Recovery of Influenza B Virus with the H273Y Point Mutation in the Neuraminidase Active Site from a Human Patient

Higgins, Rachel R.; Beniprashad, Melissa; Chong-King, Eddie; Li, Yan; Bastien, Nathalie; Low, Donald E.; Gubbay, Jonathan B.

doi:10.1128/jcm.00682-12

Cited by 22 publications

(12 citation statements)

References 17 publications

(17 reference statements)

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“…The emergence of influenza B viruses with the H274Y substi- tution was reported in a patient with no known previous antiviral treatment (69) and from surveillance studies (57 (70)(71)(72). Only by the addition of secondary permissive NA substitutions was viral fitness restored for seasonal H1N1 influenza A viruses, leading to their spread worldwide (73)(74)(75).…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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 B viruses with these NA amino acid substitutions have been identified from patients prior to initiating antiviral treatment (23,71,72) and provide epidemiological evidence that these viruses can replicate efficiently in the absence of drug selection pressure. Importantly, oseltamivir therapy was ineffective in a 7-year-old immunocompromised patient infected with influenza B virus carrying the NA N294S amino acid substitution as virus was shed for 25 days (72).…”

Section: Discussionmentioning

confidence: 99%

Fitness Costs for Influenza B Viruses Carrying Neuraminidase Inhibitor-Resistant Substitutions: Underscoring the Importance of E119A and H274Y

Burnham

Baranovich

Marathe

et al. 2014

Antimicrob Agents Chemother

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Influenza B viruses cause annual outbreaks of respiratory illness in humans and are increasingly recognized as a major cause of influenza-associated pediatric mortality. Neuraminidase (NA) inhibitors (NAIs) are the only available therapy for patients infected with influenza B viruses, and the potential emergence of NAI-resistant viruses is a public health concern. The NA substitutions located within the enzyme active site could not only reduce NAI susceptibility of influenza B virus but also affect virus fitness. In this study, we investigated the effect of single NA substitutions on the fitness of influenza B/Yamanashi/166/1998 viruses (Yamagata lineage). We generated recombinant viruses containing either wild-type (WT) NA or NA with a substitution in the catalytic (R371K) or framework (E119A, D198E, D198Y, I222T, H274Y, and N294S) residues. We assessed NAI susceptibility, NA biochemical properties, NA protein expression, and virus replication in vitro and in differentiated normal human bronchial epithelial (NHBE) cells. 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. All NA substitutions, except for D198Y and R371K, were genetically stable after seven passages in MDCK cells. Cell surface NA protein expression was significantly increased by H274Y and N294S substitutions. Viruses with the E119A, I222T, H274Y, or N294S substitution were not attenuated in replication efficiency in vitro or in NHBE cells. Overall, viruses with the E119A or H274Y NA substitution possess fitness comparable to NAI-susceptible virus, and the acquisition of these substitutions by influenza B viruses should be closely monitored.

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“…Influenza B viruses with reduced susceptibility to NAIs have been identified in patients before initiation of antiviral therapy and without any known exposure to the drug (Carr et al, 2011; Fujisaki et al, 2012; Hatakeyama et al, 2007; Higgins et al, 2012) (Table 1). To date, clinical studies have identified influenza B viruses carrying NA mutations either in the framework (D198N, I222T, H274Y, and N294S) (Carr et al, 2011; Hatakeyama et al, 2007; Higgins et al, 2012) or in close proximity to the enzyme active site (E105K and S250G) (Fujisaki et al, 2012; Hatakeyama et al, 2007).…”

Section: Nai Resistance Among Influenza B Virusesmentioning

confidence: 99%

“…To date, clinical studies have identified influenza B viruses carrying NA mutations either in the framework (D198N, I222T, H274Y, and N294S) (Carr et al, 2011; Hatakeyama et al, 2007; Higgins et al, 2012) or in close proximity to the enzyme active site (E105K and S250G) (Fujisaki et al, 2012; Hatakeyama et al, 2007). One common feature of these reports has been the isolation of viruses with NAI resistance-associated mutations from other close household contacts infected with influenza B and treated with antiviral drugs.…”

Section: Nai Resistance Among Influenza B Virusesmentioning

confidence: 99%

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Neuraminidase inhibitors for influenza B virus infection: Efficacy and resistance

2013

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Many aspects of the biology and epidemiology of influenza B viruses are far less studied than for influenza A viruses, and one of these aspects is effectiveness and resistance to the clinically available antiviral drugs, the neuraminidase (NA) inhibitors (NAIs). Acute respiratory infections are one of the leading causes of death in children and adults, and influenza is among the few respiratory infections that can be prevented and treated by vaccination and antiviral treatment. Recent data has suggested that influenza B virus infections are of specific concern to pediatric patients because of the increased risk of severe disease. Treatment of influenza B is a challenging task for the following reasons: NAIs (e.g., oseltamivir and zanamivir) are the only FDA-approved class of antivirals available for treatment;the data suggest that oseltamivir is less effective than zanamivir in pediatric patients;zanamivir is not prescribed to patients younger than 7;influenza B viruses are less susceptible than influenza A viruses to NAIs in vitro;although the level of resistance to NAIs is low, the number of different molecular markers of resistance is higher than for influenza A viruses, and they are not well defined;the relationship between levels of NAI phenotypic resistance and known molecular markers, frequency of emergence, transmissibility, and fitness of NAI-resistant variants are not well established. This review presents current knowledge of the effectiveness of NAIs for influenza B virus and antiviral resistance in clinical, surveillance, and experimental studies.

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Recovery of Influenza B Virus with the H273Y Point Mutation in the Neuraminidase Active Site from a Human Patient

Cited by 22 publications

References 17 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

Fitness Costs for Influenza B Viruses Carrying Neuraminidase Inhibitor-Resistant Substitutions: Underscoring the Importance of E119A and H274Y

Neuraminidase inhibitors for influenza B virus infection: Efficacy and resistance

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