hemaglutinin

Hemagglutinin (HA) is a surface glycoprotein of influenza A and B viruses that plays a central role in viral entry. It is a type I transmembrane protein that forms homotrimers on the virion surface. The HA gene is produced as a precursor, HA0, which must be proteolytically cleaved into HA1 and HA2 subunits to become fusogenic. Cleavage efficiency and site composition can influence tissue distribution and pathogenicity, with multibasic cleavage sites associated with higher pathogenicity in avian influenza.

Functionally, HA mediates attachment to host cells and membrane fusion. The HA1 subunit contains the receptor-binding site that recognizes sialic acid residues on host glycoproteins and glycolipids. Receptor specificity varies by host and strain, with avian-adapted viruses favoring alpha-2,3-linked sialic acids and human-adapted strains favoring alpha-2,6 linkages, contributing to host range and tissue tropism. After endocytosis, a drop in endosomal pH triggers a conformational change in HA2, exposing a fusion peptide that drives fusion of viral and endosomal membranes to release the viral genome.

HA is a major antigen and primary target of neutralizing antibodies. The HA1 “head” is highly variable and drives antigenic drift, while the HA2 “stalk” region is more conserved and a focus of broader-protection research. The protein is heavily glycosylated, and changes in glycosylation can affect receptor binding and immune recognition.

Influenza viruses are categorized by HA subtypes (for example, H1–H16, with additional bat-derived H17 and H18) and corresponding neuraminidase subtypes. Antigenic drift and shift involving HA underlie seasonal epidemics and occasional pandemics. The term “hemagglutinin” reflects its original demonstration of red blood cell agglutination in assays.