File:Vaccines-08-00587-g001.webp

English: Schematic structures of an influenza A virus (IAV) and its HA. (a) The virion is pleomorphic from spherical to filamentous. It contains eight negative sense, single-stranded RNA genomic segments, each coated with nucleoproteins (NPs) and bound to a heterotrimeric RNA polymerase complex of PA, PB1 and PB2 that forms as a viral ribonucleoprotein (vRNP). All 8 vRNPs are surrounded by a lipid bilayer (envelope). Whereas the inner layer of the envelope is attached to matrix 1 (M1) proteins bound to vRNPs and to nuclear export proteins (NEPs, formerly named NS2 proteins), the outer layer is spiked with HAs and NAs and channeled with matrix 2 (M2) proteins. (b) Diagram of an unfolded HA polypeptide. The signal peptide (SP) at the N-terminus is removed during the cotranslational translocation of a nascent HA into the ER. The synthesized single polypeptide HA is designed to be HA0 (inactive form) that carries HA1 and HA2 subunits. The HA1 subunit, in addition to being a major antigen, contains a receptor binding site, which binds specifically to a sialyl glycan as indicated, except for H17 and H18 viruses. A cleavage site (CS) is located at the end of the HA1 subunit. The HA1 CS usually contains a single basic aa (X-R/K) that can be cleaved extracellularly by tissue-specific expressed trypsin-like serine endoproteases. In contrast, the HA1 CS with additional basic amino acids (R/K-R) may be cleaved intracellularly by ubiquitous proteases (furin and PC5/6) in the trans-Golgi compartment recognizing the R-X-R/K-R motif or cleaved extracellularly by ubiquitous proteases (MSPL and TMPRSS13) in the plasma membrane recognizing the R/K-X-R/K-R motif, and the virus can thus cause systemic infection and is classified as a highly pathogenic (HP) virus. After the cleavage, the HA1 and HA2 subunits remain disulfide-linked between Cys (C, red) and Cys (C, green) of the two subunits, giving the fusion-active form of the HA. The HA2 subunit carries a hydrophobic fusion peptide (FP) at the N-terminus followed by heptad repeats 1 and 2 (HR1 and HR2). Upon activation at low pH, these 3 regions work cooperatively to fuse viral and cellular membranes together, releasing vRNPs into the host cell. The HA2 subunit also contains a transmembrane domain (TM) anchoring the viral membrane (envelope) and promoting full fusion. A hydrophilic cytoplasmic tail (CT) at the C-terminus of the HA2 subunit can also affect the fusion process. (c) Side view of a surface diagram of a trimeric HA. This representative viral HA is from pdb ID of 3ube, which showed a 2009 pandemic HA in complex with lactoseries tetrasaccharide c (LSTc, Neu5Acα2,6Galβ1,4GlcNAcβ1,3Galβ1,4Glc). Each monomer of the HA trimer is colored as follows: deep blue, HA1 and marine blue, HA2; green smudge, HA1 and lemon, HA2; raspberry, HA1 and red, HA2. The receptor binding site, which carries a part of the LSTc ligand (magenta stick, Neu5Ac; yellow stick, Gal; blue stick, GlcNAc; yellow stick, Gal), is located on each globular head, which is a part of HA1 on a stalk composed of the remaining part of HA1 and all HA2.