Abstract
The anti-influenza therapeutic baloxavir targets cap-dependent endonuclease activity of polymerase acidic (PA) protein. We monitored baloxavir susceptibility in the United States with next generation sequencing analysis supplemented by phenotypic one-cycle infection assay. Analysis of PA sequences of 6,891 influenza A and B viruses collected during 2016/17 and 2017/18 seasons showed amino acid substitutions: I38L (two A(H1N1)pdm09 viruses), E23G (two A(H1N1)pdm09 viruses) and I38M (one A(H3N2) virus); conferring 4-10-fold reduced susceptibility to baloxavir.
Keywords:
Cap-dependent endonuclease inhibitor; drug resistance; influenza; influenza surveillance; next generation sequencing; phenotypic testing; polymerase acidic protein.
MeSH terms
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Amino Acid Substitution / drug effects*
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Amino Acid Substitution / genetics
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Antiviral Agents / pharmacology*
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Antiviral Agents / therapeutic use
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Dibenzothiepins
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Drug Resistance, Viral / genetics*
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Enzyme Inhibitors / pharmacology*
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Humans
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Influenza A Virus, H1N1 Subtype / genetics
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Influenza A Virus, H3N2 Subtype / drug effects*
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Influenza A Virus, H3N2 Subtype / genetics
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Influenza A Virus, H3N2 Subtype / isolation & purification
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Influenza B virus / drug effects*
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Influenza B virus / genetics
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Influenza B virus / isolation & purification
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Influenza, Human / drug therapy*
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Influenza, Human / epidemiology
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Influenza, Human / virology
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Microbial Sensitivity Tests
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Morpholines
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Oxazines / pharmacology*
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Pyridines / pharmacology*
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Pyridones
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Seasons
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Sentinel Surveillance
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Thiepins / pharmacology*
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Triazines / pharmacology*
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United States
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Viral Proteins / genetics
Substances
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Antiviral Agents
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Dibenzothiepins
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Enzyme Inhibitors
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Morpholines
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Oxazines
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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