LAIV Mutations Selectively Alter Influenza Viral RNA Polymerase Function, Favoring Transcription over Genome Synthesis

Influenza viruses cause mild to severe lower respiratory infections, sometimes resulting in hospitalization and death. Vaccination remains the primary prophylactic strategy. Live attenuated influenza vaccines (LAIVs) efficiently induce antiviral immune responses and contain temperature-sensitive and...

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Vydáno v:	Viruses Ročník 17; číslo 11; s. 1412
Hlavní autoři:	Leach, Justin R., Oo, Adrian, Nogales, Aitor, Bosch, Sebastian I., Martínez-Sobrido, Luis, Feng, Changyong, Kim, Baek, Dewhurst, Stephen
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	Switzerland MDPI AG 23.10.2025
Témata:	Analysis Animals Cell Line DNA-directed RNA polymerase DNA-Directed RNA Polymerases - genetics DNA-Directed RNA Polymerases - metabolism Dogs Enzymes Ethylenediaminetetraacetic acid Genes Genetic aspects Genetic transcription Genome, Viral Genomics H1N1 Health aspects High temperature Humans Immune response Influenza Influenza A Virus, H1N1 Subtype - enzymology Influenza A Virus, H1N1 Subtype - genetics Influenza A Virus, H1N1 Subtype - immunology Influenza A Virus, H2N2 Subtype - enzymology Influenza A Virus, H2N2 Subtype - genetics Influenza vaccines Influenza Vaccines - genetics Influenza Vaccines - immunology Influenza viruses LAIV Madin Darby Canine Kidney Cells Mutants Mutation Penicillin polymerase Proteins Replicase Respiratory tract infection RNA RNA polymerase RNA-Dependent RNA Polymerase - genetics RNA-Dependent RNA Polymerase - metabolism Temperature Transcription Transcription, Genetic Vaccination Vaccines Vaccines, Attenuated - genetics Vaccines, Attenuated - immunology Viral antigens Viral infections Viral proteins Viral Proteins - genetics Viral Proteins - metabolism Virus Replication Viruses California United States Massachusetts Michigan Russia Ann Arbor Michigan United States > US Puerto Rico influenza LAIV H1N1 polymerase vaccination
ISSN:	1999-4915, 1999-4915
On-line přístup:	Získat plný text
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Popis
Shrnutí:	Influenza viruses cause mild to severe lower respiratory infections, sometimes resulting in hospitalization and death. Vaccination remains the primary prophylactic strategy. Live attenuated influenza vaccines (LAIVs) efficiently induce antiviral immune responses and contain temperature-sensitive and cold-adapted mutations that render them safe. These mutations are principally located in the PB1 and PB2 subunits of the viral RNA polymerase, but the mechanism by which they attenuate the virus is unclear. We introduced the PB1 and PB2 mutations from two LAIV backbones, A/Ann Arbor/6/1960 H2N2 (AA) and A/Leningrad/134/17/1957 H2N2 (Len), into the model influenza strain A/Puerto Rico/8/1934 H1N1 (PR8). In contrast to the wild-type (WT) PR8 polymerase, the two “PR8-LAIV” polymerase complexes demonstrated maximal activity at cold temperatures (30–32 °C) and greatly reduced activity at elevated temperatures (>37 °C). To further understand the impact of the LAIV mutations, we infected MDCK cells with WT and mutated PR8 viruses that contain the Len and AA LAIV mutations in PB1 and PB2. The PR8-LAIV mutant viruses exhibited a selective, temperature-dependent defect in the replicase activity of the viral RNA polymerase relative to WT PR8, while also demonstrating a temperature-dependent enhancement in the transcriptional activity of the enzyme. In addition, the PR8-LAIV mutant viruses produced similar levels of viral proteins to WT PR8 at 37 °C, but greatly (2–3 log10) reduced levels of infectious viral progeny. Collectively, these data show that LAIV mutations selectively alter influenza viral RNA polymerase function, favoring transcription over genome synthesis at 37 °C, thereby preserving viral antigen production while also contributing to viral attenuation.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	1999-4915 1999-4915
DOI:	10.3390/v17111412