mechanism of antigenic variation

Antigenic variation in influenza A comes in a multitude of forms, enabling it to effectively evade the immune system. As with all RNA viruses, the influenza virus lacks a proofreader for replication, allowing the virus to mutate quickly. The host immune system selects for mutants by making antibodies to the original strain of virus. This leads to antigenic drift, whereby the virus slowly changes its form. In humans, changes in certain genes can lead to increasing virulency. Interestingly, antigenic drift in avian influenza is at a standstill; mutant viruses contain only silent changes in amino acid sequences.

Influenza viral genes are carried on different segments: Influenza A and B both have 8 segments, while C has only 7. The virus is able to reassort its genes, swapping parts and whole segments of the virus in co-infected cells. Co-infection can also lead to complementation, whereby segments of one viral strain can replace nonfunctional segments of other strains.

Of the three influenza strains, only A appears to infect humans and animals (birds, swine, horses and seals). Influenza strains are usually species specific, yet both avian and human influenza strains can infect swine. If cells in the pig are co-infected with human and avian virus, reassortment can lead to major changes in the make-up of the virus. This is called antigenic shift, whereby a sudden dramatic change in the viral genome occurs. Major epidemics and pandemics have occurred when either or both of the two major surface glycoproteins, hemagglutinin (HA) and neuraminidase (NA), from birds recombined with other human segments.

Click here to see an animation on how antigenic shift occurs
(National Foundation for Infectious Diseases)
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Figure adapted from Murphy B.R, Webster RG. Orthomyxoviruses.

Charts provided by International Influenza Education Panel
HA functions in cell recognition and attachment to host cells. Point mutations in HA antigenic sites can result in variants that evade the host immune system. The other major surface antigen, NA, acts to release viral particles from the infected cells. Both NA and HA have subtypes which account for the diversity of influenza strains.

The 1957 Asian flu and the 1968 Hong Kong flu pandemics can be attributed to antigenic shift, whereby strains of avian flu and human flu mixed together in swine to form a new virulent strain. The 1957 Asian flu caused a high rate of mortality because the H2N2 subtype of the HA and NA antigens had not been seen by the immune systems of the vast majority of humans infected. When the 1968 Hong Kong virus swept through the world, the virulent H3N2 subtype did not cause as many fatalities, as survivors of the 1957 pandemic had partial immunity to the N2 subtype.


Diagram of HA viral surface protein
with antigenic variable regions shown

The 1977 Russian H1N1 flu is not attributable to genetic recombinations between avian and human flus. With identical protein subtypes as the earlier 1950 flu, it is believed that a frozen stock of the older virus may account for the outbreak 27 years later. Mortaility rates were low as with the 1968 pandemic, since many people had immunity based on previous exposure.
Influenza A viruses in humans have shifted several times during the last 100 years. The illustration indicates the origin and number of gene segments transferred to the current A viruses. Birds are the most likely source of the newly introduced gene segments for the 1918, 1957 and 1968 shifts. The H1N1 virus reintroduced in 1977, had a very high degree of similarity to the H1N1 virus isolate of 1950. Since that time, the two subtypes of A-virus have co-circulated amongst humans. (Adapted from Webster R.G. et al.)