Oseltamivir-resistant influenza viruses get by with a little help from permissive mutations

Abstract

Evaluation of: Bloom JD, Gong LI, Baltimore D. Permissive secondary mutations enable the evolution of influenza oseltamivir resistance. Science 328(5983), 1272–1275 (2010).

Influenza A viruses (IAVs) encode two critical glycoproteins, hemagglutinin and neuraminidase (NA). Hemagglutinin promotes viral docking onto cells via interactions with IAV’s receptor, sialic acid and NA facilitates release of newly synthesized virions by cleaving cellular and viral sialic acid. NA inhibitors, such as oseltamivir, are widely used drugs that work by binding to the active site of NA. Although oseltamivir-resistant viruses were easily generated years ago in laboratory experiments, it was widely believed that these viruses would not be able to circulate in the human population as they did not replicate efficiently. However, oseltamivir-resistant H1N1 viruses rapidly spread during the 2007–2008 IAV season and these viruses contained precisely the same exact drug-resistance mutation identified years prior, a histidine to tyrosine substitution at NA residue 274 (H274Y). Unlike the experimentally derived NA inhibitor-resistant viruses, 2007–2008 H1N1 viruses containing H274Y replicated efficiently. Bloom et al. have solved this riddle by identifying permissive NA mutations that allow viruses to tolerate H274Y. Here, we discuss these important findings and speculate how these studies may facilitate early detection of drug-resistant strains in the future.

Keywords::

• influenza virus
• neuraminidase
• neuraminidase inhibitors
• oseltamivir

Financial & competing interests disclosure

Scott E Hensley is supported by the NIH (NIAID K22AI091651), a Pew Foundation Recruitment Grant and the Wistar Cancer Center Core Grant. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.