Influenza A virus polymerase acidic protein E23R substitution is a marker of reduced susceptibility to baloxavir

In our ongoing efforts to identify baloxavir resistance markers, we demonstrated that the influenza A polymerase acidic (PA) protein E23R substitution is genetically stable, increases baloxavir EC50 values (13- to 19-fold vs. wild-type), synergizes with PA I38T, and only modestly decreases viral fitness. E23R is, therefore, a potential threat to baloxavir treatment efficacy.