Favipiravir-resistant influenza A virus shows potential for transmission
| Autor: | Jie Zhou, Monica Galiano, Daniel H. Goldhill, Shahjahan Miah, Wendy S. Barclay, Maria Zambon, Omolola Akinbami, Rebecca Frise, Jennifer Shelley, Ana Gallego Cortés, Angie Lackenby, Ada W. C. Yan |
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| Rok vydání: | 2020 |
| Předmět: |
MECHANISM
RNA viruses Viral Diseases CONTACT Epidemiology viruses Reassortment Drug resistance VARIANTS medicine.disease_cause Biochemistry Polymerases Virions Medical Conditions Influenza A Virus H1N1 Subtype 1108 Medical Microbiology Pandemic Medicine and Health Sciences Influenza A virus Biology (General) Pathology and laboratory medicine Mammals 0303 health sciences Mutation Microbial Mutation INHIBITOR Eukaryota Medical microbiology Resistance mutation 3. Good health Infectious Diseases 1107 Immunology Pyrazines Vertebrates Viruses Pathogens Life Sciences & Biomedicine 0605 Microbiology Research Article QH301-705.5 T-705 FAVIPIRAVIR Immunology Viral Structure Biology Favipiravir Microbiology Antiviral Agents Virus 03 medical and health sciences Orthomyxoviridae Infections Virology DNA-binding proteins Drug Resistance Viral Influenza Human Genetics medicine Animals Influenza viruses Humans Molecular Biology Pandemics 030304 developmental biology Science & Technology MUTATIONS 030306 microbiology OSELTAMIVIR-RESISTANT Wild type Organisms Ferrets Viral pathogens Biology and Life Sciences Proteins RC581-607 Amides EVOLUTION Influenza Viral Replication Microbial pathogens Viral replication Amniotes Parasitology Immunologic diseases. Allergy Zoology Orthomyxoviruses |
| Zdroj: | PLoS Pathogens PLoS Pathogens, Vol 17, Iss 6, p e1008937 (2021) |
| DOI: | 10.1101/2020.09.01.277343 |
| Popis: | Favipiravir is a nucleoside analogue which has been licensed to treat influenza in the event of a new pandemic. We previously described a favipiravir resistant influenza A virus generated by in vitro passage in presence of drug with two mutations: K229R in PB1, which conferred resistance at a cost to polymerase activity, and P653L in PA, which compensated for the cost of polymerase activity. However, the clinical relevance of these mutations is unclear as the mutations have not been found in natural isolates and it is unknown whether viruses harbouring these mutations would replicate or transmit in vivo. Here, we infected ferrets with a mix of wild type p(H1N1) 2009 and corresponding favipiravir-resistant virus and tested for replication and transmission in the absence of drug. Favipiravir-resistant virus successfully infected ferrets and was transmitted by both contact transmission and respiratory droplet routes. However, sequencing revealed the mutation that conferred resistance, K229R, decreased in frequency over time within ferrets. Modelling revealed that due to a fitness advantage for the PA P653L mutant, reassortment with the wild-type virus to gain wild-type PB1 segment in vivo resulted in the loss of the PB1 resistance mutation K229R. We demonstrated that this fitness advantage of PA P653L in the background of our starting virus A/England/195/2009 was due to a maladapted PA in first wave isolates from the 2009 pandemic. We show there is no fitness advantage of P653L in more recent pH1N1 influenza A viruses. Therefore, whilst favipiravir-resistant virus can transmit in vivo, the likelihood that the resistance mutation is retained in the absence of drug pressure may vary depending on the genetic background of the starting viral strain. Author summary In the event of a new influenza pandemic, drugs will be our first line of defence against the virus. However, drug resistance has proven to be particularly problematic to drugs against influenza. Favipiravir is a novel drug which might be used against influenza virus in the event of a new pandemic. Is resistance likely to be a problem for the use of favipiravir? Our previous work has shown that resistance to favipiravir can be generated in cell culture but we don’t know whether there will be a cost preventing the spread of resistance in whole organisms. Here, we used a mix of wild-type and resistant influenza viruses from early in the 2009 pandemic to test whether viruses resistant to favipiravir could transmit between ferrets. We found that the resistant viruses could transmit but that the resistance mutation was selected against within some ferrets. Using modelling and in vitro experiments, we found that the resistant mutation was selected against in the influenza strain from our experiment but not in more recently evolved strains. Our results show that favipiravir resistant viruses could spread if resistance is generated but the probability will depend on the genetic background of the virus. |
| Databáze: | OpenAIRE |
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