InfluenzaHemagglutinin

Influenza hemagglutinin, commonly abbreviated HA, is a glycoprotein on the surface of influenza A and B viruses that drives entry into host cells and serves as a major target of the immune response. In influenza A, HA is a trimeric, single-pass transmembrane protein that anchors the viral envelope to the host.

HA is synthesized as a single precursor protein, HA0, which is cleaved by host proteases into two subunits, HA1 and HA2, linked by a disulfide bond. HA1 forms the receptor-binding head, while HA2 contains the fusion machinery, including the fusion peptide. This cleavage is essential for infectivity and influences pathogenicity, with polybasic cleavage sites associated with highly pathogenic avian influenza enabling broader tissue distribution.

During infection, HA binds to sialic acid receptors on target cells. The preference for sialic acid linkages (for example, α-2,3 or α-2,6 to human or avian cells) affects host range and tissue tropism. After endocytosis, the acidic environment triggers a conformational change in HA2, exposing the fusion peptide and mediating fusion of viral and endosomal membranes, releasing the viral genome into the cytoplasm.

HA undergoes frequent genetic variation through antigenic drift—accumulation of mutations that alter antigenic sites—and, less commonly, antigenic shift via reassortment of gene segments, potentially producing novel, pandemic strains. Because HA is the principal target of neutralizing antibodies, its antigenic properties critically influence vaccine design and effectiveness.

Influenza A viruses are categorized by HA subtypes (H1–H18) and neuraminidase subtypes (N1–N11), with common human strains labeled H1N1 or H3N2. HA’s structure and function make it central to pathogenesis, immunity, and vaccine development.