Multiple Natural Substitutions in Avian Influenza A Virus PB2 Facilitate Efficient Replication in Human Cells

Benjamin Mänz, Miranda de Graaf, Ramona Mögling, Mathilde Richard, Theo M. Bestebroer, Guus F. Rimmelzwaan, Ron A.M. Fouchier*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

32 Citations (Scopus)

Abstract

A strong restriction of the avian influenza A virus polymerase in mammalian cells generally limits viral host-range switching. Although substitutions like E627K in the PB2 polymerase subunit can facilitate polymerase activity to allow replication in mammals, many human H5N1 and H7N9 viruses lack this adaptive substitution. Here, several previously unknown, naturally occurring, adaptive substitutions in PB2 were identified by bioinformatics, and their enhancing activity was verified using in vitro assays. Adaptive substitutions enhanced polymerase activity and virus replication in mammalian cells for avian H5N1 and H7N9 viruses but not for a partially human-adapted H5N1 virus. Adaptive substitutions toward basic amino acids were frequent and were mostly clustered in a putative RNA exit channel in a polymerase crystal structure. Phylogenetic analysis demonstrated divergent dependency of influenza viruses on adaptive substitutions. The novel adaptive substitutions found in this study increase basic understanding of influenza virus host adaptation and will help in surveillance efforts.

Original languageEnglish
Pages (from-to)5928-5938
Number of pages11
JournalJournal of Virology
Volume90
Issue number13
DOIs
Publication statusPublished - 10 Jun 2016

Bibliographical note

Funding Information:
This work, including the efforts of Benjamin Manz, Mathilde Richard, Theo M. Bestebroer, and Ron A. M. Fouchier, was funded by HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID) (HHSN272201400008C). This work, including the efforts of Benjamin Manz, Theo M. Bestebroer, and Ron A. M. Fouchier, was funded by HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID) (HHSN266200700010C). This work, including the efforts of Theo M. Bestebroer and Ron A. M. Fouchier, was funded by European Commission (EC) (278976).

Publisher Copyright:
© 2016, American Society for Microbiology.

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