Role of hemagglutinin cleavage for the pathogenicity of influenza virus

Although human epidemics of influenza occur on nearly an annual basis and r esult in a significant number of "excess deaths," the viruses responsible a re not generally considered highly pathogenic. On occasion, however, an out break occurs that demonstrates the potential lethality of influenza viruses . The human pandemic of 1918 spread worldwide and killed millions, and the limited human outbreak of highly pathogenic avian viruses in Hong Kong at t he end of 1997 is a warning that this could happen again. In avian species such as chickens and turkeys, several outbreaks of highly pathogenic influe nza viruses have been documented. Although the reason for the lethality of the human 1918 viruses remains unclear, the pathogenicity of the avian viru ses, including those that caused the human 1997 outbreak, relates primarily to properties of the hemagglutinin glycoprotein (HA). Cleavage of the HA p recursor molecule HA, is required to activate virus infectivity, and the di stribution of activating proteases in the host is one of the determinants o f tropism and, as such, pathogenicity. The HAs of mammalian and nonpathogen ic avian viruses are cleaved extracellularly, which limits their spread in hosts to tissues where the appropriate proteases are encountered. On the ot her hand, the HAs of pathogenic viruses are cleaved intracellularly by ubiq uitously occurring proteases and therefore have the capacity to infect vari ous cell types and cause systemic infections. The x-ray crystal structure o f HA, has been solved recently and shows that the cleavage site forms a loo p that extends from the surface of the molecule, and it is the composition and structure of the cleavage loop region that dictate the range of proteas es that can potentially activate infectivity, Here influenza virus pathogen icity is discussed, with an emphasis on the role of HA, cleavage as a deter mining factor. (C) 1999 Academic Press.