The influenza virus relies on specialized structures found on its outer surface to infect and spread. These structures are two distinct types of glycoproteins, Hemagglutinin (H) and Neuraminidase (N), embedded within the viral envelope. These two proteins are fundamental to the virus’s life cycle, enabling binding to host cells and allowing newly created viruses to escape. Understanding the opposing roles of H and N is central to comprehending how the influenza virus operates and how scientists combat it.
The Function of Hemagglutinin in Viral Entry
Hemagglutinin acts as the primary attachment mechanism, initiating infection by binding the virus to a susceptible host cell. This protein is a homotrimeric structure that protrudes from the viral surface, featuring a distinct head region responsible for receptor recognition. Viral entry begins with the specific binding of the Hemagglutinin head to sialic acid receptors found on the membrane of respiratory epithelial cells.
The virus is then internalized by the host cell through endocytosis, becoming encased within a membrane-bound compartment known as an endosome. As the endosome travels deeper inside the cell, its internal environment becomes increasingly acidic. This pH drop triggers a conformational change in the Hemagglutinin protein.
This structural rearrangement exposes a hydrophobic sequence, known as the fusion peptide, which is inserted into the endosomal membrane. The protein’s refolding energy pulls the viral envelope and the endosomal membrane together. This action causes the two membranes to fuse, creating a pore that allows the viral genetic material to be released directly into the host cell’s cytoplasm. Hemagglutinin mediates both the initial attachment and the final membrane fusion step required for the viral genome to gain entry.
The Function of Neuraminidase in Viral Release
Neuraminidase, the second major surface glycoprotein, performs a function that directly counteracts the binding activity of Hemagglutinin. Its primary role is to act as a sialidase enzyme, which cleaves sialic acid molecules. This enzymatic activity is essential for the successful completion of the viral life cycle and the subsequent spread of the infection.
As new influenza virions are assembled and bud from the host cell surface, their own Hemagglutinin proteins could cause them to remain tethered to the host cell membrane’s sialic acid receptors. Newly formed virus particles could also aggregate by binding to their own surface glycoproteins. Neuraminidase prevents this self-limiting scenario by strategically removing sialic acid residues from both the host cell surface and the viral envelope itself.
By cleaving these binding sites, Neuraminidase ensures the newly assembled progeny virions are efficiently released from the infected cell. This action allows the viruses to become free-floating infectious agents capable of migrating to and infecting new cells. Neuraminidase also helps the virus navigate the protective mucus layer in the respiratory tract, which is rich in sialic acid, by removing these decoy receptors.
How H and N Subtypes Classify Influenza Strains
The names assigned to influenza A viruses, such as H1N1 or H3N2, are derived directly from the specific subtypes of the Hemagglutinin and Neuraminidase proteins they possess. Influenza A viruses have 18 distinct Hemagglutinin subtypes and 11 distinct Neuraminidase subtypes. The combination of these two surface proteins dictates the virus’s classification.
Variability in these surface proteins is the reason new flu strains emerge yearly, a process driven by two mechanisms: antigenic drift and antigenic shift. Antigenic drift involves minor, continuous changes resulting from point mutations in the genes encoding H and N. This gradual accumulation of small changes allows the virus to slightly alter its surface structure, which can be enough to escape the immune system’s memory from previous infections or vaccinations.
Antigenic shift occurs when two different influenza A viruses infect the same host cell simultaneously. This co-infection allows for a major genetic reassortment, where gene segments are swapped, resulting in a completely novel combination of H and N proteins. Since the general population has little to no pre-existing immunity against this new combination, antigenic shift is the mechanism responsible for major flu pandemics.
Targeting H and N for Medical Intervention
The distinct functions of Hemagglutinin and Neuraminidase have made them the primary targets for medical interventions designed to prevent and treat influenza. Vaccines are designed to exploit Hemagglutinin’s role in viral entry. They introduce a form of the H protein to the immune system to stimulate the production of neutralizing antibodies that can physically block the virus from binding to host cell receptors.
If these antibodies successfully bind to the Hemagglutinin on the virus surface, they neutralize the virus by preventing the initial attachment and subsequent membrane fusion required for infection. Annual influenza vaccines are formulated to match the Hemagglutinin variants predicted to be circulating each season, reflecting the protein’s dominance as an immune target.
In contrast, antiviral medications specifically target the Neuraminidase protein to treat an active infection. These drugs, known as neuraminidase inhibitors, are structural mimics of sialic acid that fit into and block the active site of the N enzyme. By inhibiting Neuraminidase, the antivirals prevent the newly formed viruses from being released from the infected cell, stopping the infection from spreading throughout the body and reducing the severity and duration of the illness.