Influenza A virus hemagglutinin (HA) stem-region trimer interface (HA stem interface)

The Influenza A virus hemagglutinin (HA) stem-region trimer interface is a critical, highly conserved structural domain located within the stalk of the HA surface glycoprotein. While the HA head region undergoes rapid antigenic drift to evade the host immune system, the stem region remains relatively invariant across diverse influenza A subtypes, making it a premier target for universal influenza vaccines and broadly neutralizing antibodies (Ekiert et al., 2009, Science). Biologically, this region is responsible for mediating the fusion between the viral envelope and the host cell endosomal membrane. Upon exposure to the acidic environment of the endosome, the HA stem undergoes a massive, irreversible conformational rearrangement that inserts a fusion peptide into the host membrane (Corti et al., 2011, Science). Therapeutic agents targeting this interface, including monoclonal antibodies like MEDI8852 and small molecules such as JNJ-4796, function by binding to a hydrophobic pocket at the trimer interface and locking the protein in its pre-fusion state. By stabilizing this conformation, these inhibitors prevent the structural transition required for membrane fusion, effectively neutralizing the virus by blocking its entry into the host cytoplasm (van Dongen et al., 2019, Science). This target is particularly valuable because it offers the potential for broad-spectrum protection against both seasonal and emerging pandemic influenza strains that may possess novel head-region antigenicity.

Other names

Hemagglutinin stalkHA stemHA2 subunit interfaceConserved HA stem epitopeHA fusion peptide pocket

Inhibition of the pH-triggered conformational change of hemagglutinin, which prevents the fusion of the viral envelope with the host endosomal membrane and blocks the release of the viral genome into the host cell (van Dongen et al., 2019, Science; Kallewaard et al., 2016, Cell).