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

The hemagglutinin (HA) stalk domain is a highly conserved region of the influenza A virus surface glycoprotein, situated beneath the more variable head domain (PubMed: 29567637). Unlike the head domain, which frequently undergoes antigenic drift, the stalk domain remains relatively stable across different influenza subtypes, making it a primary target for "universal" influenza vaccines and broad-spectrum monoclonal antibodies (PubMed: 30846593). Biologically, the stalk domain, primarily composed of the HA2 subunit, mediates the critical process of membrane fusion between the viral envelope and the host endosomal membrane following endocytosis (UniProt P03437). This process is triggered by the acidic environment of the endosome, causing the stalk to undergo a dramatic conformational rearrangement. Therapeutic agents targeting this domain, such as MEDI8852 or small molecules like JNJ-4796, typically function by binding to and stabilizing the pre-fusion structure, effectively locking the protein and preventing the fusion event necessary for viral genome release (Nature Communications: 10.1038/s41467-019-10442-2). Consequently, targeting the HA stalk offers a promising strategy for providing long-lasting protection against a wide range of seasonal and pandemic influenza strains.

Other names

HA stem domainHA2 subunitHemagglutinin stemConserved stalk region of HA

Binding to the conserved stalk region prevents the pH-triggered conformational change of hemagglutinin required for the fusion of the viral envelope with the endosomal membrane, thereby blocking viral entry into the host cell.