Abstract
Since 2003, more than 380 cases of H5N1 influenza virus infection of humans have been reported. Although the resultant disease in these cases was often severe or fatal, transmission of avian influenza viruses between humans is rare. The precise nature of the barrier blocking human-to-human spread is unknown. It is clear, however, that efficient human-to-human transmission of an antigenically novel influenza virus would result in a pandemic. Influenza viruses with changes at amino acids 627 or 701 of the PB2 protein have been isolated from human cases of highly pathogenic H5 and H7 avian influenza. Herein, we have used the guinea pig model to test the contributions of PB2 627 and 701 to mammalian transmission. To this end, viruses carrying mutations at these positions were generated in the A/Panama/2007/99 (H3N2) and A/Viet Nam/1203/04 (H5N1) backgrounds. In the context of either rPan99 or rVN1203, mutation of lysine 627 to the avian consensus residue glutamic acid was found to decrease transmission. Introduction of an asparagine at position 701, in conjunction with the K627E mutation, resulted in a phenotype more similar to that of the parental strains, suggesting that this residue can compensate for the lack of 627K in terms of increasing transmission in mammals. Thus, our data show that PB2 amino acids 627 and 701 are determinants of mammalian inter-host transmission in diverse virus backgrounds.
Highlights
Repeated introductions of avian H5N1 influenza viruses into the human population have resulted in more than 380 reported cases of severe disease since 2003
Prior to the 1997 and ongoing 2003 outbreaks of H5N1 zoonoses, it was generally assumed that an influenza virus with the traits of efficient viral growth and pathogenicity in a given host species would transmit between individuals of that species
An animal which we have previously shown to model the human transmission of influenza, we have identified two specific residues in the viral polymerase, at PB2 positions 627 and 701, that can contribute to efficient transmission
Summary
Repeated introductions of avian H5N1 influenza viruses into the human population have resulted in more than 380 reported cases of severe disease since 2003. Prior to the 1997 and ongoing 2003 outbreaks of H5N1 zoonoses, it was generally assumed that an influenza virus with the traits of efficient viral growth and pathogenicity in a given host species would transmit between individuals of that species. The phenotype of H5N1 viruses in humans has changed that view: it is clear that specific viral factors are required to support inter-host transmission. As a result of these efforts, it has become clear that transmissibility among humans is a complex and polygenic trait [2,3]. Additional viral proteins as well as host and environmental factors [7,8] are likely to impact the success of human-to-human spread of influenza viruses
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