Hemagglutinins

Hemagglutinins are viral envelope glycoproteins that mediate binding to sialic acid–containing receptors on host cells, enabling attachment and entry. In influenza viruses, the major surface glycoprotein hemagglutinin (HA) is a trimeric protein that is initially synthesized as HA0 and cleaved by host proteases into the two subunits HA1 and HA2. The HA1 subunit contains the receptor-binding domain, while HA2 contains the fusion peptide that drives membrane fusion. Receptor preference for different linkages of sialic acids (for example alpha-2,3 versus alpha-2,6) influences host range and tissue tropism.

During infection, after endocytosis, acidification of the endosome induces a conformational change in HA that facilitates fusion of the viral envelope with the endosomal membrane, releasing the viral genome into the cytoplasm. HA is a major target of neutralizing antibodies, and its genetic and antigenic variation underpins trends in influenza evolution, including antigenic drift and, when accompanied by changes in other segments, antigenic shift. Influenza A viruses are categorized by their HA subtypes (H1–H18; H17 and H18 identified in bats), often referenced together with neuraminidase subtypes (N1–N9) to name strains such as H1N1 or H3N2. Vaccines typically aim to induce protective responses against circulating HA antigens.

Hemagglutination, the clumping of red blood cells by HA binding to surface sialic acids, is exploited in laboratory assays to quantify virus and characterize strains. Hemagglutination inhibition assays measure antibodies that block HA receptor binding and are widely used in serology and vaccine efficacy studies. While the term hemagglutinins also appears in contexts outside influenza, the influenza HA protein remains the most studied example of this class of proteins.