Giuseppe
Emeritus
[Source: Antimicrobial Agents and Chemotherapy, full page: (LINK). Abstract, edited.]
Fitness Costs for Influenza B Viruses Carrying Neuraminidase Inhibitor-Resistant Substitutions: Underscoring the Importance of E119A and H274Y
Andrew J. Burnham, Tatiana Baranovich, Bindumadhav M. Marathe, Jianling Armstrong, Robert G. Webster and Elena A. Govorkova*
Author Affiliations: Department of Infectious Diseases, St. Jude Children's Research Hospital, 262 Danny Thomas Place Memphis, Tennessee, 38105-3678, USA
ABSTRACT
Influenza B viruses cause annual outbreaks of respiratory illness in humans and are increasingly recognized as a major cause of influenza-associated pediatric mortality. Neuraminidase (NA) inhibitors (NAIs) are the only available therapy for patients infected with influenza B viruses and the potential emergence of NAI-resistant viruses is a public health concern. The NA substitutions located within enzyme active site could not only reduce NAI susceptibility of influenza B virus but also affect virus fitness. In this study we investigated the effect of single NA substitutions on fitness of influenza B/Yamanashi/166/1998 viruses (Yamagata lineage). We generated recombinant viruses containing either WT NA or NA with a substitution in the catalytic (R371K) or framework residues (E119A, D198E, D198Y, I222T, H274Y, N294S). We assessed NAI susceptibility, NA biochemical properties, NA protein expression, and virus replication in vitro and in differentiated normal human bronchial epithelial (NHBE) cells. Our results showed that four NA substitutions (D198E, I222T, H274Y, and N294S) conferred reduced inhibition by oseltamivir and 3 (E119A, D198Y, and R371K) conferred highly reduced inhibition by oseltamivir, zanamivir, and peramivir. All NA substitutions, except for D198Y and R371K, were genetically stable after 7 passages in MDCK cells. Cell surface NA protein expression was significantly increased by H274Y and N294S substitutions. Viruses with E119A, I222T, H274Y, or N294S substitutions were not attenuated in replication efficiency in vitro or in NHBE cells. Overall, viruses with E119A or H274Y NA substitutions possess fitness comparable to NAI-susceptible virus and their acquisition by influenza B viruses should be closely monitored.
FOOTNOTES
* Correspondence should be addressed to: Elena A. Govorkova, Department of Infectious Diseases, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105-3678; E-mail: elena.govorkova@stjude.org; Tel.: 901-595-2243; Fax: 901-595-8559
Copyright ? 2014, American Society for Microbiology. All Rights Reserved.
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Fitness Costs for Influenza B Viruses Carrying Neuraminidase Inhibitor-Resistant Substitutions: Underscoring the Importance of E119A and H274Y
Andrew J. Burnham, Tatiana Baranovich, Bindumadhav M. Marathe, Jianling Armstrong, Robert G. Webster and Elena A. Govorkova*
Author Affiliations: Department of Infectious Diseases, St. Jude Children's Research Hospital, 262 Danny Thomas Place Memphis, Tennessee, 38105-3678, USA
ABSTRACT
Influenza B viruses cause annual outbreaks of respiratory illness in humans and are increasingly recognized as a major cause of influenza-associated pediatric mortality. Neuraminidase (NA) inhibitors (NAIs) are the only available therapy for patients infected with influenza B viruses and the potential emergence of NAI-resistant viruses is a public health concern. The NA substitutions located within enzyme active site could not only reduce NAI susceptibility of influenza B virus but also affect virus fitness. In this study we investigated the effect of single NA substitutions on fitness of influenza B/Yamanashi/166/1998 viruses (Yamagata lineage). We generated recombinant viruses containing either WT NA or NA with a substitution in the catalytic (R371K) or framework residues (E119A, D198E, D198Y, I222T, H274Y, N294S). We assessed NAI susceptibility, NA biochemical properties, NA protein expression, and virus replication in vitro and in differentiated normal human bronchial epithelial (NHBE) cells. Our results showed that four NA substitutions (D198E, I222T, H274Y, and N294S) conferred reduced inhibition by oseltamivir and 3 (E119A, D198Y, and R371K) conferred highly reduced inhibition by oseltamivir, zanamivir, and peramivir. All NA substitutions, except for D198Y and R371K, were genetically stable after 7 passages in MDCK cells. Cell surface NA protein expression was significantly increased by H274Y and N294S substitutions. Viruses with E119A, I222T, H274Y, or N294S substitutions were not attenuated in replication efficiency in vitro or in NHBE cells. Overall, viruses with E119A or H274Y NA substitutions possess fitness comparable to NAI-susceptible virus and their acquisition by influenza B viruses should be closely monitored.
FOOTNOTES
* Correspondence should be addressed to: Elena A. Govorkova, Department of Infectious Diseases, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105-3678; E-mail: elena.govorkova@stjude.org; Tel.: 901-595-2243; Fax: 901-595-8559
Copyright ? 2014, American Society for Microbiology. All Rights Reserved.
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