Influenza A virus hemagglutinin stalk region (Group 1) (HA stalk (Group 1))

The Influenza A virus hemagglutinin (HA) stalk region is a highly conserved domain of the primary surface glycoprotein responsible for viral entry into host cells (Ekiert et al., 2009, Science). While the globular head of HA facilitates binding to sialic acid receptors, the stalk region mediates the critical step of membrane fusion by undergoing a dramatic pH-induced conformational change within the endosome (Harrison, 2008, Nature). Because the stalk is significantly more conserved across different influenza strains than the rapidly evolving head region, it has become a focal point for the development of universal influenza vaccines and broadly neutralizing antibodies (bnAbs) (Impagliazzo et al., 2015, Science). Group 1 subtypes, which include H1, H2, H5, and others, share structural similarities in this region that allow specific antibodies like CR6261 to neutralize a wide range of viruses by preventing the fusion process (Throsby et al., 2008, PLoS One). Therapeutic agents targeting this region, including small molecules like JNJ-4796, typically function by stabilizing the pre-fusion conformation of the HA trimer, thereby blocking viral infection (van Dongen et al., 2019, Science). This stabilization prevents the insertion of the fusion peptide into the host membrane, effectively halting the viral life cycle before the genome is released. Clinical development of stalk-targeting therapies aims to provide broad protection against seasonal drift and potential pandemic shifts within the Group 1 lineage. However, challenges remain regarding the lower intrinsic potency of stalk-binding antibodies compared to those targeting the receptor-binding site on the HA head (Corti et al., 2011, Science).

Other names

Hemagglutinin stem regionHA stalk domainHA2 subunitConserved HA stemInfluenza A HA Group 1 stalk

Inhibition of the pH-triggered conformational change of the hemagglutinin protein, which prevents the fusion of the viral envelope with the host cell endosomal membrane and subsequent release of the viral ribonucleoprotein complex into the cytoplasm (Ekiert et al., 2009, Science; van Dongen et al., 2019, Science).