Orthomyxoviruses: Structure of Antigens☆

The orthomyxoviruses include influenza viruses, thogotoviruses, and isaviruses. Influenza A viruses circulate in reservoir of wild aquatic birds, occasionally cause human pandemics, undergo antigenic drift and antigentic shift, and have been used as model viruses to understand many fundamental processes including receptor binding, membrane fusion, protein structure, and adaptive immunity. Influenza A and B viruses contain a hemagglutinin (HA) surface glycoprotein, the dominant surface antigen that promotes receptor binding and membrane fusion during viral entry, and a neuraminidase (NA) glycoprotein, a secondary antigen that has receptor-destroying activity necessary for virus release from infected cells. Influenza C viruses contain a single antigen, the hemagglutinin-esterase-fusion (HEF) protein, which possesses receptor binding, membrane fusion, and virus release functions. The HA and HEF proteins are prototypic, trimeric, structural class I viral fusion proteins with a membrane-distal, immunodominant (and highly variable) receptor-binding head domain and a more highly conserved membrane-proximal, metastable, stalk domain that catalyzes membrane fusion. The tetrameric NA protein has a membrane-distal globular head domain with an antiparallel β-propeller topology and a membrane-proximal coiled-coil stalk. For the influenza A and B viruses, the HA protein is the predominant target for naturally acquired and vaccine-induced adaptive immunity. Recent structural studies of broadly reactive monoclonal antibodies bound to the HA protein, along with complementary immunological experiments, suggest ways to generate “universal” influenza vaccines that are effective after antigenic drift and shift.