Abstract
The role of the influenza virus polymerase complex in host range restriction has been well-studied and several host range determinants, such as the polymerase PB2-E627K and PB2-D701N mutations, have been identified. However, there may be additional, currently unknown, human adaptation polymerase mutations. Here, we used a database search of influenza virus H5N1 clade 1.1, clade 2.3.2.1 and clade 2.3.4 strains isolated from 2008–2012 in Southern China, Vietnam and Cambodia to identify polymerase adaptation mutations that had been selected in infected patients. Several of these mutations acted either alone or together to increase viral polymerase activity in human airway cells to levels similar to the PB2-D701N and PB2-E627K single mutations and to increase progeny virus yields in infected mouse lungs to levels similar to the PB2-D701N single mutation. In particular, specific mutations acted synergistically with the PB2-D701N mutation and showed synergistic effects on viral replication both in human airway cells and mice compared with the corresponding single mutations. Thus, H5N1 viruses in infected patients were able to acquire multiple polymerase mutations that acted cooperatively for human adaptation. Our findings give new insight into the human adaptation of AI viruses and help in avian influenza virus risk assessment.
Highlights
The role of the influenza virus polymerase complex in host range restriction has been well-studied and several host range determinants, such as the polymerase PB2-E627K and PB2-D701N mutations, have been identified
We extended that study to other H5N1 clades and carried out a database search of H5N1 clade 1.1, clade 2.3.2.1, and clade 2.3.4 viruses that had circulated in geographically close areas of Southern China, Vietnam and Cambodia during 2008–2012
To avoid such potential problems, we conducted a database search targeting a geographically and chronologically close group of PB2, PB1, and PA polymerase and NP nucleoprotein gene sequences in human and avian H5N1 strains isolated in Southern China, Vietnam and Cambodia during 2008–2012
Summary
The role of the influenza virus polymerase complex in host range restriction has been well-studied and several host range determinants, such as the polymerase PB2-E627K and PB2-D701N mutations, have been identified. We used a database search of influenza virus H5N1 clade 1.1, clade 2.3.2.1 and clade 2.3.4 strains isolated from 2008–2012 in Southern China, Vietnam and Cambodia to identify polymerase adaptation mutations that had been selected in infected patients. Other H5N1 strains isolated from human infections in Asia do not carry previously identified adaptation mutations This indicated that there are currently unknown adaptation mutations in the H5N1 polymerase complex that enable viral replication in human cells. We identified here novel polymerase mutations in clade 1.1, clade 2.3.2.1 and clade 2.3.4 virus strains isolated from humans in these areas These mutations acted alone and/or together in the genetic background of both Asian and Middle Eastern H5N1 clades to optimize human infection. These results give new insight into the adaptation of AI viruses for human infection and should help in virus surveillance efforts
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