Influenza A virus hemagglutinin stem domain (HA stem) (HA stem)

The Influenza A virus hemagglutinin (HA) stem domain is a critical structural component of the HA surface glycoprotein, primarily responsible for mediating the fusion between the viral envelope and the host cell endosomal membrane (Skehel and Wiley, 2000). While the globular head of HA is subject to frequent antigenic drift, the stem domain is highly conserved across diverse influenza subtypes, making it an ideal target for the development of “universal” influenza vaccines and broadly neutralizing antibodies (bnAbs) (Ekiert et al., 2009; Corti et al., 2011). During the infection process, the acidic environment of the endosome triggers a massive irreversible conformational rearrangement in the stem domain, which propels the fusion peptide into the host membrane (Harrison, 2008). This structural transition is essential for the release of the viral ribonucleoprotein complex into the host cytoplasm, a prerequisite for viral replication (Bullough et al., 1994). Therapeutic strategies targeting this region, such as monoclonal antibodies like MEDI8852 or small molecules like JNJ-4796, function by binding to the stem and mechanically preventing this conformational change, thereby neutralizing the virus by blocking entry (van Dongen et al., 2019; Pappas et al., 2014). Furthermore, the high conservation of this domain across Group 1 and Group 2 influenza A viruses offers a pathway toward long-lasting, cross-protective immunity that could mitigate the impact of both seasonal epidemics and potential pandemics (Impagliazzo et al., 2015).

Other names

Hemagglutinin stalkHA2 subunitHA stalk domainInfluenza HA stemHA stem fusion domain

The primary mechanism involves binding to the conserved hydrophobic groove of the HA stem, which stabilizes the pre-fusion conformation and sterically blocks the structural rearrangements required for membrane fusion (Ekiert et al., 2009; van Dongen et al., 2019).