August 27, 2007

Predicting the Shape of Things to Come May Help Beat Bird Flu

Waterfowl flying over a lake

To foretell how the avian flu virus might one day jump from birds to humans, scientists are using crystal-gazing of a different sort. Rather than a crystal ball, they're using crystal structures of viral molecules to help identify mutations that might make it easier for the bird virus to infect and spread between people. Their studies could help researchers prepare vaccines and therapies against deadly flu viruses before they emerge.

The H5N1 avian flu virus primarily infects birds now, but influenza viruses constantly change, or mutate. Future mutations might help the virus more easily latch onto and infect human cells, causing a worldwide flu epidemic. H5N1 has already infected more than 320 people and caused more than 190 deaths worldwide, according to the World Health Organization. But so far the virus has not passed readily from person to person.

Researchers at NIH's National Institute of Allergy and Infectious Diseases (NIAID) looked for mutations that might help the virus shift its adaptability. They focused on the hemagglutinin viral protein (H5 on the avian flu virus), which binds to a specific type of receptor on the cell surface. These receptors are slightly different on bird and human cells.

As reported in the August 10, 2007, issue of Science, the scientists initially compared the H5 protein found on the bird flu virus with that on the human-adapted strain that caused the 1918 pandemic. They looked specifically at changes to one portion of the H5 protein — a portion called the receptor-binding domain. They showed that as few as 2 mutations to this protein region could make it easier for H5N1 to bind to human cells.

The researchers found that these mutations also changed how the immune system recognized the virus. Mouse antibodies that targeted the normal H5 protein were up to 10-fold less potent against the human-adapted mutants.

The scientists next used their knowledge of the H5 interaction with its receptor to create a vaccine with a mutated form of H5. The vaccine triggered production of several antibodies, including one that could latch onto and neutralize both bird- and human-adapted forms of the H5N1 virus.

"Insight into the structure of the avian flu virus has enabled us to target a critical region of hemagglutinin that directs its specificity," says lead researcher Dr. Gary Nabel, director of NIAID's Vaccine Research Center. "Such a structure-based vaccine design may allow us to respond to this future threat in advance of an actual outbreak."

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