Transmission of Influenza Virus in a Mammalian Host Is Increased by PB2 Amino Acids 627K or 627E/701N

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. To cause a pandemic, an influenza virus must transmit efficiently from human to human. The viral factors that enable person-to-person spread of influenza viruses remain elusive. Using the guinea pig, 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. Interestingly, the two adaptive mutations examined act independently to achieve the same phenotype. Furthermore, these residues impact the transmission of both H3N2 and H5N1 subtype influenza viruses in the context of a mammalian host. The common importance of these amino acids to two diverse virus strains—the human-adapted H3N2 and the more avian-like H5N1—indicates that their mutation may be a common route to the development of a transmission-competent virus. These findings suggest one feature that contributes to the making of a pandemic influenza virus.