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Impact of the Baloxavir-Resistant Polymerase Acid I38T Substitution on the Fitness of Contemporary Influenza A(H1N1)pdm09 and A(H3N2) Strains.
The Journal of Infectious Diseases ( IF 6.4 ) Pub Date : 2020-01-01 , DOI: 10.1093/infdis/jiz418
Liva Checkmahomed 1 , Zeineb M'hamdi 1 , Julie Carbonneau 1 , Marie-Christine Venable 1 , Mariana Baz 1 , Yacine Abed 1 , Guy Boivin 1
Affiliation  

BACKGROUND Baloxavir is a cap-dependent inhibitor of the polymerase acid (PA) protein of influenza viruses. While appearing virologically superior to oseltamivir, baloxavir exhibits a low barrier of resistance. We sought to assess the impact of the common baloxavir-resistant I38T PA substitution on in vitro properties and virulence. METHODS Influenza A/Quebec/144147/2009 (H1N1)pdm09 and A/Switzerland/9715293/2013 (H3N2) recombinant viruses and their I38T PA mutants were compared in single and competitive infection experiments in ST6GalI-MDCK cells and C57/BL6 mice. Virus titers in cell culture supernatants and lung homogenates were determined by virus yield assays. Ratios of wild-type (WT) and I38T mutant were assessed by digital RT-PCR. RESULTS I38T substitution did not alter the replication kinetics of A(H1N1)pdm09 and A(H3N2) viruses. In competition experiments, a 50%:50% mixture evolved to 70%:30% (WT/mutant) for A(H1N1) and 88%:12% for A(H3N2) viruses after a single cell passage. The I38T substitution remained stable after 4 passages in vitro. In mice, the WT and its I38T mutant induced similar weight loss with comparable lung titers in both viral subtypes. The mutant virus tended to predominate over the WT in mouse competition experiments. CONCLUSION The fitness of baloxavir-resistant I38T PA mutants appears relatively unaltered in seasonal subtypes warranting surveillance for its dissemination.

中文翻译:

耐Baloxavir的聚合酶I38T取代对当代A(H1N1)pdm09和A(H3N2)流感病毒适应性的影响。

背景技术Baloxavir是流感病毒聚合酶酸(PA)蛋白的帽依赖性抑制剂。虽然在病毒学上优于奥司他韦,但巴洛沙韦显示出低的抗药性屏障。我们试图评估常见的抗Baloxavir的I38T PA替代物对体外特性和毒力的影响。方法在ST6GalI-MDCK细胞和C57 / BL6小鼠的单次和竞争感染实验中比较了A / Quebec / 144147/2009(H1N1)pdm09和A / Switzerland / 9715293/2013(H3N2)重组病毒及其I38T PA突变体。通过病毒产量测定法测定细胞培养上清液和肺匀浆中的病毒滴度。通过数字RT-PCR评估野生型(WT)和I38T突变体的比率。结果I38T取代并没有改变A(H1N1)pdm09和A(H3N2)病毒的复制动力学。在竞争实验中,单细胞传代后,A(H1N1)病毒的50%:50%混合物演变为A(H1N1)的70%:30%(WT /突变体),而A(H3N2)病毒则演变为88%:12%。在体外传4代后,I38T取代保持稳定。在小鼠中,WT和其I38T突变体在两种病毒亚型中诱导了相似的体重减轻,具有相似的肺滴度。在小鼠竞争实验中,突变病毒往往比野生型病毒占优势。结论抗baloxavir I38T PA突变体的适应性在季节性亚型中相对未变,需要对其传播进行监测。WT和它的I38T突变体在两种病毒亚型中诱导了相似的体重减轻和相似的肺滴度。在小鼠竞争实验中,突变病毒往往比野生型病毒占优势。结论抗baloxavir I38T PA突变体的适应性在季节性亚型中相对未变,需要对其传播进行监测。WT和它的I38T突变体在两种病毒亚型中诱导了相似的体重减轻和相似的肺滴度。在小鼠竞争实验中,突变病毒往往比野生型病毒占优势。结论抗baloxavir I38T PA突变体的适应性在季节性亚型中相对未变,需要对其传播进行监测。
更新日期:2019-12-17
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