15 Fusion of Influenza Virus in Endosomes: Role of the Hemagglutinin

Abstract

Influenza virus enters cells by receptor-mediated endocytosis. Consequently, the virus is delivered to mildly acidic intracellular organelles called endosomes (see Marsh and Pelchen-Matthews, this volume). The next step in the virus entry pathway is fusion between the viral membrane and the endosomal membrane, a process that provides a nondisruptive and efficient means for the virus to deliver its genome into the cytoplasm to initiate the replication cycle. Consistent with the intracellular site of genome penetration, the fusion activity of influenza virus is triggered by the mildly acidic pH of the endosomal lumen. Although the exact pH dependence for fusion differs for different strains of influenza, all strains demonstrate sharp pH profiles with midpoints in the pH 5 to pH 6 range. The low-pH-induced fusion reaction of influenza virus has been the object of much study and has served as a paradigm for the fusion reactions of other enveloped viruses that enter cells by receptor-mediated endocytosis. The process of influenza virus fusion is mediated by its membrane fusion protein, the hemagglutinin (HA). HA is the product of a single gene. This fact, coupled with knowledge of the structure of HA to high resolution (Wilson et al. 1981), has attracted many investigators to study details of how the HA protein causes membrane fusion. The working model for HA-mediated membrane fusion entails three major steps: a low-pH-induced conformational change in HA, a hydrophobic interaction between HA and the target membrane, and the formation and opening of a fusion pore. During the last step,...