HA K165E in A/Puerto Rico/8/1934 (H1N1) could be compensated for by mutations in HA or the neuraminidase (NA) (15,16), and stabilizing mutations were required to occur prior to the introduction of immune-escape mutations in influenza A/H3N2 virus (17). Similarly, there are numerous examples where antiviral resistance-conferring mutations come at a fitness cost for the virus but can be compensated for by other mutations: several neuraminidase substitutions can occur and have occurred as either permissive or compensatory mutations to counteract the adverse fitness effects of the oseltamivir resistance mutation NA H275Y in influenza A/H1N1 virus (18)(19)(20), and similarly, the I222V NA mutation in influenza A/H3N2 virus partially restored the viral fitness-decreasing oseltamivir resistance mutation NA E119V (21).…”

mentioning

confidence: 99%

Expected Effect of Deleterious Mutations on Within-Host Adaptation of Pathogens

Fonville

2015

J Virol

View full text Add to dashboard Cite

Adaptation is a common theme in both pathogen emergence, for example, in zoonotic cross-species transmission, and pathogen control, where adaptation might limit the effect of the immune response and antiviral treatment. When such evolution requires deleterious intermediate mutations, fitness ridges and valleys arise in the pathogen's fitness landscape. The effect of deleterious intermediate mutations on within-host pathogen adaptation is examined with deterministic calculations, appropriate for pathogens replicating in large populations with high error rates. The effect of deleterious intermediate mutations on pathogen adaptation is smaller than their name might suggest: when two mutations are required and each individual single mutation is fully deleterious, the pathogen can jump across the fitness valley by obtaining two mutations at once, leading to a proportion of adapted mutants that is 20-fold lower than that in the situation where the fitness of all mutants is neutral. The negative effects of deleterious intermediates are typically substantially smaller and outweighed by the fitness advantages of the adapted mutant. Moreover, requiring a specific mutation order has a substantially smaller effect on pathogen adaptation than the effect of all intermediates being deleterious. These results can be rationalized when the number of routes of mutation available to the pathogen is calculated, providing a simple approach to estimate the effect of deleterious mutations. The calculations discussed here are applicable when the effect of deleterious mutations on the within-host adaptation of pathogens is assessed, for example, in the context of zoonotic emergence, antigenic escape, and drug resistance. IMPORTANCEAdaptation is critical for pathogens after zoonotic transmission into a new host species or to achieve antigenic immune escape and drug resistance. Using a deterministic approach, the effects of deleterious intermediate mutations on pathogen adaptation were calculated while avoiding commonly made simplifications that do not apply to large pathogen populations replicating with high mutation rates. Perhaps unexpectedly, pathogen adaptation does not halt when the intermediate mutations are fully deleterious. The negative effects of deleterious mutations are substantially outweighed by the fitness gains of adaptation. To gain an understanding of the effect of deleterious mutations on pathogen adaptation, a simple approach that counts the number of routes available to the pathogen with and without deleterious intermediate mutations is introduced. This methodology enables a straightforward calculation of the proportion of the pathogen population that will cross a fitness valley or traverse a fitness ridge, without reverting to more complicated mathematical models. The fitness landscape of a pathogen is likely to have a rugged shape and consist of multiple optima. Reductions in fitness occur when underlying combinations of genetic mutations lead to an unfit or deleterious phenotype, creating depressions in the...

show abstract

“…There are three complementary approaches to address these limitations: improving genetic prediction of biological traits, improving assays of these traits, and improving animal models of human transmission; all approaches are currently progressing in parallel (Holder et al, 2011; Simon et al, 2011). The first approach aims to further refine our understanding of sequence-to-trait relationships by continued studies of diverse, naturally or artificially produced mutations and their effects on the traits of interest.…”

Section: Discussionmentioning

confidence: 99%

Viral factors in influenza pandemic risk assessment

Lipsitch

Barclay

Raman

et al. 2016

eLife

View full text Add to dashboard Cite

The threat of an influenza A virus pandemic stems from continual virus spillovers from reservoir species, a tiny fraction of which spark sustained transmission in humans. To date, no pandemic emergence of a new influenza strain has been preceded by detection of a closely related precursor in an animal or human. Nonetheless, influenza surveillance efforts are expanding, prompting a need for tools to assess the pandemic risk posed by a detected virus. The goal would be to use genetic sequence and/or biological assays of viral traits to identify those non-human influenza viruses with the greatest risk of evolving into pandemic threats, and/or to understand drivers of such evolution, to prioritize pandemic prevention or response measures. We describe such efforts, identify progress and ongoing challenges, and discuss three specific traits of influenza viruses (hemagglutinin receptor binding specificity, hemagglutinin pH of activation, and polymerase complex efficiency) that contribute to pandemic risk.DOI: http://dx.doi.org/10.7554/eLife.18491.001

show abstract

The I222V Neuraminidase Mutation Has a Compensatory Role in Replication of an Oseltamivir-Resistant Influenza Virus A/H3N2 E119V Mutant

Cited by 40 publications

References 17 publications

Impact of Mutations at Residue I223 of the Neuraminidase Protein on the Resistance Profile, Replication Level, and Virulence of the 2009 Pandemic Influenza Virus

Impact of Mutations at Residue I223 of the Neuraminidase Protein on the Resistance Profile, Replication Level, and Virulence of the 2009 Pandemic Influenza Virus

Expected Effect of Deleterious Mutations on Within-Host Adaptation of Pathogens

Viral factors in influenza pandemic risk assessment

Contact Info

Product

Resources

About