Influenza virus hemagglutinin stalk region (HA stalk)

The influenza virus hemagglutinin (HA) stalk region is a highly conserved domain of the HA surface glycoprotein, which is essential for viral entry into host cells (UniProt P03435). Unlike the immunodominant and highly variable globular head, the stalk region—primarily composed of the HA2 subunit and the N- and C-terminal segments of HA1—mediates the fusion of the viral envelope with the endosomal membrane (PubMed: 21852404). This fusion process is triggered by the acidic environment of the endosome, which induces a massive conformational rearrangement in the stalk, transitioning it from a metastable pre-fusion state to a stable post-fusion state (PubMed: 26303263). Because the stalk is relatively conserved across different influenza strains and subtypes, it has become a primary target for the development of universal influenza vaccines and broadly neutralizing antibodies (bnAbs) (Nature: 10.1038/nature10376). Therapeutic agents targeting this region, such as the monoclonal antibodies MEDI8852 and CR9114 or small molecules like JNJ-4796, work by stabilizing the pre-fusion conformation or sterically hindering the structural rearrangements necessary for membrane fusion, thereby preventing the release of the viral genome into the host cytoplasm (Science: 10.1126/science.1224208).

Other names

Hemagglutinin stem regionHA2 subunitConserved HA stalk domainInfluenza HA stalk

Binding to the conserved HA stalk region to sterically inhibit the pH-induced conformational change required for viral-host membrane fusion, thereby preventing viral entry and genome release (PubMed: 21852404, 22878502).