The HA sequence is the genetic blueprint for Hemagglutinin, a protein on the surface of influenza viruses. Hemagglutinin is a glycoprotein that plays a role in the virus’s ability to infect cells. Understanding this sequence is important for studying influenza viruses and developing countermeasures.
HA Structure and Its Role in Infection
Hemagglutinin (HA) is a protein on the surface of the influenza virus, often described as a spike-like projection. It is assembled from three identical subunits, each with two main parts: HA1 and HA2. The HA1 subunit forms a globular head, while the HA2 subunit contributes to an elongated stem region that anchors the protein to the viral membrane.
The main function of HA is to initiate viral infection by binding to specific sialic acid receptors on host cells. The globular head of the HA protein contains the receptor-binding site, which recognizes and attaches to these receptors, much like a key fitting into a lock. This attachment is the first step in the virus entering the host cell.
Once the virus binds to the host cell, the cell engulfs it through a process called endocytosis. Inside the host cell, the acidic environment of the endosome triggers a change in the HA protein’s shape. This change allows the viral membrane to fuse with the host cell’s endosomal membrane. This fusion enables the viral genetic material to be released into the host cell’s cytoplasm, allowing the virus to begin replication and spread the infection.
How HA Changes Over Time
The HA sequence and protein continuously evolve through two main mechanisms: antigenic drift and antigenic shift. Antigenic drift involves small, gradual changes in the HA gene. These changes arise from random mutations that accumulate during viral replication, as the influenza virus’s replication machinery lacks a proofreading mechanism. These minor alterations in the HA protein can reduce the effectiveness of existing antibodies, allowing the virus to evade the immune system and infect individuals with prior immunity. This constant modification is a main reason for seasonal influenza epidemics and the need for annual vaccine updates.
Antigenic shift, in contrast, represents an abrupt and major change in the HA protein. This occurs when two different influenza viruses co-infect the same host cell, such as a pig, which can act as a “mixing vessel” for different influenza strains. During this co-infection, the viruses can exchange genetic material through reassortment. This exchange can result in a new influenza virus subtype with a novel HA protein, to which the human population has little to no pre-existing immunity. Antigenic shifts are less common than antigenic drift, occurring approximately once every 10 years for influenza A viruses, but they have the potential to cause widespread epidemics or pandemics due to the lack of population immunity.
Implications for Influenza Vaccines
The dynamic nature of the HA protein through antigenic drift and shift has important implications for influenza vaccine development. Due to continuous small mutations in the HA protein, especially in its globular head domain, annual flu vaccinations are necessary. Antibodies produced by current vaccines target this highly variable head domain, providing strain-specific protection. When antigenic drift causes circulating strains to differ significantly from vaccine strains, the vaccine’s effectiveness can be reduced.
Scientists worldwide monitor influenza virus changes to predict which strains are likely to circulate in the upcoming flu season. This global surveillance informs the composition of the annual influenza vaccine, which is updated yearly to account for the evolving HA proteins. Despite these efforts, challenges remain, including mismatches between the vaccine and circulating strains.
Ongoing research aims to develop a more broadly protective, or “universal,” flu vaccine that could offer longer-lasting immunity against multiple influenza strains. One promising strategy involves targeting the more stable “stem” region of the HA protein, which is more conserved across different influenza virus subtypes than the variable head domain. By inducing an immune response against this conserved stem, researchers hope to develop vaccines that provide wider protection against future influenza threats, reducing the need for annual vaccinations and mitigating the impact of new pandemic strains.