Functional balance between neuraminidase and haemagglutinin in influenza viruses

Gaymard, Alexandre; Briand, Nolwenn; Frobert, Émilie; Lina, Bruno; Escuret, Vanessa

doi:10.1016/j.cmi.2016.07.007

Cited by 128 publications

(116 citation statements)

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“…When, measured, the IC50 values were mostly reduced inhibition, and some were normal inhibition, due to mixed genotypes (H275 & 275Y) and the use of the chemiluminescent assay. The resistant Brisbane H1N1 that emerged in 2008 was supposed to be related to structural changes in the backbone of the NA that facilitated (imposed) the introduction of 275Y in the NA pocket to maintain both virus fitness and HA‐NA balanced activities 11, 25. In our study, the frequency of detection of resistance due to a 275Y substitution gradually increased during the surveillance, but the limited number of cases makes any interpretation difficult.…”

Section: Discussionmentioning

confidence: 72%

Five years of monitoring for the emergence of oseltamivir resistance in patients with influenza A infections in the Influenza Resistance Information Study

Lina

Boucher

Osterhaus

et al. 2018

Influenza Resp Viruses

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Background and objectivesThe Influenza Resistance Information Study (IRIS) was initiated in 2008 to study the emergence of neuraminidase inhibitor (NAI) resistance and the clinical course of influenza in immunocompetent treated and untreated patients.MethodsPatients had throat/nose swabs collected on days 1, 3, 6 and 10 for analyses of influenza type, subtype and virus susceptibility to NAIs. RT‐PCR‐positive samples were cultured and tested for NAI resistance by specific RT‐PCR and phenotypic testing. Scores for influenza symptoms were recorded on diary cards (Days 1‐10). This study focuses on influenza A‐infected cases only.ResultsAmong 3230 RT‐PCR‐positive patients, 2316 had influenza A of whom 1216 received oseltamivir monotherapy within 2 days of symptom onset (9 seasonal H1N1; 662 H3N2; 545 H1N1pdm2009). Except for 9 patients with naturally resistant seasonal H1N1 (2008/9), no resistance was detected in Day 1 samples. Emergence of resistance (post‐Day 1) was detected in 43/1207 (3.56%) oseltamivir‐treated influenza A‐infected patients, with a higher frequency in 1‐ to 5‐year‐olds (11.8%) vs >5‐year‐olds (1.4%). All N1‐ and N2‐resistant viruses had H275Y (n = 27) or R292K (n = 16) substitutions, respectively. For 43 patients, virus clearance was significantly delayed vs treated patients with susceptible viruses (8.1 vs 10.9 days; P < .0001), and 11 (23.2%) remained RT‐PCR positive for influenza at Day 10. However, their symptoms resolved by Day 6 or earlier.ConclusionsOseltamivir resistance was only detected during antiviral treatment, with the highest incidence occurring among 1‐ to 5‐year‐olds. Resistance delayed viral clearance, but had no impact on symptom resolution.

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Section: Discussionmentioning

confidence: 72%

Five years of monitoring for the emergence of oseltamivir resistance in patients with influenza A infections in the Influenza Resistance Information Study

Lina

Boucher

Osterhaus

et al. 2018

Influenza Resp Viruses

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“…NA inhibitors such as oseltamivir (Tamiflu), zanamivir (Relenza) and peramivir (Rapivab) have been developed to treat influenza infections (Burnham et al 2013). Studies of drug-resistant influenza strains have demonstrated that a balance between the contrasting activities of HA and NA dictates viral growth, transmission and host adaptation (Baigent and McCauley 2001;Gaymard et al 2016b). For example, oseltamivirresistant strains isolated after 2007 exhibited a particular mutation in NA, which coexisted with a new variant of HA, leading to a virus with better "viral fitness" likely due to a readjusted HA-NA balance (Gaymard et al 2016a;Rameix-Welti et al 2008).…”

Section: Influenza Na's Ability To Cleave Sia On Host Cell Glycoconjumentioning

confidence: 99%

Sialylation of N-glycans: mechanism, cellular compartmentalization and function

Bhide

Colley

2016

Histochem Cell Biol

183

144

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Sialylated N-glycans play essential roles in the immune system, pathogen recognition and cancer. This review approaches the sialylation of N-glycans from three perspectives. The first section focuses on the sialyltransferases that add sialic acid to N-glycans. Included in the discussion is a description of these enzymes' glycan acceptors, conserved domain organization and sequences, molecular structure and catalytic mechanism. In addition, we discuss the protein interactions underlying the polysialylation of a select group of adhesion and signaling molecules. In the second section, the biosynthesis of sialic acid, CMP-sialic acid and sialylated N-glycans is discussed, with a special emphasis on the compartmentalization of these processes in the mammalian cell. The sequences and mechanisms maintaining the sialyltransferases and other glycosylation enzymes in the Golgi are also reviewed. In the final section, we have chosen to discuss processes in which sialylated glycans, both N- and O-linked, play a role. The first part of this section focuses on sialic acid-binding proteins including viral hemagglutinins, Siglecs and selectins. In the second half of this section, we comment on the role of sialylated N-glycans in cancer, including the roles of β1-integrin and Fas receptor N-glycan sialylation in cancer cell survival and drug resistance, and the role of these sialylated proteins and polysialic acid in cancer metastasis.

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“…Neuraminidase works in conjunction with the HA receptor of the influenza virus to infect and spread virus effectively [35, 36]. As such, studying the NA and HA proteins together is crucial to understanding viral evolution.…”

Section: Discussionmentioning

confidence: 99%

Neuraminidase antigenic drift of Influenza A virus H3N2 clade 3c.2a viruses alters virus replication, enzymatic activity and inhibitory antibody binding

Powell

Pekosz

2020

Preprint

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27 In the 2014-2015 influenza season a novel neuraminidase (NA) genotype emerged in 28 the Johns Hopkins Center of Excellence for Influenza Research and Surveillance (JH 29 CEIRS) surveillance network as well as globally. This novel genotype encoded a 30 glycosylation site at position 245-247 in the NA protein from clade 3c.2a H3N2 viruses.31 In the years following the 2014-2015 season, this novel NA glycosylation genotype 32 quickly dominated the human H3N2 population of viruses. To assess the effect this 33 novel glycosylation has on virus fitness and antibody binding, recombinant viruses with 34 (NA Gly+) or without (NA Gly-) the novel NA glycosylation were created. Viruses with 35 the 245 NA Gly+ genotype grew to a significantly lower infectious virus titer on primary, 36 differentiated human nasal epithelial cells (hNEC) compared to viruses with the 245 NA 37 Gly-genotype, but growth was similar on immortalized cells. The 245 NA Gly+ blocked 38 human and rabbit monoclonal antibodies that target the enzymatic site from binding to 39 their epitope. Additionally, viruses with the 245 NA Gly+ genotype had significantly 40 lower enzymatic activity compared to viruses with the 245 NA Gly-genotype. Human 41 monoclonal antibodies that target residues near the 245 NA glycosylation were less 42 effective at inhibiting NA enzymatic activity and virus replication of viruses encoding an 43 NA Gly+ protein compared to ones encoding NA Gly-protein. Additionally, a 44 recombinant H6N2 virus with the 245 NA Gly+ protein was more resistant to enzymatic 45 inhibition from convalescent serum from H3N2-infected humans compared to viruses 46 with the 245 NA Gly-genotype. Finally, the 245 NA Gly+ protected from NA antibody 47 mediated virus neutralization. These results suggest that while the 245 NA Gly+ 48 decreases virus replication in hNECs and decreases enzymatic activity, the 49 glycosylation blocks the binding of monoclonal and human serum NA specific antibodies 50 that would otherwise inhibit enzymatic activity and virus replication. Influenza virus infects millions of people worldwide and leads to thousands of deaths 74 and millions in economic loss each year. During the 2014/2015 season circulating 75 human H3N2 viruses acquired a novel mutation in the neuraminidase (NA) protein. This 76 mutation has since fixed in human H3N2 viruses. This mutation at position 245 through 77 247 in the amino acid sequence of NA encoded an N-linked glycosylation. Here, we 78 studied how this N-linked glycosylation impacts virus fitness and protein function. We 79 found that this N-linked glycosylation on the NA protein decreased viral replication 80 fitness on human nasal epithelial cells (hNEC) but not immortalized Madin-Darby 81 Canine Kidney (MDCK) cells. We also determined this glycosylation decreases NA 82 enzymatic activity, enzyme kinetics and affinity for substrate. Furthermore, we show that 83 this N-linked glycosylation at position 245 blocks some NA specific inhibitory antibodies 84 from binding to the protein, inhibiting enzyma...

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Functional balance between neuraminidase and haemagglutinin in influenza viruses

Cited by 128 publications

References 62 publications

Five years of monitoring for the emergence of oseltamivir resistance in patients with influenza A infections in the Influenza Resistance Information Study

Five years of monitoring for the emergence of oseltamivir resistance in patients with influenza A infections in the Influenza Resistance Information Study

Sialylation of N-glycans: mechanism, cellular compartmentalization and function

Neuraminidase antigenic drift of Influenza A virus H3N2 clade 3c.2a viruses alters virus replication, enzymatic activity and inhibitory antibody binding

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