Fitness Costs for Influenza B Viruses Carrying Neuraminidase Inhibitor-Resistant Substitutions: Underscoring the Importance of E119A and H274Y

• Published in: Antimicrobial agents and chemotherapy Vol. 58; no. 5; pp. 2718 - 2730
• Main Authors: BURNHAM, Andrew J, BARANOVICH, Tatiana, MARATHE, Bindumadhav M, JIANLING ARMSTRONG, WEBSTER, Robert G, GOVORKOVA, Elena A
• Format: Journal Article
• Language: English
• Published: Washington, DC American Society for Microbiology 01.05.2014
• Subjects: Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral Agents; Antiviral Agents - pharmacology; Biological and medical sciences; Cell Line; Cells, Cultured; Dogs; Drug Resistance, Viral - genetics; Enzyme Inhibitors; Enzyme Inhibitors - pharmacology; Human viral diseases; Infectious diseases; Influenza B virus; Influenza B virus - drug effects; Influenza B virus - enzymology; Medical sciences; Neuraminidase; Neuraminidase - genetics; Pharmacology. Drug treatments; Protein Structure, Secondary; Viral diseases; Viral diseases of the respiratory system and ent viral diseases; Virus Replication - drug effects; Virus Replication - genetics; Infection; Resistance; Costs; Neuraminidase inhibitor; Substitution; Viral disease; Health economy; Economic aspect; Influenza B; Fitness
• ISSN: 0066-4804; 1098-6596
• DOI: 10.1128/aac.02628-13

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 the 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 the fitness of influenza B/Yamanashi/166/1998 viruses (Yamagata lineage). We generated recombinant viruses containing either wild-type (WT) NA or NA with a substitution in the catalytic (R371K) or framework (E119A, D198E, D198Y, I222T, H274Y, and N294S) residues. 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 three (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 seven passages in MDCK cells. Cell surface NA protein expression was significantly increased by H274Y and N294S substitutions. Viruses with the E119A, I222T, H274Y, or N294S substitution were not attenuated in replication efficiency in vitro or in NHBE cells. Overall, viruses with the E119A or H274Y NA substitution possess fitness comparable to NAI-susceptible virus, and the acquisition of these substitutions by influenza B viruses should be closely monitored.