Neuraminidase of 2007–2008 Influenza A(H1N1) Viruses Shows Increased Affinity for Sialic Acids Due to the D344N Substitution

Rameix‐Welti, Marie‐Anne; Munier, Sandie; Gal, Sébastien Le; Cuvelier, Frédérique; Agou, Fabrice; Enouf, Vincent; Naffakh, Nadia; Werf, Sylvie van der

doi:10.3851/imp1804

Cited by 37 publications

(34 citation statements)

References 22 publications

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“…This finding has been previously reported in a study investigating the NA enzymatic properties of seasonal H1N1 virus (54) and also identified the D344N substitution among H1N1 viruses circulating in 2007-2008 as the major determinant for increased affinity to sialic acids (55). The uniqueness of Brisbane-like NA has been described in other studies, including the identification of secondary mutations (4) or epistatic mutations (39) that may restore the NA function upon acquisition of the H275Y NA mutation.…”

Section: Discussionmentioning

confidence: 54%

Comparable Fitness and Transmissibility between Oseltamivir-Resistant Pandemic 2009 and Seasonal H1N1 Influenza Viruses with the H275Y Neuraminidase Mutation

Wong

Choy

Chan

et al. 2012

J Virol

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Limited antiviral compounds are available for the control of influenza, and the emergence of resistant variants would further narrow the options for defense. The H275Y neuraminidase (NA) mutation, which confers resistance to oseltamivir carboxylate, has been identified among the seasonal H1N1 and 2009 pandemic influenza viruses; however, those H275Y resistant variants demonstrated distinct epidemiological outcomes in humans. Specifically, dominance of the H275Y variant over the oseltamivir-sensitive viruses was only reported for a seasonal H1N1 variant during 2008-2009. Here, we systematically analyze the effect of the H275Y NA mutation on viral fitness and transmissibility of A(H1N1)pdm09 and seasonal H1N1 influenza viruses. The NA genes from A(H1N1)pdm09 A/California/04/09 (CA04), seasonal H1N1 A/New Caledonia/20/1999 (NewCal), and A/Brisbane/59/2007 (Brisbane) were individually introduced into the genetic background of CA04. The H275Y mutation led to reduced NA enzyme activity, an increased K m for 3′-sialylactose or 6′-sialylactose, and decreased infectivity in mucin-secreting human airway epithelial cells compared to the oseltamivir-sensitive wild-type counterparts. Attenuated pathogenicity in both RG-CA04 NA-H275Y and RG-CA04 × Brisbane NA-H275Y viruses was observed in ferrets compared to RG-CA04 virus, although the transmissibility was minimally affected. In parallel experiments using recombinant Brisbane viruses differing by hemagglutinin and NA, comparable direct contact and respiratory droplet transmissibilities were observed among RG-NewCal HA,NA , RG-NewCal HA,NA-H275Y , RG-Brisbane HA,NA-H275Y , and RG-NewCal HA × Brisbane NA-H275Y viruses. Our results demonstrate that, despite the H275Y mutation leading to a minor reduction in viral fitness, the transmission potentials of three different antigenic strains carrying this mutation were comparable in the naïve ferret model.

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Section: Discussionmentioning

confidence: 54%

Comparable Fitness and Transmissibility between Oseltamivir-Resistant Pandemic 2009 and Seasonal H1N1 Influenza Viruses with the H275Y Neuraminidase Mutation

Wong

Choy

Chan

et al. 2012

J Virol

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“…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). It was reported that the viruses involved in outbreaks of H274Y-containing H1N1pdm09 influenza A viruses possessed permissive secondary NA substitutions that also enhanced viral fitness (76,77).…”

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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“…Interestingly, the same NA H274Y amino acid substitution severely diminished the fitness of seasonal influenza A (H1N1) viruses (60). Only the accumulation of secondary permissive NA substitutions (R222Q, V234M, and D344N; N1 numbering) favored higher NA activity and affinity, increased NA cell surface expression, and restored virus fitness (13,61) (63)(64)(65). Indeed, of the five studies that passaged influenza B virus in the presence of a NAI, all five identified HA substitutions in addition to NAI resistance-associated NA substitutions (56-58, 66, 67).…”

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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Neuraminidase of 2007–2008 Influenza A(H1N1) Viruses Shows Increased Affinity for Sialic Acids Due to the D344N Substitution

Abstract: The D344N substitution, by modifying the enzymatic property of the N1, may have favoured the emergence and spread of viruses naturally resistant to oseltamivir.

Cited by 37 publications

References 22 publications

Comparable Fitness and Transmissibility between Oseltamivir-Resistant Pandemic 2009 and Seasonal H1N1 Influenza Viruses with the H275Y Neuraminidase Mutation

Comparable Fitness and Transmissibility between Oseltamivir-Resistant Pandemic 2009 and Seasonal H1N1 Influenza Viruses with the H275Y Neuraminidase Mutation

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

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