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Low replicative fitness of neuraminidase inhibitor-resistant H7N9 avian influenza a virus with R292K substitution in neuraminidase in cynomolgus macaques compared with I222T substitution.
Antiviral Res. 2020 06; 178:104790.AR

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.

Authors+Show Affiliations

Division of Pathogenesis and Disease Regulation, Department of Pathology, Shiga University of Medical Science, Otsu, Shiga, 520-2192, Japan.Division of Pathogenesis and Disease Regulation, Department of Pathology, Shiga University of Medical Science, Otsu, Shiga, 520-2192, Japan; National Research Center for the Control and Prevention of Infectious Diseases, Nagasaki University, Nagasaki, 852-8523, Japan; Department of Emerging Infectious Diseases, Institute of Tropical Medicine (NEKKEN), Nagasaki University, Nagasaki, 852-8523, Japan.Division of Pathogenesis and Disease Regulation, Department of Pathology, Shiga University of Medical Science, Otsu, Shiga, 520-2192, Japan. Electronic address: yasushii@belle.shiga-med.ac.jp.Division of Pathogenesis and Disease Regulation, Department of Pathology, Shiga University of Medical Science, Otsu, Shiga, 520-2192, Japan.Division of Pathogenesis and Disease Regulation, Department of Pathology, Shiga University of Medical Science, Otsu, Shiga, 520-2192, Japan.Division of Pathogenesis and Disease Regulation, Department of Pathology, Shiga University of Medical Science, Otsu, Shiga, 520-2192, Japan.Division of Pathogenesis and Disease Regulation, Department of Pathology, Shiga University of Medical Science, Otsu, Shiga, 520-2192, Japan.Division of Pathogenesis and Disease Regulation, Department of Pathology, Shiga University of Medical Science, Otsu, Shiga, 520-2192, Japan.Laboratory of Microbiology, Department of Disease Control, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, Hokkaido, 060-0818, Japan.Laboratory of Microbiology, Department of Disease Control, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, Hokkaido, 060-0818, Japan; Global Institution for Collaborative Research and Education (GI-CoRE), Hokkaido University, Sapporo, Hokkaido, 060-0808, Japan.National Research Center for the Control and Prevention of Infectious Diseases, Nagasaki University, Nagasaki, 852-8523, Japan; Global Institution for Collaborative Research and Education (GI-CoRE), Hokkaido University, Sapporo, Hokkaido, 060-0808, Japan; Research Center for Zoonosis Control, Hokkaido University, Sapporo, Hokkaido, 001-0020, Japan.Division of Pathogenesis and Disease Regulation, Department of Pathology, Shiga University of Medical Science, Otsu, Shiga, 520-2192, Japan; Research Center for Animal Life Science, Shiga University of Medical Science, Otsu, Shiga, 520-2192, Japan.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

32272175

Citation

Suzuki, Saori, et al. "Low Replicative Fitness of Neuraminidase Inhibitor-resistant H7N9 Avian Influenza a Virus With R292K Substitution in Neuraminidase in Cynomolgus Macaques Compared With I222T Substitution." Antiviral Research, vol. 178, 2020, p. 104790.
Suzuki S, Shichinohe S, Itoh Y, et al. Low replicative fitness of neuraminidase inhibitor-resistant H7N9 avian influenza a virus with R292K substitution in neuraminidase in cynomolgus macaques compared with I222T substitution. Antiviral Res. 2020;178:104790.
Suzuki, S., Shichinohe, S., Itoh, Y., Nakayama, M., Ishigaki, H., Mori, Y., Ogata-Nakahara, A., Nguyen, C. T., Okamatsu, M., Sakoda, Y., Kida, H., & Ogasawara, K. (2020). Low replicative fitness of neuraminidase inhibitor-resistant H7N9 avian influenza a virus with R292K substitution in neuraminidase in cynomolgus macaques compared with I222T substitution. Antiviral Research, 178, 104790. https://doi.org/10.1016/j.antiviral.2020.104790
Suzuki S, et al. Low Replicative Fitness of Neuraminidase Inhibitor-resistant H7N9 Avian Influenza a Virus With R292K Substitution in Neuraminidase in Cynomolgus Macaques Compared With I222T Substitution. Antiviral Res. 2020;178:104790. PubMed PMID: 32272175.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Low replicative fitness of neuraminidase inhibitor-resistant H7N9 avian influenza a virus with R292K substitution in neuraminidase in cynomolgus macaques compared with I222T substitution. AU - Suzuki,Saori, AU - Shichinohe,Shintaro, AU - Itoh,Yasushi, AU - Nakayama,Misako, AU - Ishigaki,Hirohito, AU - Mori,Yuya, AU - Ogata-Nakahara,Ayako, AU - Nguyen,Cong Thanh, AU - Okamatsu,Masatoshi, AU - Sakoda,Yoshihiro, AU - Kida,Hiroshi, AU - Ogasawara,Kazumasa, Y1 - 2020/04/06/ PY - 2019/10/06/received PY - 2020/03/29/revised PY - 2020/04/01/accepted PY - 2020/4/10/pubmed PY - 2020/4/10/medline PY - 2020/4/10/entrez KW - H7N9 avian influenza virus KW - Neuraminidase inhibitor KW - Nonhuman primates KW - Resistance KW - Reverse genetics KW - Revertant SP - 104790 EP - 104790 JF - Antiviral research JO - Antiviral Res. VL - 178 N2 - 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. SN - 1872-9096 UR - https://www.unboundmedicine.com/medline/citation/32272175/Low_replicative_fitness_of_neuraminidase_inhibitor-resistant_H7N9_avian_influenza_a_virus_with_R292K_substitution_in_neuraminidase_in_cynomolgus_macaques_compared_with_I222T_substitution L2 - https://linkinghub.elsevier.com/retrieve/pii/S0166-3542(20)30204-7 DB - PRIME DP - Unbound Medicine ER -
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