Hemagglutinin (HA) is a large glycoprotein found on the surface of the influenza virus. This protein functions as the viral “key,” enabling the influenza particle to unlock and enter host cells, specifically those in the respiratory tract. HA is the major surface feature recognized by the host’s immune system. The immune response, particularly the production of neutralizing antibodies, focuses on this protein to prevent viral entry.
Molecular Structure and Location
Hemagglutinin projects outward from the viral envelope as a rod-shaped spike, anchored in the lipid membrane. This surface protein is structured as a homotrimer, formed by three identical protein units clustered together in a cylindrical shape. It is the most abundant protein on the influenza virion surface, giving the virus its characteristic spiky appearance.
Each of the three units is made up of two distinct polypeptides: the HA1 and HA2 subunits, which remain linked by a disulfide bond after cleavage by host enzymes. The HA1 subunit forms the large, bulbous globular head, which is furthest from the viral membrane. The HA2 subunit forms the slender stalk or stem that anchors the structure to the viral surface and contains the machinery for membrane fusion.
The Mechanism of Infection
The process of infection begins when the globular head (HA1 subunit) of the hemagglutinin protein binds to sialic acid receptors on host respiratory cells. This attachment tethers the viral particle to the outer cell membrane. Following this initial binding, the host cell internalizes the viral particle through endocytosis, encapsulating the virus within a membrane-bound compartment called an endosome.
As the endosome moves deeper into the cell, its internal environment is acidified, causing the pH to drop significantly (usually to a range between 5.0 and 5.5). This decrease in acidity triggers a change in the hemagglutinin structure. The HA2 subunit, which makes up the stalk, undergoes a conformational rearrangement, extending itself.
This structural transformation exposes a hydrophobic segment, known as the fusion peptide, which is inserted into the endosomal membrane. The extended HA2 then refolds, pulling the viral and endosomal membranes into direct contact. This action forces the two membranes to merge, or fuse, creating a pore that allows the influenza virus to release its genetic material into the host cell’s cytoplasm, commencing the replication cycle.
How Hemagglutinin Determines Flu Strains
The letter “H” in the naming convention of influenza A viruses (e.g., H1N1 or H3N2) refers to the hemagglutinin subtype. There are currently 18 known hemagglutinin subtypes (H1 through H18), classified based on the distinct antigenic properties of the protein. Diversity in the HA protein is driven by two main evolutionary processes: antigenic drift and antigenic shift.
Antigenic drift involves continuous, small-scale mutations in the genes that code for the HA protein, most often affecting the globular head region. These minor changes accumulate over time, altering the shape of the HA protein’s receptor-binding site. These alterations allow the virus to gradually evade antibodies developed against previous versions, necessitating the annual adjustment of flu vaccine formulations.
Antigenic shift is an abrupt, major change that occurs when two different influenza strains co-infect the same cell, leading to a genetic reassortment of entire gene segments. If this reassortment results in a novel HA subtype for which the human population has little to no pre-existing immunity, it can lead to a pandemic.
The Role of Hemagglutinin in Vaccine Development
Hemagglutinin is the central component of nearly all current seasonal influenza vaccines because it is the primary target for neutralizing antibodies. The vaccine works by exposing the immune system to the HA protein, prompting the production of antibodies that are specific to the protein’s globular head. These antibodies then bind to the HA on circulating viruses, physically blocking the virus from attaching to the sialic acid receptors on host cells.
The need to reformulate the seasonal vaccine annually stems from antigenic drift. Mutations in the globular head mean that antibodies from a previous vaccine year are no longer effective. Scientists must predict which HA variants will circulate in the upcoming season to ensure the vaccine is a match.
However, the stalk region (HA2) of the hemagglutinin protein is significantly more conserved, meaning its structure changes very little across different subtypes. This highly conserved stalk region is the focus of research for developing a “universal” flu vaccine that could offer long-lasting protection against many different strains. Antibodies directed against this stalk domain have been shown to neutralize a broad range of influenza viruses by preventing the acid-triggered conformational change necessary for membrane fusion. Targeting the conserved stalk would eliminate the need for annual vaccine updates by providing immunity that is not susceptible to the frequent mutations in the globular head.