Shape shifter: Seasonal viruses typically have outer envelopes studded with sugar-attachment sites (blue) that help deflect immune attacks. But the pandemic influenza virus shown here–a composite of both 1918 and 2009 viruses–has three antibody binding sites (red) that lack sugars. Credit: Jeffrey C. Boyington and Gary J. Nabel
Researchers are plotting strategies against the next major flu outbreak using clues from the 1918 virus.
By Lauren Gravitz
When the H1N1 virus swelled into a pandemic last year, it seemed to defy the rules: Not only was it completely resistant to the seasonal flu vaccine, but it also seemed least dangerous to people over 65 years old–the very population that’s usually most susceptible to influenza. Now, two new studies that take a look at the structure of the swine flu virus begin to explain why. And in the near future, they could also help inform vaccine development.
The research, published today in Science Express and Science Translational Medicine, offers both a structural and chemical close-up of the 2009 H1N1 virus. In fact, both studies examine hemagglutinin, a protein found on the surface of virus particles that activates the human immune system’s protective response. The results reveal remarkable similarities between both pandemic-causing swine flu and 1918 Spanish flu viruses, two fast-spreading troublemakers separated by more than 90 years.
Influenza has a well-earned reputation for speedy evolution–hemagglutinin mutations allow the virus to effectively evade the human immune response and reinfect the same population every year. But despite the near-century-long gap between the 1918 and the 2009 viruses, they have surprisingly similar hemagglutinin structures. In research led by Ian Wilson, a structural immunologist at the Scripps Research Institute in La Jolla, CA, x-ray crystallography shows that the two viruses share a near-identical binding site for the flu-fighting immune proteins called antibodies. Together with colleagues at Vanderbilt University, Wilson shows that an antibody isolated from someone who survived the 1918 pandemic was equally effective at attacking and neutralizing the 2009 virus.
“We looked at the site the antibodies respond to in the 1918 virus, and that site was completely conserved in the novel H1N1,” Wilson says. “There are similarities between the 1918 influenza virus and the recent swine flu, at least at the level at which our immune system recognizes these different viruses.”
The structural similarities explain why the 2009 H1N1 virus was having a reverse age-group effect. “We all realized we weren’t seeing the mortality rates that we’d expect to see in elderly people, and now we know why. These viruses share a characteristic in their most important protein,” says flu specialist Greg Poland, director of the Mayo Clinic’s Vaccine Research Group, in Rochester, MN, who was not involved with the research.
The second study, led by virologist Gary Nabel of the National Institute of Allergy and Infectious Diseases, also found striking similarities between the two pandemic viruses as well as one shared difference from the seasonal flu viruses that have been circulating for the last few decades. When Nabel and colleagues found that immunizing mice against the 1918 flu also protected them from the new 2009 virus–a result explained by Wilson’s research–they, too, took a hard look at the viruses’ structure.
Typically, one of the ways the influenza virus fends off antibody attacks is by using sugars called glycans as a shield, covering the hemagglutinin rather “like an umbrella,” Nabel says. He and his colleagues found that both the 1918 and the 2009 H1N1 viruses lack glycans at the tip of their hemagglutinin proteins.
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