Abstract: Viruses with H274Y, E119V and E119G mutations demonstrated faster dissociation of the inhibitor to which they were resistant.
Method: Stocks of the following viruses were grown in Madin Darby Canine Kidney Cells, (MDCK): A/Mississippi/03/01 H1N1 wild type and oseltamivir resistant H274Y mutant,, A/Fukui/45/04 H3N2 wild type and E119V oseltamivir resistant mutant, B/Perth/211/01 influenza B wild type and D197E mutant with decreased susceptibility to all NAIs, NWS/G70C H1N9 wild type and E119G mutant with decreased susceptibility to zanamivir and peramivir.
Result: For the H1N1 H274Y, H3N2 E119V
Dynamic residue interaction network analysis of the oseltamivir binding site of N1 neuraminidase and its H274Y mutation site conferring drug resistance in influenza A virus.
PMID: 24566185
2014
Antimicrobial agents and chemotherapy
Abstract: Cell surface NA protein expression was significantly increased by H274Y and N294S substitutions.
Abstract: Our results showed that four NA substitutions (D198E, I222T, H274Y, and N294S) conferred reduced inhibition by oseltamivir and three (E119A, D198Y, and R371K) conferred highly reduced inhibition by oseltamivir, zanamivir, and peramivir.
Abstract: Overall, viruses with the E119A or H274Y NA substitution possess fitness comparable to NAI-
Study of oseltamivir and zanamivir resistance-related mutations in influenza viruses isolated from wild mallards in Sweden.
Method: The literature describing NAI resistance mutations has been reviewed, whereupon nine OC (V116A, I117V, E119V, D198N, I222V, H274Y, R292K, N
Discussion: For example, the OC resistance-related mutation H274Y (N2 numbering) in pandemic H1N1 A/Osaka/180/2009 resulted in IC50 of 93.9, 1,048.2 and 1,333.8 nM analyzed by CL, FL or CM assay respectively.
Discussion: In the case of H5N1 2.2 A/Turkey/15/06 recombinant virus and inhibition by OC the IC50 for E119A, H274Y and N294S were 236.5, 6308.0 and 424.2 nM respectively (FL assay).
Dynamic residue interaction network analysis of the oseltamivir binding site of N1 neuraminidase and its H274Y mutation site conferring drug resistance in influenza A virus.
PMID: 24366752
2014
Antimicrobial agents and chemotherapy
Abstract: Furthermore, the I222K and I222T substitutions had a combinational effect of further increasing resistance in the presence of H274Y, which might result from a conformational restriction in the NA binding site.
Abstract: Moreover, significantly attenuated NA function and viral growth abilities were found in the I222K+H274Y double mutant, while the I222T+H274Y double mutant exhibited slightly delayed growth but had a peak viral titer similar to that of the wild-type virus in MDCK cells.
Abstract: Of note, by using molecular dynamics simulations, R152, the neighbor of T222, was observed to translate to a position closer to T222, resulting in the narrowing of the
Evolution of the influenza A virus genome during development of oseltamivir resistance in vitro.
Abstract: Following drug treatment, the H274Y resistance mutation fixed reproducibly within the population.
Abstract: In addition, once evolved, the H274Y mutation persisted after the withdrawal of the drug, even when not fixed in viral populations.
Abstract: The presence of the H274Y mutation in the viral population, at either a low or a high frequency, led to measurable changes in the neuraminidase inhibition assay.
Abstract: We conclude that only selection of H274Y is required for oseltamivir resistance and that H274Y is not deleterious in the absence of the drug.
Abstract: While the neighboring K248E mutation was also a target of positive selection prior to H274Y fixation,
Neuraminidase inhibitor susceptibility profile of pandemic and seasonal influenza viruses during the 2009-2010 and 2010-2011 influenza seasons in Japan.
Abstract: Among influenza A(H1N1)pdm09 viruses, the prevalence of H274Y viruses increased from 0% in the 2009-2010 season to 3% in the 2010-2011 season.
Abstract: For paired samples that were collected before and after drug treatment, three (3/11; 27.3%) H274Y viruses were identified among A(H1N1)pdm09 viruses after oseltamivir treatment but no outliers were found in the laninamivir-treatment group (n=3).
Abstract: These H274Y viruses were resistant to oseltamivir and peramivir with 200-300 fold increase in IC50 values but remained sensitive to zanamivir and laninamivir.
Functional and structural analysis of influenza virus neuraminidase N3 offers further insight into the mechanisms of oseltamivir resistance.
Abstract: Furthermore, we found that members of NA serotype N3 also possess Y252, raising the key question as to whether or not H274Y resistance may also be possible for some group 2 NAs.
Abstract: Here, we demonstrate that the H274Y substitution results in mild oseltamivir resistance for N3.
Abstract: However, H274Y has only been reported in N1 subtypes, which indicates that there must be additional key residues that determine H274Y resistance.
Abstract: Previous structural studies suggest that the group specific 252 residue (Y252 in group 1 and T252 in group 2) might be a key factor underlying H274Y resistance.
Abstract: The influenza virus neuraminidase PMID: 23860768
2013
mBio
Discussion: Surveillance studies suggest that the emergence of NA mutations conferring resistance to NA inhibitors has reportedly been low, with the exception of the naturally emergent H274Y NA mutation in H1N1 seasonal influenza viruses during the influenza season of 2007 to 2008.
Resistance mutation R292K is induced in influenza A(H6N2) virus by exposure of infected mallards to low levels of oseltamivir.
Abstract: We previously demonstrated that an influenza A(H1N1) virus
Discussion: It is possible that the additional mutations D113N or D141N in NA and/or E216K in HA might have influenced such an adaptation, like permissive mutations have been demonstrated in N1 virus that can compensate for the resistance mutation H274Y.
Discussion: We do however argue that there are reasons to take our results into environmental account as the threshold for resistance development could lie anywhere between 1.2 and 12 microg/L and as seen in our previous experiment with an A(H1N1) virus the resistance mutation (H274Y) was detected at 1 microg/L in only two samples; a similar resistance development could have been missed in the present, shorter experiment.
Synergistic combinations of favipiravir and oseltamivir against wild-type pandemic and oseltamivir-resistant influenza A virus infections in mice.
Discussion: In this report we used a wild-type (oseltamivirsensitive) pandemic H1N1 and oseltamivir-resistant H274Y seasonal H1N1 virus infections in mice for evaluating drug combination efficacy.
IV mutation literature information.
PMID: 
2014
Antiviral research
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