Prevalence of PB1-F2 of influenza A viruses

Abstract

PB1-F2 is a pro-apoptotic polypeptide of many influenza A virus (FLUAV) isolates encoded by an alternative ORF of segment 2. A comprehensive GenBank search was conducted to analyse its prevalence. This search yielded 2226 entries of 80 FLUAV subtypes. Of these sequences, 87 % encode a PB1-F2 polypeptide greater than 78 aa. However, classic swine influenza viruses and human H1N1 isolates collected since 1950 harbour a truncated PB1-F2 sequence. While PB1-F2 of human H1N1 viruses terminates after 57 aa, classic swine H1N1 sequences have in-frame stop codons after 11, 25 and 34 codons. Of the avian sequences, 96 % encode a full-length PB1-F2. One genetic lineage of segment 2 sequences which is avian-like and different from the classic swine FLUAV comprises PB1-F2 sequences of porcine FLUAVs isolated in Europe (H1N1, H1N2, H3N2). Of these PB1-F2 sequences, 42 % also exhibit stop codons after 11, 25 and 34 codons. These amino acid positions are highly conserved among all FLUAV isolates irrespective of their origin. Molecular genetic analyses reveal that PB1-F2 is under constraint of the PB1 gene. The PB1-F2 polypeptide of FLUAVs isolated from European pigs is expressed in host cells as demonstrated by immunohistochemistry. Using different PB1-F2 versions fused to an enhanced GFP, mitochondrial localization is demonstrated for those PB1-F2 polypeptides which are greater than 78 aa while a truncated version (57 aa) shows a diffuse cytoplasmic distribution. This indicates similar properties and function of porcine and human FLUAV PB1-F2.

Virulence determinants of pandemic influenza viruses

“…Interestingly, 2009 S-OIVs express only a truncated, 11-amino acid PB1-F2 protein, although introduction of PB1-F2, either with 66N or 66S, into recombinant 2009 S-OIV did not substantially enhance its virulence in mice or ferrets or predispose mice to secondary bacterial infection with Streptococcus pneumoniae (94). PB1-F2 is expressed by nearly all avian influenza viruses, but these proteins tend to become truncated following introduction into humans or pigs (95), which suggests that there is some selective advantage for full-length PB1-F2 in the avian host that is lost during adaptation to mammals (92). It may be that PB1-F2 only contributes to the virulence of pandemic strains when the PB1 gene segment is recently derived from an avian reservoir (92).…”

Resurrected Pandemic Influenza Viruses

“…The PB1-F2 protein has intrigued scientists ever since its initial discovery by Chen and colleagues in 2001. It can be found in various lengths in all known influenza A subtypes but is generally a 87-amino-acid peptide generated from a +1 reading frame by virtue of ribosomal scanning (124). Of note, all the contemporary H1N1 viruses have truncated PB1-F2 proteins consisting of 57 amino acids.…”

PB1-F2 Modulates Early Host Responses but Does Not Affect the Pathogenesis of H1N1 Seasonal Influenza Virus

“…Within the H1N1 subtype, human viruses isolated between 1918 and 1947 express a full-length PB1-F2 protein. In 1950, a stop codon was introduced after amino acid residue 57, resulting in a C-terminally truncated protein (35), and the recently emerged pandemic 2009 H1N1 viruses have a stop codon at residue 11 (9).…”