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. 2010 Aug 26;6(8):e1001079.
doi: 10.1371/journal.ppat.1001079.

Characterization of oseltamivir-resistant 2009 H1N1 pandemic influenza A viruses

Maki Kiso  1 , Kyoko Shinya, Masayuki Shimojima, Ryo Takano, Kei Takahashi, Hiroaki Katsura, Satoshi Kakugawa, Mai Thi Quynh Le, Makoto Yamashita, Yousuke Furuta, Makoto Ozawa, Yoshihiro Kawaoka
Affiliations

Characterization of oseltamivir-resistant 2009 H1N1 pandemic influenza A viruses

Maki Kiso et al. PLoS Pathog. .

Abstract

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.

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Conflict of interest statement

Dr. Kawaoka has received speaker's honoraria from Chugai Pharmaceuticals, Novartis, Daiichi-Sankyo, Toyama Chemical, Wyeth, and GlaxoSmithKline; grant support from Chugai Pharmaceuticals, Daiichi Sankyo, and Toyama Chemical; is a consultant for Theraclone and Crucell; and is a founder of FluGen.

Figures

Figure 1
Figure 1. Antiviral sensitivity of viruses in mice.
Mice were intranasally inoculated with 102 (A, D, G, and J) or 103 PFU of O164s, O180r (A–F), VN9727s, or VN32060r (G–L). At one hour post-infection (pi), mice were administered oseltamivir, zanamivir, CS-8958, favipiravir, or distilled water and PBS (control). Ten (A, B, D, E, G, H, J, and K) or three (C, F, I, and L) mice per group were euthanized on days 3 and 6 pi and virus titers in the lungs were determined by plaque assays in MDCK cells (detection limit: 1.0 log10 PFU/g). Error bars indicate the standard deviations of viral titers detected in the lungs of ten or three mice. Statistical significance was assessed by use of the Student's t-test: *, p<0.05, **, p<0.01.
Figure 2
Figure 2. Pathological findings in the lungs of infected ferrets.
Ferrets intranasally inoculated with 106 PFU of O164s, O180r, VN9727s, or VN32060r were euthanized on day 6 pi. The nasal turbinates, lungs, and trachea were subjected to pathological examination. (A) Bronchopneumonia in a ferret infected with VN9727s (H&E staining). (B) Bronchopneumonia in a ferret infected with VN32060r (H&E staining). (C) Viral antigen (brown pigment) in the lungs of a ferret infected with O164s (immunohistological staining). (D) Viral antigen (brown pigment) in the lungs of a ferret infected with O180r (immunohistological staining).
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