Transmission and pathogenicity of H5N1 influenza viruses

Abstract

The interaction between multiple viral and host factors determine the pathogenicity and transmissibility of H5N1 influenza viruses. The viral surface glycoprotein haemagglutinin (HA) plays a crucial role in attachment to the host-cell sialic acid (SA) receptor and in viral growth and tissue tropism. Other viral factors known as host range or virulence determinants include viral polymerase, particularly residue 627 in the PB2 protein, and the ability to evade the host immune response through the viral NS1 protein. Applying plasmid-based reverse genetics, we have provided a good model system to study the molecular basis for pathogenicity. Differences in the pathogenicity in mammalian species were previously observed between human (A/Vietnam/1203/04) and chicken (A/Chicken/Vietnam/C58/04) H5N1 isolates. Detailed molecular characterization by plasmid-based reverse genetics showed that the polymerase subunits PB1 and PB2 contribute to the lethality of A/Vietnam/1203/04. The polymerase complex possessed significantly higher transcription/replication activity than the A/Chicken/Vietnam/C58/04 polymerase complex. Our results suggest that high polymerase activity acts as a molecular determinant for virulence in mammalian species. We also evaluated the transmissibility and pathogenicity of H5N1 viruses isolated from humans during the years 2003-2006 using a ferret contact model comprising one inoculated and two contact ferrets. This animal model has been shown to support efficient transmission of seasonal human influenza viruses. At 103 TCID50, A/Vietnam/1203/04 and A/Vietnam/JP36-2/05 viruses, which have 'avian-like' α2,3-linked SA receptor affinity, caused neurological symptoms and death in ferrets. A/HongKong/213/03 and A/Turkey/65-596/06 viruses, which have affinity for both 'human-like' (α2,6-linked) and 'avian-like' SA receptors, caused mild clinical symptoms and were not lethal to ferrets. No transmission of A/Vietnam/1203/04 and A/Turkey/65-596/06 viruses was detected, and transmission of A/HongKong/213/03 and A/Vietnam/JP36-2/05 viruses was inefficient. These results demonstrate that despite their receptor binding affinity, circulating H5N1 viruses retain molecular determinants that restrict their spread among mammals. Copyright © Novartis Foundation 2008.