Neuraminidase inhibitor susceptibility testing of influenza type B viruses in China during 2010 and 2011 identifies viruses with reduced susceptibility to oseltamivir and zanamivir

Wang, Dayang; Sleeman, Katrina; Huang, Weijuan; Nguyen, Ha; Levine, Marnie; Cheng, Yanhui; Li, Xiyan; Tan, Minju; Xing, Xiaohui; Xu, Xinhua; Klimov, Alexander; Gubareva, Larisa V.; Shu, Yuelong

doi:10.1016/j.antiviral.2012.12.013

Cited by 26 publications

(18 citation statements)

References 23 publications

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“…The capacity of the NAI-resistant influenza virus to efficiently transmit among humans can be an important indicator of fitness advantages (19). To date, only sporadic transmission of NAI-resistant influenza B viruses has been reported, with small clusters of viruses containing either the D198N, I222T, or I222V NA substitution being identified from Japan, China, or the United States, respectively (20)(21)(22)(23). Additionally, limited information about the consequence of NAI resistance-associated substitutions on the fitness of influenza B viruses is available from animal models.…”

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confidence: 99%

Competitive Fitness of Influenza B Viruses with Neuraminidase Inhibitor-Resistant Substitutions in a Coinfection Model of the Human Airway Epithelium

Burnham

Armstrong

Webster

et al. 2015

J Virol

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Influenza A and B viruses are human pathogens that are regarded to cause almost equally significant disease burdens. Neuraminidase (NA) inhibitors (NAIs) are the only class of drugs available to treat influenza A and B virus infections, so the development of NAI-resistant viruses with superior fitness is a public health concern. The fitness of NAI-resistant influenza B viruses has not been widely studied. Here we examined the replicative capacity and relative fitness in normal human bronchial epithelial (NHBE) cells of recombinant influenza B/Yamanashi/166/1998 viruses containing a single amino acid substitution in NA generated by reverse genetics (rg) that is associated with NAI resistance. The replication in NHBE cells of viruses with reduced inhibition by oseltamivir (recombinant virus with the E119A mutation generated by reverse genetics [rg-E119A], rg-D198E, rg-I222T, rg-H274Y, rg-N294S, and rg-R371K, N2 numbering) or zanamivir (rg-E119A and rg-R371K) failed to be inhibited by the presence of the respective NAI. In a fluorescence-based assay, detection of rg-E119A was easily masked by the presence of NAI-susceptible virus. We coinfected NHBE cells with NAI-susceptible and -resistant viruses and used next-generation deep sequencing to reveal the order of relative fitness compared to that of recombinant wild-type (WT) virus generated by reverse genetics (rg-WT): rg-H274Y > rg-WT > rg-I222T > rg-N294S > rg-D198E > rg-E119A Ͼ Ͼ rg-R371K. Based on the lack of attenuated replication of rg-E119A in NHBE cells in the presence of oseltamivir or zanamivir and the fitness advantage of rg-H274Y over rg-WT, we emphasize the importance of these substitutions in the NA glycoprotein. Human infections with influenza B viruses carrying the E119A or H274Y substitution could limit the therapeutic options for those infected; the emergence of such viruses should be closely monitored. Annual vaccination is an effective method for controlling influenza disease. The current FDA-approved quadrivalent seasonal influenza vaccine includes both antigenically distinct hemagglutinin (HA) lineages of influenza B virus (i.e., Yamagata and Victoria) (8, 9). Antiviral treatment is another option for the control of influenza, and the neuraminidase (NA) inhibitors (NAIs) are currently the only class of antivirals approved for prophylaxis and treatment of influenza B virus infections. NAIs limit influenza

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confidence: 99%

Competitive Fitness of Influenza B Viruses with Neuraminidase Inhibitor-Resistant Substitutions in a Coinfection Model of the Human Airway Epithelium

Burnham

Armstrong

Webster

et al. 2015

J Virol

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“…For example, substitutions at residue 222 confer reduced susceptibility in N1, N2, and type B viruses (18,19). The amino acid substitutions at residue 222 of NA are varied, including substitutions of I222T/V in type B, I222V/ M/T/R in N1, and I222V in N2 (18)(19)(20)(21)(22)(23)(24)(25), and these exhibit varied effects on the enzymatic properties of NA and NAI susceptibility. They emerged either naturally or after oseltamivir treatment or prophylaxis.…”

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confidence: 99%

A Conformational Restriction in the Influenza A Virus Neuraminidase Binding Site by R152 Results in a Combinational Effect of I222T and H274Y on Oseltamivir Resistance

Huang

Cao

Zhou

et al. 2014

Antimicrob Agents Chemother

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cThe I222K, I222R, and I222T substitutions in neuraminidase (NA) have been found in clinically derived 2009 pandemic influenza A/H1N1 viruses with altered susceptibilities to NA inhibitors (NAIs). The effects of these substitutions, together with the most frequently observed resistance-related substitution, H274Y, on viral fitness and resistance mechanisms were further investigated in this study. Reduced sensitivities to oseltamivir were observed in all three mutants (I222K, I222R, and I222T). 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. 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 binding pocket, which otherwise only subtends the residue substitution of H274Y. 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. The relative growth advantage of the I222T mutant versus the I222K mutant and the higher frequency of I222T emerging in N1 subtype influenza viruses raise concerns necessitating close monitoring of the dual substitutions I222T and H274Y.

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“…Apart from the H274Y-associated OS-resistant variants, other NA substitutions conferring reduced or highly reduced sensitivity to NAIs have been reported to be clinically relevant. These substitutions conferred distinctive levels of susceptibility to NAIs and have been found to be NA subtype specific: in human H1N1 (Q136K, S246N, and I222R/V), H3N2 (E119V, Q136K, and N294S), H5N1 (N294S), and type B (E105K, R152K, D198N, I222T, N294S, and R371K) viruses (10,(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26).…”

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confidence: 99%

Unique Determinants of Neuraminidase Inhibitor Resistance among N3, N7, and N9 Avian Influenza Viruses

Song

Marathe

Kumar

et al. 2015

J Virol

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Human infections with avian influenza viruses are a serious public health concern. The neuraminidase (NA) inhibitors (NAIs) are the frontline anti-influenza drugs and are the major option for treatment of newly emerging influenza. Therefore, it is essential to identify the molecular markers of NAI resistance among specific NA subtypes of avian influenza viruses to help guide clinical management. NAI-resistant substitutions in NA subtypes other than N1 and N2 have been poorly studied. Here, we identified NA amino acid substitutions associated with NAI resistance among influenza viruses of N3, N7, and N9 subtypes which have been associated with zoonotic transmission. We applied random mutagenesis and generated recombinant influenza viruses carrying single or double NA substitution(s) with seven internal genes from A/Puerto Rico/8/1934 (H1N1) virus. In a fluorescencebased NA inhibition assay, we identified three categories of NA substitutions associated with reduced inhibition by NAIs (oseltamivir, zanamivir, and peramivir): (i) novel subtype-specific substitutions in or near the enzyme catalytic site (R152W, A246T, and D293N, N2 numbering), (ii) subtype-independent substitutions (E119G/V and/or D and R292K), and (iii) substitutions previously reported in other subtypes (Q136K, I222M, and E276D). Our data show that although some markers of resistance are present across NA subtypes, other subtype-specific markers can only be determined empirically. IMPORTANCE The number of humans infected with avian influenza viruses is increasing, raising concerns of the emergence of avian influenza viruses resistant to neuraminidase (NA) inhibitors (NAIs).Since most studies have focused on NAI-resistance in human influenza viruses, we investigated the molecular changes in NA that could confer NAI resistance in avian viruses grown in immortalized monolayer cells, especially those of the N3, N7, and N9 subtypes, which have caused human infections. We identified not only numerous NAI-resistant substitutions previously reported in other NA subtypes but also several novel changes conferring reduced susceptibility to NAIs, which are subtype specific. The findings indicate that some resistance markers are common across NA subtypes, but other markers need to be determined empirically for each subtype. The study also implies that antiviral surveillance monitoring could play a critical role in the clinical management of influenza virus infection and an essential component of pandemic preparedness.

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Neuraminidase inhibitor susceptibility testing of influenza type B viruses in China during 2010 and 2011 identifies viruses with reduced susceptibility to oseltamivir and zanamivir

Cited by 26 publications

References 23 publications

Competitive Fitness of Influenza B Viruses with Neuraminidase Inhibitor-Resistant Substitutions in a Coinfection Model of the Human Airway Epithelium

Competitive Fitness of Influenza B Viruses with Neuraminidase Inhibitor-Resistant Substitutions in a Coinfection Model of the Human Airway Epithelium

A Conformational Restriction in the Influenza A Virus Neuraminidase Binding Site by R152 Results in a Combinational Effect of I222T and H274Y on Oseltamivir Resistance

Unique Determinants of Neuraminidase Inhibitor Resistance among N3, N7, and N9 Avian Influenza Viruses

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