Characterization of Oseltamivir-Resistant 2009 H1N1 Pandemic Influenza A Viruses

Autor: Maki Kiso, Yoshihiro Kawaoka, Yousuke Furuta, Ryo Takano, Makoto Yamashita, Satoshi Kakugawa, Masayuki Shimojima, Kei Takahashi, Kyoko Shinya, Makoto Ozawa, Mai thi Quynh Le, Hiroaki Katsura
Jazyk: angličtina
Rok vydání: 2010
Předmět:
Male
viruses
medicine.disease_cause
Virus Replication
chemistry.chemical_compound
Mice
Influenza A Virus
H1N1 Subtype
Pandemic
Influenza A virus
lcsh:QH301-705.5
Mice
Inbred BALB C
biology
virus diseases
Virology/Animal Models of Infection
Female
medicine.drug
Research Article
lcsh:Immunologic diseases. Allergy
Oseltamivir
Immunology
Neuraminidase
Microbiology
H5N1 genetic structure
Antiviral Agents
Zanamivir
Orthomyxoviridae Infections
Virology
Drug Resistance
Viral
Genetics
medicine
Animals
Molecular Biology
Pandemics
Virology/Antivirals
including Modes of Action and Resistance
Ferrets
biochemical phenomena
metabolism
and nutrition
Virology/Mechanisms of Resistance and Susceptibility
including Host Genetics
Influenza A virus subtype H5N1
Virology/New Therapies
including Antivirals and Immunotherapy
respiratory tract diseases
chemistry
Viral replication
lcsh:Biology (General)
Mutation
biology.protein
Parasitology
lcsh:RC581-607
Zdroj: PLoS Pathogens
PLoS Pathogens, Vol 6, Iss 8, p e1001079 (2010)
ISSN: 1553-7374
1553-7366
Popis: Influenza viruses resistant to antiviral drugs emerge frequently. Not surprisingly, the widespread treatment in many countries of patients infected with 2009 pandemic influenza A (H1N1) viruses with the neuraminidase (NA) inhibitors oseltamivir and zanamivir has led to the emergence of pandemic strains resistant to these drugs. Sporadic cases of pandemic influenza have been associated with mutant viruses possessing a histidine-to-tyrosine substitution at position 274 (H274Y) in the NA, a mutation known to be responsible for oseltamivir resistance. Here, we characterized in vitro and in vivo properties of two pairs of oseltaimivir-sensitive and -resistant (possessing the NA H274Y substitution) 2009 H1N1 pandemic viruses isolated in different parts of the world. An in vitro NA inhibition assay confirmed that the NA H274Y substitution confers oseltamivir resistance to 2009 H1N1 pandemic viruses. In mouse lungs, we found no significant difference in replication between oseltamivir-sensitive and -resistant viruses. In the lungs of mice treated with oseltamivir or even zanamivir, 2009 H1N1 pandemic viruses with the NA H274Y substitution replicated efficiently. Pathological analysis revealed that the pathogenicities of the oseltamivir-resistant viruses were comparable to those of their oseltamivir-sensitive counterparts in ferrets. Further, the oseltamivir-resistant viruses transmitted between ferrets as efficiently as their oseltamivir-sensitive counterparts. Collectively, these data indicate that oseltamivir-resistant 2009 H1N1 pandemic viruses with the NA H274Y substitution were comparable to their oseltamivir-sensitive counterparts in their pathogenicity and transmissibility in animal models. Our findings highlight the possibility that NA H274Y-possessing oseltamivir-resistant 2009 H1N1 pandemic viruses could supersede oseltamivir-sensitive viruses, as occurred with seasonal H1N1 viruses.
Author Summary Although most of the currently circulating 2009 pandemic influenza A (H1N1) viruses are susceptible to neuraminidase (NA) inhibitors (oseltamivir and zanamivir), oseltamivir-resistant mutants have sporadically appeared. Yet, the pathogenicity and transmissibility of these oseltamivir-resistant 2009 H1N1 pandemic viruses remain unknown. Here, we compared the pathogenicity and transmissibility of two pairs of oseltamivir-sensitive and -resistant viruses in mouse and ferret models. We found that the oseltamivir-resistant viruses efficiently replicated in the lungs of mice treated with oseltamivir or even zanamivir. Further, we demonstrated that these oseltamivir-resistant viruses caused lung lesions in ferrets and efficiently transmitted between ferrets, as did their oseltamivir-sensitive counterparts. Overall, our results suggest the possibility that oseltamivir-resistant viruses could spread among humans without loss of pathogenicity.
Databáze: OpenAIRE
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