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      A novel E198K substitution in the PA gene of influenza A virus with reduced susceptibility to baloxavir acid

      brief-report
      Author(s): 1 , , 2
      Publication date (Electronic):
      Journal: Archives of Virology
      Publisher: Springer Vienna

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          Abstract

          Baloxavir acid (BXA), the active compound in baloxavir marboxil (BXM), reduces the propagation of influenza A and B viruses by inhibiting the cap-dependent endonuclease activity of the polymerase acidic (PA) subunit. Although BXM has been used to treat influenza virus infections, recently, there has been general concern about the emergence of viruses with low susceptibility to BXA. Here, we identified a novel PA subunit substitution, PA E198K, that reduced susceptibility to BXA. The IC 50 of BXA toward influenza A viruses containing PA E198K increased approximately 2- to 6-fold. These findings help to understand the mechanism by which PA substitutions reduce susceptibility to BXA.

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          SWISS-MODEL: homology modelling of protein structures and complexes

          Andrew Waterhouse, Martino Bertoni, Stefan Bienert … (2018)
          Abstract Homology modelling has matured into an important technique in structural biology, significantly contributing to narrowing the gap between known protein sequences and experimentally determined structures. Fully automated workflows and servers simplify and streamline the homology modelling process, also allowing users without a specific computational expertise to generate reliable protein models and have easy access to modelling results, their visualization and interpretation. Here, we present an update to the SWISS-MODEL server, which pioneered the field of automated modelling 25 years ago and been continuously further developed. Recently, its functionality has been extended to the modelling of homo- and heteromeric complexes. Starting from the amino acid sequences of the interacting proteins, both the stoichiometry and the overall structure of the complex are inferred by homology modelling. Other major improvements include the implementation of a new modelling engine, ProMod3 and the introduction a new local model quality estimation method, QMEANDisCo. SWISS-MODEL is freely available at https://swissmodel.expasy.org.
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            The cap-snatching endonuclease of influenza virus polymerase resides in the PA subunit.

            Alexandre Dias, Denis Bouvier, Thibaut Crépin … (2009)
            The influenza virus polymerase, a heterotrimer composed of three subunits, PA, PB1 and PB2, is responsible for replication and transcription of the eight separate segments of the viral RNA genome in the nuclei of infected cells. The polymerase synthesizes viral messenger RNAs using short capped primers derived from cellular transcripts by a unique 'cap-snatching' mechanism. The PB2 subunit binds the 5' cap of host pre-mRNAs, which are subsequently cleaved after 10-13 nucleotides by the viral endonuclease, hitherto thought to reside in the PB2 (ref. 5) or PB1 (ref. 2) subunits. Here we describe biochemical and structural studies showing that the amino-terminal 209 residues of the PA subunit contain the endonuclease active site. We show that this domain has intrinsic RNA and DNA endonuclease activity that is strongly activated by manganese ions, matching observations reported for the endonuclease activity of the intact trimeric polymerase. Furthermore, this activity is inhibited by 2,4-dioxo-4-phenylbutanoic acid, a known inhibitor of the influenza endonuclease. The crystal structure of the domain reveals a structural core closely resembling resolvases and type II restriction endonucleases. The active site comprises a histidine and a cluster of three acidic residues, conserved in all influenza viruses, which bind two manganese ions in a configuration similar to other two-metal-dependent endonucleases. Two active site residues have previously been shown to specifically eliminate the polymerase endonuclease activity when mutated. These results will facilitate the optimisation of endonuclease inhibitors as potential new anti-influenza drugs.
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              Viral Loads and Duration of Viral Shedding in Adult Patients Hospitalized with Influenza

              Nelson Lee, Paul K S Chan, David S. C. Hui … (2009)
              Abstract BackgroundThe goal of this study was to characterize viral loads and factors affecting viral clearance in persons with severe influenza MethodsThis was a 1-year prospective, observational study involving consecutive adults hospitalized with influenza. Nasal and throat swabs were collected at presentation, then daily until 1 week after symptom onset. Real-time reverse-transcriptase polymerase chain reaction to determine viral RNA concentration and virus isolation were performed. Viral RNA concentration was analyzed using multiple linear or logistic regressions or mixed-effect models ResultsOne hundred forty-seven inpatients with influenza A (H3N2) infection were studied (mean age ± standard deviation, 72±16 years). Viral RNA concentration at presentation positively correlated with symptom scores and was significantly higher than that among time-matched outpatients (control subjects). Patients with major comorbidities had high viral RNA concentration even when presenting >2 days after symptom onset (mean ± standard deviation, 5.06±1.85 vs 3.62±2.13 log10 copies/mL; P=.005; β, +0.86 [95% confidence interval, +0.03 to +1.68]). Viral RNA concentration demonstrated a nonlinear decrease with time; 26% of oseltamivir-treated and 57% of untreated patients had RNA detected at 1 week after symptom onset. Oseltamivir started on or before symptom day 4 was independently associated with an accelerated decrease in viral RNA concentration (mean β [standard error], −1.19 [0.43] and −0.68 [0.33] log10 copies/mL for patients treated on day 1 and days 2–3, respectively; P<.05) and viral RNA clearance at 1 week (odds ratio, 0.10 [95% confidence interval, 0.03–0.35] and 0.30 [0.10–0.90] for patients treated on day 1–2 and day 3–4, respectively). Conversely, major comorbidities and systemic corticosteroid use for asthma or chronic obstructive pulmonary disease exacerbations were associated with slower viral clearance. Viral RNA clearance was associated with a shorter hospital stay (7.0 vs 13.5 days; P=.001) ConclusionPatients hospitalized with severe influenza have more active and prolonged viral replication. Weakened host defenses slow viral clearance, whereas antivirals started within the first 4 days of illness enhance viral clearance
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                Author and article information

                Contributors
                Naoki Takizawa:
                ORCID: http://orcid.org/0000-0002-3714-2219
                takizawan@bikaken.or.jp
                Journal
                Journal ID (nlm-ta): Arch Virol
                Journal ID (iso-abbrev): Arch Virol
                Title: Archives of Virology
                Publisher: Springer Vienna (Vienna )
                ISSN (Print): 0304-8608
                ISSN (Electronic): 1432-8798
                Publication date (Electronic): 5 May 2022
                Pages: 1-6
                Affiliations
                [1 ]GRID grid.418798.b, ISNI 0000 0000 9187 2234, Laboratory of Virology, , Institute of Microbial Chemistry (BIKAKEN), ; 3-14-23 Kamiosaki, Shinagawa-ku, Tokyo, 141-0021 Japan
                [2 ]GRID grid.410786.c, ISNI 0000 0000 9206 2938, Satoshi Ōmura Memorial Research Institute and Graduate School for Infection Control, , Kitasato University, ; 5-9-1 Shirokane, Minato-ku, Tokyo, 108-8641 Japan
                Author notes

                Handling Editor: Carolina Scagnolari.

                Author information
                http://orcid.org/0000-0002-3714-2219
                Article
                Publisher ID: 5456
                DOI: 10.1007/s00705-022-05456-0
                PMC ID: 9069958
                PubMed ID: 35511288
                SO-VID: 8b0cacd4-479f-40e8-bde1-54b90f22e534
                Copyright © © The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature 2022
                License:

                This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.

                History
                Date received : 12 October 2021
                Date accepted : 23 March 2022
                Categories
                Subject: Brief Report

                ScienceOpen disciplines: Microbiology & Virology
                Data availability:
                ScienceOpen disciplines: Microbiology & Virology

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