A primary oseltamivir-resistant mutation in influenza hemagglutinin and its implications for antiviral resistance
Lei Zhang1,2, Yuekun Shao1, Xiaohui Zou3
1Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.
Abstract:
Oseltamivir, a neuraminidase (NA) inhibitor, is currently the most widely used antiviral drug for influenza worldwide. The emergence of primary oseltamivir-resistant mutations in NA protein of seasonally circulating viruses has been extensively monitored to evaluate drug efficacy. In addition to primary mutations in NA, mutations in the viral hemagglutinin (HA) protein have been observed to arise alongside NA mutations in previous laboratory selection experiments under neuraminidase inhibitor pressure, such HA mutations have not yet been reported in circulating viruses. Here, we present the experimental evidence that an A(H1N1)pdm09 virus can independently acquire oseltamivir-resistance mutations K130N or K130E in the HA receptor binding site (RBS) during serial passages under drug selection. Notably, HA-K130N mutation has been prevalent in currently circulating seasonal viruses worldwide since 2019. More importantly, we demonstrate that the HA-K130N can enhance the oseltamivir resistance conferred by the well-characterized NA-N295S mutation. Our study provides essential evidence that mutations in HA are closely associated with the occurrence of neuraminidase inhibitor resistance, highlighting the urgent need for global monitoring and assessment of oseltamivir-resistant mutations in the HA protein, in addition to NA, during the ongoing H1N1 epidemics.
Insights
Oseltamivir resistance in influenza can arise from mutations in hemagglutinin (HA), not just neuraminidase (NA). The prevalent HA-K130N mutation enhances resistance, necessitating broader monitoring of influenza viruses.
Area of Science:
- Virology
- Antimicrobial Resistance
- Molecular Biology
Background:
- Oseltamivir is a key antiviral for influenza, targeting neuraminidase (NA).
- Monitoring NA mutations for oseltamivir resistance is standard practice.
- Previous studies suggested HA mutations could co-occur with NA resistance mutations under drug pressure.
Purpose of the Study:
- To investigate if influenza A(H1N1)pdm09 virus can develop oseltamivir resistance through mutations in the hemagglutinin (HA) protein.
- To determine if HA mutations can influence the level of oseltamivir resistance conferred by NA mutations.
- To assess the clinical relevance of observed HA mutations in circulating influenza strains.
Main Methods:
- Serial passage of A(H1N1)pdm09 virus under oseltamivir selection pressure.
- Identification and characterization of mutations in HA and NA genes.
- Assessment of oseltamivir resistance levels in vitro.
- Analysis of mutation prevalence in global influenza surveillance data.
Main Results:
- Influenza A(H1N1)pdm09 virus acquired oseltamivir resistance mutations (K130N or K130E) in the HA receptor binding site (RBS) under drug selection.
- The HA-K130N mutation, prevalent in recent seasonal influenza viruses, was identified.
- HA-K130N significantly enhanced the oseltamivir resistance conferred by the NA-N295S mutation.
Conclusions:
- Hemagglutinin (HA) mutations can independently contribute to oseltamivir resistance in influenza viruses.
- The prevalent HA-K130N mutation plays a role in enhancing neuraminidase inhibitor resistance.
- Global surveillance for oseltamivir resistance should include monitoring HA mutations alongside NA mutations, especially for H1N1 strains.
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