Constrained evolution drives limited influenza diversity

See research article: http://www.biomedcentral.com/1741-7007/10/38 webciteInfluenza viruses are responsible for 3 to 5 million cases of severe disease and between 250,000 and 500,000 deaths annually worldwide [1]. Novel influenza viruses are zoonotically transferred from avian and swine hosts into humans, and can give rise to pandemics. There have been several flu pandemics that have claimed many thousands of lives, most notably the 1918 H1N1 pandemic, estimated to have killed 50 million people.Influenza viruses are negative-strand RNA viruses consisting of three genera (A, B, C). Influenza A and B are the most clinically important viruses, with respect to numbers of individuals infected and subsequent disease severity. Influenza A viruses are significantly more diverse than B or C, with a large number of subtypes defined by antibodies produced in response to the two surface proteins: hemagglutinin (HA or H) and neuraminidase (NA or N). There are 16 HA subtypes and 9 NA subtypes currently circulating in wild ducks, while only two strains are currently circulating in humans, H1N1 (introduced in 2009) and H3N2 (introduced in 1968). These introduction events are referred to as antigenic shift, when a virus with HA and NA molecules that have not previously circulated widely in humans is introduced (probably through recombination with an avian or animal virus) and spreads effectively. Once established in the population, the virus undergoes continual small mutations that can affect recognition of the HA molecule that is the principal target of antibodies. This process is known as antigenic drift, and while the majority of HA mutations lead to minor antigenic changes, some have large effects on antibody recognition, leading to evasion of established antibody responses and vaccine mismatch. Despite over 40 years of evolution under immune pressure that should promote antigenic diversification, H3N2 influenza viruses exhibit very limited genetic and antigenic diversity at any