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Epistatic Interactions within the Influenza A Virus Polymerase Complex Mediate Mutagen Resistance and Replication Fidelity.
Article in mSphere. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 18 citations in OpenAlex.
- Concepts of RNA virus evolution for the design of better antiviral countermeasures.Nature reviews. Microbiology · 2026Review
- Mutation rate variability in viral populations: Implications for lethal mutagenesis.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- PB1 mutations as key drivers of influenza A virus evolution.Frontiers in microbiology · 2026Review
- Deep mutational scanning reveals the functional constraints and evolutionary potential of the influenza A virus PB1 protein.Journal of virology · 2023Article
- Evolution of the SARS-CoV-2 Mutational Spectrum.Molecular biology and evolution · 2023Article
- Mutual information networks reveal evolutionary relationships within the influenza A virus polymerase.bioRxiv : the preprint server for biology · 2023Article
- Mutual information networks reveal evolutionary relationships within the influenza A virus polymerase.Virus evolution · 2023Article
- Evolution of the SARS-CoV-2 mutational spectrum.bioRxiv : the preprint server for biology · 2022Article
- Next-generation T cell-activating vaccination increases influenza virus mutation prevalence.Science advances · 2022Article
- A paucigranulocytic asthma host environment promotes the emergence of virulent influenza viral variants.eLife · 2021Article
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- Viral RNA-dependent RNA polymerase mutants display an altered mutation spectrum resulting in attenuation in both mosquito and vertebrate hosts.PLoS pathogens · 2019Article
- The mechanism of resistance to favipiravir in influenza.Proceedings of the National Academy of Sciences of the United States of America · 2018Article
- RNA Virus Fidelity Mutants: A Useful Tool for Evolutionary Biology or a Complex Challenge?Viruses · 2018Review
- Mutation and Epistasis in Influenza Virus Evolution.Viruses · 2018Review
- Low-fidelity Venezuelan equine encephalitis virus polymerase mutants to improve live-attenuated vaccine safety and efficacy.Virus evolution · 2018Article
Corrections and comments
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
Lethal mutagenesis is a broad-spectrum antiviral strategy that employs mutagenic nucleoside analogs to exploit the high mutation rate and low mutational tolerance of many RNA viruses. Studies of mutagen-resistant viruses have identified determinants of replicative fidelity and the importance of mutation rate to viral population dynamics. We have previously demonstrated the effective lethal mutagenesis of influenza A virus using three nucleoside analogs as well as the virus's high genetic barrier to mutagen resistance. Here, we investigate the mutagen-resistant phenotypes of mutations that were enriched in drug-treated populations. We find that PB1 T123A has higher replicative fitness than the wild type, PR8, and maintains its level of genome production during 5-fluorouracil (2,4-dihydroxy-5-fluoropyrimidine) treatment. Surprisingly, this mutagen-resistant variant also has an increased baseline rate of C-to-U and G-to-A mutations. A second drug-selected mutation, PA T97I, interacts epistatically with PB1 T123A to mediate high-level mutagen resistance, predominantly by limiting the inhibitory effect of nucleosides on polymerase activity. Consistent with the importance of epistatic interactions in the influenza virus polymerase, our data suggest that nucleoside analog resistance and replication fidelity are strain dependent. Two previously identified ribavirin {1-[(2
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.