RRC ID 58850
Author Suzuki S, Shichinohe S, Itoh Y, Nakayama M, Ishigaki H, Mori Y, Ogata-Nakahara A, Nguyen CT, Okamatsu M, Sakoda Y, Kida H, Ogasawara K.
Title Low replicative fitness of neuraminidase inhibitor-resistant H7N9 avian influenza a virus with R292K substitution in neuraminidase in cynomolgus macaques compared with I222T substitution.
Journal Antiviral Res
Abstract Human cases of H7N9 influenza A virus infection have been increasing since 2013. The first choice of treatment for influenza is neuraminidase (NA) inhibitors (NAIs), but there is a concern that NAI-resistant viruses are selected in the presence of NAIs. In our previous study, an H7N9 virus carrying AA substitution of threonine (T) for isoleucine (I) at residue 222 in NA (NA222T, N2 numbering) and an H7N9 virus carrying AA substitution of lysine (K) for arginine (R) at residue 292 in NA (NA292K, N2 numbering) were found in different macaques that had been infected with A/Anhui/1/2013 (H7N9) and treated with NAIs. In the present study, the variant with NA292K showed not only resistance to NAIs but also lower replication activity in MDCK cells than did the virus with wild-type NA, whereas the variant with NA222T, which was less resistant to NAIs, showed replication activity similar to that of the wild-type virus. Next, we examined the pathogenicity of these H7N9 NAI-resistant viruses in macaques. The variants caused clinical signs similar to those caused by the wild-type virus with similar replication potency. However, the virus with NA292K was replaced within 7 days by that with NA292R (same as the wild-type) in nasal samples from macaques infected with the virus with NA292K, i.e. the so-called revertant (wild-type virus) became dominant in the population in the absence of an NAI. These results suggest that the clinical signs observed in macaques infected with the NA292K virus are caused by the NA292K virus and the NA292R virus and that the virus with NA292K may not replicate continuously in the upper respiratory tract of patients without treatment as effectively as the wild-type virus.
Volume 178
Pages 104790
Published 2020-6-1
DOI 10.1016/j.antiviral.2020.104790
PII S0166-3542(20)30204-7
PMID 32272175
MeSH Amino Acid Substitution Animals Antiviral Agents / pharmacology* Drug Resistance, Viral Enzyme Inhibitors / pharmacology Influenza A Virus, H7N9 Subtype / drug effects* Influenza A Virus, H7N9 Subtype / genetics* Influenza A Virus, H7N9 Subtype / pathogenicity Influenza A Virus, H7N9 Subtype / physiology Macaca fascicularis Mutation Neuraminidase / antagonists & inhibitors* Neuraminidase / chemistry Neuraminidase / genetics* Nose / virology Orthomyxoviridae Infections / drug therapy Orthomyxoviridae Infections / pathology Orthomyxoviridae Infections / virology* Pneumonia, Viral / pathology Pneumonia, Viral / virology Respiratory System / virology Selection, Genetic Viral Proteins / antagonists & inhibitors* Viral Proteins / chemistry Viral Proteins / genetics* Virus Replication
IF 4.101
Times Cited 0
Human and Animal Cells MDCK(RCB0995) A549