ABSTRACT
A new type of influenza virus appears every few decades and causes pandemic outbreaks of fatal influenza; examples include Spanish influenza (H1N1, 1918), Asian flu (H2N2, 1957), and Hong Kong flu (H3N2, 1968). These three pandemic influenza viruses are classified type A virus on the basis of the internal protein antigens. New influenza viruses evolve in avian hosts and then quickly spread worldwide by means of bird migration. In the 1990s, some clinical cases of human infection with avian influenza A/H5N1 virus were reported,1-5 suggesting that the H5N1 virus has mutated and acquired great potential to cause pandemic influenza in humans. The original H5N1 avian viruses can bind to avian-type receptors on the human lower respiratory tract6,7; however, this infection mechanism does not cause pandemic human influenza. We should pay attention to the binding affinity of H5N1 virus to human-type receptors. Recent studies revealed the molecular biological bases of virus infection as well as the mechanism of virus host range alteration from
9.6 Conclusion and Perspectives ......................................................................... 211 Acknowledgments .................................................................................................. 212 References .............................................................................................................. 212
Influenza Virus
avian to human. Reverse genetics studies demonstrated that several two-point amino acid substitutions in H5N1 hemagglutinin (HA) markedly increased the virus’s affinity for human-type receptors.8,9 Steavens et al. and Yang et al. reported that single-or double-point mutations of H5 gave larger binding affinity to human-type receptors.10,11
Figure 9.1 illustrates the influenza virus and host cell surface. Two membrane glycoproteins hemagglutinin (HA) and neuraminidase (NA) work on the virus infection to host cell and on the virus budding from the host.12-14 The host range of influenza A viruses has been mainly determined by HA binding specificity to host cell surface receptors sialoglycoproteins and sialoglycolipids.15,16
Several X-ray crystallographic structures of HAs complexed with sialooligosaccharide receptor analogues show their intermolecular interaction patterns.8,17-22 HA forms a trimer and three sialosides can attach to the surface sialoside binding site on each HA1 monomer (Figure 9.2). HA specifically recognizes the nonreducing terminal of sialoside receptor and which is sensitive to differences in sialic acid (Sia) species and sialic acid-galactose (Gal) linkage.15,23
Two major Sia are 5-N-glycolylneuraminic acid (Neu5Gc) and 5-N-acetylneuraminic acid (Neu5Ac) (Figure 9.3). Neu5Gc-type glycoconjugates are widely found in many animals such as duck, swine, and horses, whereas Neu5Ac are expressed on the normal human tissues and chicken. Duck, a natural host of influenza viruses, also expresses a limited amount of Neu5Ac.15,16 Figure 9.4 shows chemical structures of nonreducing terminal Sia-Gal disaccharides on sialoside receptors. Human HA more strongly binds to human-type receptor Neu5Acα(2-6)Gal than to avian-type receptor Neu5Ac and 5Gcα(2-3)Gal.
