Understanding influenza virus pathogenicity

The haemagglutinin glycoprotein (HA) of influenza A virus plays an essential role in virus entry. After binding to the cellular receptor, the virus is internalized by receptor-mediated endocytosis. HA then induces fusion of the viral envelope with the endosomal membrane, thus allowing delivery of the nucleocapsid into the cytoplasm. To show fusion activity, HA has to undergo a biphasic activation process. The first step involves cleavage by host proteases into the fragments HA1 and HA2 ( 1 Klenk H.D. Garten W. Trends Microbiol. 1994; 2: 39-43 Abstract Full Text PDF PubMed Scopus (388) Google Scholar ). This proteolytic cleavage renders the metastable HA susceptible to a conformational change that is triggered by a low pH in the endosome. This second step in the activation process results in the exposure of a hydrophobic domain on HA2 that presumably interacts with the lipid bilayer of the target membrane. The importance of the pH shift in the fusion process became clear some time ago, when the three-dimensional structures of the neutral and the low pH forms of cleaved HA were elucidated 2 Bullough P.A. et al. Nature. 1994; 371: 37-43 Crossref PubMed Scopus (1399) Google Scholar , 3 Carr C.M. Kim P.S. Cell. 1993; 7: 823-832 Abstract Full Text PDF Scopus (796) Google Scholar , 4 Wiley D.C. Skehel J.J. Annu. Rev. Biochem. 1987; 56: 365-394 Crossref PubMed Scopus (1179) Google Scholar . The conformational analysis of HA has now been completed by a recently published crystallographic study of uncleaved HA ( 5 Chen J. et al. Cell. 1998; 95: 409-417 Abstract Full Text Full Text PDF PubMed Scopus (404) Google Scholar ). The results further our understanding of HA cleavage, which, as indicated by a large body of evidence, is an important factor in the pathogenicity of this virus.