Date Published: January 2, 2014
Publisher: Public Library of Science
Author(s): Christopher R. Cotter, Hong Jin, Zhongying Chen, Andrew Pekosz.
The 2009 H1N1 pandemic (H1N1pdm) viruses have evolved to contain an E47K substitution in the HA2 subunit of the stalk region of the hemagglutinin (HA) protein. The biological significance of this single amino acid change was investigated by comparing A/California/7/2009 (HA2-E47) with a later strain, A/Brisbane/10/2010 (HA2-K47). The E47K change was found to reduce the threshold pH for membrane fusion from 5.4 to 5.0. An inter-monomer salt bridge between K47 in HA2 and E21 in HA1, a neighboring highly conserved residue, which stabilized the trimer structure, was found to be responsible for the reduced threshold pH for fusion. The higher structural and acid stability of the HA trimer caused by the E47K change also conferred higher viral thermal stability and infectivity in ferrets, suggesting a fitness advantage for the E47K evolutionary change in humans. Our study indicated that the pH of HA fusion activation is an important factor for influenza virus replication and host adaptation. The identification of this genetic signature in the HA stalk region that influences vaccine virus thermal stability also has significant implications for influenza vaccine production.
The swine-origin H1N1 2009 influenza virus (H1N1pdm) caused an estimated 151,700 to 575,400 deaths worldwide during the first 12 months of the 2009 pandemic , , . Children and young adults were most vulnerable to infection because they lacked pre-existing immunity to the H1N1pdm virus . This virus continues to be the predominant circulating H1N1 virus in the human population and has been a component of the annual seasonal influenza vaccine since the 2010 season.
The original A/California/7/09 (Cal/09)-like H1N1pdm strains contained E47 in the HA2 stalk region. Since July 2009, an E47K mutation emerged and rapidly became predominant worldwide. Our studies have demonstrated the importance of this residue for viral membrane fusion activity, acid and thermal stability and infectivity in vivo. The pH for fusion activation has been shown to regulate the virulence and transmission of influenza H5N1 viruses in ferrets and mice , . Our study on H1N1pdm supports the model that the pH of fusion activation is an important factor in determining viral fitness in humans.