Pandemic Influenza A Viruses Escape from Restriction by Human MxA Through Adaptive Mutations in the Nucleoprotein

Overview

Journal PLoS Pathog

Specialty Microbiology

Date 2013 Apr 5

PMID 23555271

Citations 114

Authors

Benjamin Manz

Dominik Dornfeld

Veronika Gotz

Roland Zell

Petra Zimmermann

Otto Haller

Georg Kochs

Martin Schwemmle

Affiliations

Soon will be listed here.

Abstract

The interferon-induced dynamin-like MxA GTPase restricts the replication of influenza A viruses. We identified adaptive mutations in the nucleoprotein (NP) of pandemic strains A/Brevig Mission/1/1918 (1918) and A/Hamburg/4/2009 (pH1N1) that confer MxA resistance. These resistance-associated amino acids in NP differ between the two strains but form a similar discrete surface-exposed cluster in the body domain of NP, indicating that MxA resistance evolved independently. The 1918 cluster was conserved in all descendent strains of seasonal influenza viruses. Introduction of this cluster into the NP of the MxA-sensitive influenza virus A/Thailand/1(KAN-1)/04 (H5N1) resulted in a gain of MxA resistance coupled with a decrease in viral replication fitness. Conversely, introduction of MxA-sensitive amino acids into pH1N1 NP enhanced viral growth in Mx-negative cells. We conclude that human MxA represents a barrier against zoonotic introduction of avian influenza viruses and that adaptive mutations in the viral NP should be carefully monitored.

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