Abstract
Host-adaptive strategies, such as the E627K substitution in the PB2 protein, are critical for replication of avian influenza A viruses in mammalian hosts. Here we show that mutation PB2-K526R is present in some human H7N9 influenza isolates, in nearly 80% of H5N1 human isolates from Indonesia and, in conjunction with E627K, in almost all seasonal H3N2 viruses since 1970. Polymerase complexes containing PB2-526R derived from H7N9, H5N1 or H3N2 viruses exhibit increased polymerase activity. PB2-526R also enhances viral transcription and replication in cells. In comparison with viruses carrying 627K, H7N9 viruses carrying both 526R and 627K replicate more efficiently in mammalian (but not avian) cells and in mouse lung tissues, and cause greater body weight loss and mortality in infected mice. PB2-K526R interacts with nuclear export protein and our results suggest that it contributes to enhance replication for certain influenza virus subtypes, particularly in combination with 627K.
Highlights
Influenza viruses utilize the viral polymerase complex, which is composed of PB1, PB2 and PA subunits, to replicate and transcribe the viral genome in the cell nucleus
We show that nearly 80% of H5N1 human isolates from Indonesia and almost all seasonal H3N2 influenza A viruses isolated since 1970 contain PB2-526R
Subsequent analysis found three distinct major PB2 genotypes, 526R/627K, 526R/701N and 526R alone, to be present within some isolates obtained from our own study and in some reported H7N9 human cases identified since March 2013 in China (Table 1)[20,31,32]
Summary
Influenza viruses utilize the viral polymerase complex, which is composed of PB1, PB2 and PA subunits, to replicate and transcribe the viral genome in the cell nucleus. Several adaptation markers in the polymerase have been identified among seasonal influenza viruses that are circulating in humans and avian influenza viruses, which cause sporadic human infections[1,2]. PB2 has been reported to interact with host a-importins; it is thought that differential binding of PB2 with importin-a1 and -a7 may regulate influenza virus polymerase activity[14,15] Details of how these genetic substitutions translate into adaptive mechanisms remain largely unknown. Apart from the markers described above, influenza viruses probably utilize uncharacterized adaptive substitutions in the PB2 polymerase subunit to support virus replication in human cells. In addition to 627K, 701N, 590S/591R and 591K, 526R is another marker of mammalian adaption by avian influenza viruses, possibly functioning through interaction between viral PB2 and nuclear export protein (NEP) during virus replication
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