1st quarter 2007

Genetic mutation discovered which increases the possibility of an influenza pandemic

In 1918 an H1N1 influenza virus caused the Spanish flu pandemic that led to the deaths of almost 50 million victims. The H5N1 influenza virus, which has been in circulation for a few years, has not only infected a large number of birds in Asia, Europe, and Africa but also a small number of people — often with a fatal outcome.

Influenza viruses are usually adapted to a particular host organism, e.g. birds or humans. Occasionally this changes. Virus scientists have now found out how avian influenza viruses manage to infect humans. In normal circumstances, H5N1 can only infect birds. This is because the influenza viruses need a specific structure on the surface of the cells in order to infect them. Only then can the viruses attach themselves to the cell surface and enter into the cells, which is a further prerequisite for an infection. It is based on a lock and key principle — only the right key will open the respective door.

Human influenza viruses recognise certain receptors with saccharides ending with sialic acid-α2,6-galactose (α2,6). In contrast, bird flu viruses prefer endings with sialic acid-α2,3-galactose (α2,3). Put simply: human flu viruses have the key for the α2,6 lock on human cells, while the α2,3 lock on bird cells can be opened with the bird flu virus key. It was thought that being able to recognise α2,6 instead of α2,3 is one of the changes that has to occur so that H5N1 viruses can successfully replicate in humans. This would be a requirement for a pandemic.

An international group of researchers — in Japan, Vietnam, Indonesia, the United Kingdom and the USA — has now investigated the attachment behaviour of the H5N1 viruses that had infected humans. They have shown that these viruses could in fact bind to both receptors — α2,6 and α2,3 — in contrast to H5N1 viruses taken from birds, which could only attach themselves to α2,6 receptors. The genetic material of the human H5N1 viruses was then investigated. The researchers found genetic changes in the viral haemagglutinin gene (position Asn182Lys and Gln192Arg), which were associated with the new ability to bind to human cells.

Another American research group was able to show that the H1N1 influenza virus from 1918 can no longer be transmitted if it carries certain mutations. This does not affect its lethality. Here, too, mutations are in the viral haemagglutinin gene (position Asp225Gly and Asp190Glu) and change the binding from α2,6 to α2,3. So introduce just one single mutation into the Spanish flu virus and its ability to infect humans and cause pandemics is lost. But the reverse is also true: this genetic mutation could have been the last step before the pandemic in 1918.

Interestingly, it was always the case in the influenza pandemics of 1918, 1957, and 1968 — in which the virus had the haemagglutinin of an avian influenza virus each time — that the virus had a preference for human α2,6 even at the start of the pandemic. We can therefore conclude that the change to recognising α2,6 is an important step in the development of a pandemic influenza virus.