Hemagglutinin protein stalk region (HA stalk) (HA stalk)

The H5N1 influenza virus hemagglutinin (HA) protein stalk region is a highly conserved domain of the primary surface glycoprotein of the influenza A virus [1, 6]. While the globular head of the HA protein frequently mutates to evade the immune system, the stalk region remains relatively stable across diverse influenza subtypes, making it a critical target for universal vaccine development and broadly neutralizing antibodies (bnAbs) [2, 17]. Biologically, the stalk region facilitates the fusion of the viral envelope with the host cell's endosomal membrane, a process essential for the release of the viral genome into the cytoplasm [6, 20]. This fusion is triggered by the low-pH environment of the endosome, which causes the stalk to undergo a dramatic conformational rearrangement [3, 6]. Therapeutic agents, including bnAbs like MEDI8852 and small molecules like IY7640, target this region to lock the HA protein in its pre-fusion state, thereby neutralizing the virus [5, 12, 14]. Because the stalk is naturally immunosubdominant, current research focuses on innovative vaccine strategies, such as chimeric or headless HAs, to elicit a robust protective response against this conserved site [11, 17]. Targeting the HA stalk is considered a promising approach to provide broad protection against both seasonal and pandemic-potential strains like H5N1 [1, 12].

Other names

HA stemHA stalkHA2 subunitConserved stem domainHemagglutinin stem regionH5N1 HA stalk

Inhibition of the pH-induced conformational change of the hemagglutinin protein, 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 cytoplasm [1, 6, 14].