Abstract: In 2019, influenza A(H3N2) viruses carrying an I38T substitution in the polymerase acidic gene, which confers reduced susceptibility to baloxavir, were detected in Japan in an infant without baloxavir exposure and a baloxavir-treated sibling.
Introduction: In January 2019, we detected a mutant influenza A(H3N2) virus carrying the PA I38T substitution from a hospitalized 5-year-old child who was not treated with baloxavir.
Introduction: In phase 2 and 3 clinical trials of baloxavir, treatment-emergent amino acid substitutions--I38T or I38F for influenza A(H1N1)pdm09 (pH1N1) virus and I38T or I38M for influenza A(H3N2) virus in the polymerase acidic (PA/I38T amino acid substitution associated with reduced baloxavir susceptibility.
Discussion: A previous study reported that influenza A/Victoria/3/75(H3N2) viruses with the PA I38T, I38M, or I38F substitutions showed less growth capability than the wild-type virus in cell culture.
Discussion: Although we could not obtain specimens from family members of either children, these observations could point to a possible transmission of the PA I38T mutant A(H3N2) viruses among humans.
Discussion: Among the 11 persons infected with PA I38T or I38M mutant A(H3N2) viruses in the 2018/19 season in Japan, all but one were children younger than 12 years.
Discussion: Deep sequencing analys
Detection of influenza A(H3N2) viruses exhibiting reduced susceptibility to the novel cap-dependent endonuclease inhibitor baloxavir in Japan, December 2018.
Discussion: During the Phase II trial, the PA I38T and I38F substitutions emerged after baloxavir treatment in four (3.6%) of 112 A(H1N1)pdm09 viruses isolated from adults aged 20-64 years.
Discussion: Furthermore, influenza A/Victoria/3/75(H3N2) viruses with the PA I38T or I38M substitutions showed 56.6- and 13.8-fold higher EC50 values, respectively.
Discussion: Furthermore, our sequencing analysis revealed that these two PA I38T mutant viruses possessed different PA sequences and thus originated from different viruses, suggesting no human-to-human transmission.
Discussion: In the Phase III trials, the PA
Amino Acid Residue 217 in the Hemagglutinin Glycoprotein Is a Key Mediator of Avian Influenza H7N9 Virus Antigenicity.
Result: Further comparison of HA sequences between Anhui/13 and SF003-HA revealed that in addition to the L217Q mutation, there are 6 other substitutions in the HA1 of SF003-HA: changes
Discussion: Compared with the 2013 CVV strain Anhui/13, HK125/17 has A112T, S118N, and A125V substitutions in the HA, while SF003 has 7 substitutions in the HA: I38T, A112P, S118N, A125V, K164E, L217Q, and G261R.
Development of cycling probe based real-time PCR methodology for influenza A viruses possessing the PA/I38T amino acid substitution associated with reduced baloxavir susceptibility.
Abstract: I38T emerged between 5 and 10 passages, and when introduced into recombinant influenza A(H1N1) viruses, alone conferred RO-7 resistance (up to an 81-fold change in EC50).
Abstract: However, the change does not lead to a complete loss of replication activity in vitro Our results predict that RO-7-resistant influenza viruses carrying the I38T substitution may emerge under treatment.
Abstract: Through serial passage of influenza A(H1N1) viruses in MDCK cells under selective pressure of RO-7, we identified an I38T substitution within the PA endonuclease domain that conferred in vitro resistance to RO-7 (up to a 287-fold change in 50% effective concentration [EC50]).
Introd
Table: I38T
Figure: Crystal structures of WT and I38T PAN in complex with RO-7.
Susceptibility of Influenza Viruses to the Novel Cap-Dependent Endonuclease Inhibitor Baloxavir Marboxil.
Abstract: First, we generated a reference virus possessing an I38T substitution in the polymerase acidic subunit (PA), which is known to be associated with reduced susceptibility to baloxavir, and demonstrated the validity of our systems using this reference virus.
Introduction: Furthermore, PA I38T and I38F substitutions emerged as a result of exposure to baloxavir marboxil in four (3.6%) of 112 A(H1N1)pdm09 viruses for which PA sequences were available in a Phase II clinical trial.
Introduction: In a Phase II
Introduction: In a pediatric study, PA I38T and I38M substitutions emerged in 18(23.4%) of 77 A(H3N2) viruses.
In vitro characterization of baloxavir acid, a first-in-class cap-dependent endonuclease inhibitor of the influenza virus polymerase PA subunit.
Abstract: A reduced affinity to the I38T mutant is supported by the lower stability of the BXA-bound endonuclease.
Abstract: Co-crystal structures of wild-type and I38T influenza A and B endonucleases bound to BXA show that the mutation reduces van der Waals contacts with the inhibitor.
Abstract: The viruses harboring the I38T substitution show severely impaired replicative fitness in cells, and correspondingly reduced endonuclease activity in vitro.
Abstract: We find that the PA I38T substitution is a major pathway for reduced susceptibility to BXA, with 30- to 50-fold and 7-fold EC50 changes in A and B viruses, respectively.
Introduction: To understand better the molecular mechanisms involved, we determined the co-crystal structures of wild-type and I38T
IV mutation literature information.
PMID: 
2019
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