Antigenic Drift
Recognition of Influenza Virus by the Immune System: Structure and Function of Influenza Virus Hemagglutinin (HA)
by Gary C. Port
Influenza Virus  As shown in Figure 17-3, influenza virus is an enveloped virus with its negative single stranded RNA segmented genome encased in a lipid bilayer membrane that is taken up as the virus buds out of the host cell. Two glycoproteins are embedded within this lipid membrane, neuraminidase (NA) and hemagglutinin (HA).
Influenza Virus Hemagglutinin (HA)  Hemagglutinin was originally named because of the ability of the virus to agglutinate erythrocytes by attaching to specific sialic glycoprotein receptors. As shown with molecular image on the right, HA is a homotrimer composed of three identical subunits.  As shown in Figure 17-6, each HA subunit  consists of two disulfide-linked polypeptides that are proteolytic fragments of the HA polypeptide encoded by one of the eight viral genomic RNA molecules. 
HA plays three major roles duirng the influenza virus replicative cycle:
  1. HA binds cell surface glycoproteins containing sialic acid carbohydrate residues thereby mediating viral attachment to a cell preceding infection. 
    The "sialic acid" button highlights residues in the right image that form the HA binding pocket for sialic acid.
  2. HA is responsible for penetration of the virus into the cell cytoplasm by mediating the fusion of the membrane of the enveloped virus with the endosomal membrane.
  3. HA is the major antigen of the virus against which neurtalizing antibodies are produced and influenza virus epidemics are associated with changes in its antigenic structure.
HA is post-transcriptionally modified by the addition of oligosaccharide chains and three palmitate residues. The HA spike glycoprotein is a homotrimer of noncovalently linked monomers. In order for the virus to be infectious, cleavage must occur of HA into two disulfide linked chains HA1 (seen in green) and HA2 (seen in yellow). The HA trimer extends 135 Å from the membrane and is composed of triple-strnaded coiled-coil of alpha helices (HA2) and a globular head (HA1) which is primarily antiparallel ß-sheets.
Sialic Acid Binding
The HA receptor binding site is a pocket located on each subunit at the distal end of the molecule. The pocket is inacessable to antibodies, and the residues forming the binding pocket are highly conserved. This pocket binds to sialic acid carbohydrate groups for viral attachment to the cell surface.