A Polymorphism in the Hemagglutinin of the Human Isolate of a Highly Pathogenic H5N1 Influenza Virus Determines Organ Tropism in Mice

We characterized a human H5N1 virus isolate (KAN-1) encoding a hemagglutinin (HA) with a K-to-E substitution at amino acid position 222 that was previously described to be selected in the lung of the infected patient. In mice, the growth of the HA(222E)-encoding virus was mainly confined to the lung, but reversion to 222K allowed virus to spread to the brain. The HA(222E) variant showed an overall reduced binding affinity compared to that of HA(222K) for synthetic Neu5Ac2-3Gal-terminated receptor analogues, except for one analogue [Neu5Ac alpha 2-3Gal beta 1-4(Fuc alpha 1-3)(6-HSO3) GlcNAc beta, Su-SLe(x)]. Our results suggest that human-derived mutations in HA of H5N1 viruses can affect viral replication efficiency and organ tropism.