Abstract

Infection of mammals by avian influenza viruses requires adaptive mutations to achieve high-level replication in the new host. However, the basic mechanism underlying this adaptation process is still unknown. Here we show that avian polymerases, lacking the human signature PB2-E627K, are incapable of generating usable complementary RNA templates in cultured human cells and therefore require adaptation. Characterization of the highly pathogenic human H5N1 isolate A/Thailand/1(KAN-1)/2004 that retained the avian PB2-E627 reveals that the defect in RNA replication is only partially compensated by mutations in the polymerase. Instead, mutations in the nuclear export protein are required for efficient polymerase activity. We demonstrate that adaptive mutations in nuclear export proteins of several human isolates enhance the polymerase activity of avian polymerases in human cultured cells. In conclusion, when crossing the species barrier, avian influenza viruses acquire adaptive mutations in nuclear export protein to escape restricted viral genome replication in mammalian cells.

Authors

Mänz B, Brunotte L, Reuther P, Schwemmle M

Institution

Department of Virology, Institute for Medical Microbiology and Hygiene, University of Freiburg, 79104, Germany.

Source

Nature communications 3: 2012 pg 802

MeSH

Amino Acid Substitution
Animals
Cell Line
Female
Humans
Influenza A Virus, H5N1 Subtype
Influenza, Human
Mice
Mice, Inbred BALB C
Molecular Sequence Data
Mutation, Missense
RNA Replicase
Sequence Alignment
Viral Nonstructural Proteins
Viral Proteins
Virulence
Virus Replication

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

22549831