Influenza Virus Entry

As all the enveloped viruses, the entry of influenza viruses includes a number of steps in host cell infection. This chapter summarizes the current knowledge of the entry pathway and the role of the fusion protein of influenza virus, hemagglutinin, in this process. Hemagglutinin (HA) is a trimeric glycoprotein that is present in multiple copies in the membrane envelope of influenza virus. HA contains a fusion peptide, a receptor binding site, a metastable structural motif, and the transmembrane domain. The first step of influenza virus entry is the recognition of the host cell receptor molecule, terminal alpha-sialic acid, by HA. This multivalent attachment by multiple copies of trimetric HA triggers endocytosis of influenza virus that is contained in the endosome. The endosome-trapped virus traffics via a unidirectional pathway to near the nucleus. At this location, the interior pH of the endosome becomes acidic that induces a dramatic conformational change in HA to insert the fusion peptide into the host membrane, induce juxtaposition of the two membranes, and form a fusion pore that allows the release of the genome segments of influenza virus. HA plays a key role in the entire entry pathway. Inhibitors of virus entry are potentially effective antiviral drugs of influenza viruses.