Abstract
Susceptibility of influenza A viruses to baloxavir can be affected by changes at amino acid residue 38 in the polymerase acidic (PA) protein. Information on replicative fitness of PA-I38-substituted viruses remains sparse. We demonstrated that substitutions I38L/M/S/T not only had a differential effect on baloxavir susceptibility (9- to 116-fold) but also on in vitro replicative fitness. Although I38L conferred undiminished growth, other substitutions led to mild attenuation. In a ferret model, control viruses outcompeted those carrying I38M or I38T substitutions, although their advantage was limited. These findings offer insights into the attributes of baloxavir-resistant viruses needed for informed risk assessment.
Keywords:
baloxavir acid; drug resistance; ferret; influenza; polymerase acidic protein.
Published by Oxford University Press for the Infectious Diseases Society of America 2019.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Substitution
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Animals
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Antiviral Agents / therapeutic use*
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Dibenzothiepins
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Disease Models, Animal
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Dogs
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Drug Resistance, Viral / genetics*
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Ferrets
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High-Throughput Nucleotide Sequencing
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Influenza A Virus, H1N1 Subtype / genetics*
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Influenza A Virus, H3N2 Subtype / genetics*
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Madin Darby Canine Kidney Cells
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Male
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Microbial Sensitivity Tests
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Morpholines
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Orthomyxoviridae Infections / drug therapy*
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Orthomyxoviridae Infections / virology
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Oxazines / therapeutic use*
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Pyridines / therapeutic use*
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Pyridones
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RNA-Dependent RNA Polymerase / genetics
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Seasons
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Thiepins / therapeutic use*
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Treatment Outcome
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Triazines / therapeutic use*
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Viral Proteins / genetics
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Virus Replication / genetics*
Substances
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Antiviral Agents
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Dibenzothiepins
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Morpholines
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Oxazines
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PA protein, influenza viruses
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Pyridines
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Pyridones
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Thiepins
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Triazines
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Viral Proteins
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baloxavir
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RNA-Dependent RNA Polymerase