Like a coat of armor, the HA and NA surface proteins stud the tiny influenza virus particle. When the virus mutates, it can essentially "change coats," altering the shape of its exterior surface and becoming unrecognizable to the human (or animal) immune system. This is the essence of immune evasion, a hallmark of influenza. The virus can undergo two types of changes. Small changes in the virus coat's proteins happen continually and result in new strains. This is a main reason why people can get the flu more than once and why they need to get a new flu vaccine every year. The virus coat can also change abruptly into a new subtype that has an HA protein or an HA-NA protein combination that has not been seen in humans, at least not for many years. Most of us would have little or no innate protection against this new virus. And if the virus can spread easily from person to person, a pandemic may occur. If influenza viruses rarely changed shape, immune evasion wouldn't keep researchers up at night. But they constantly evolve, and their physical structure is again the reason. Inside its spherical shell, the virus particle houses eight separate RNA segments—which encode genes for at least 11 proteins—and this kind of segmented genome is ripe for recombination. If two different influenza viruses infect the same cell, for instance, they can easily exchange gene segments—generating, by some estimates, up to 256 different offspring. Scientists call this phenomenon a genetic "reassortment."

		Influenza scientists widely agree on one point: The world is not prepared for a flu pandemic. Scientists have expressed concern that public policy lags the need for action. As Peter Palese of Mount Sinai School of Medicine says: "We have markets for F16 fighters, but not vaccines." Currently, no vaccine is available to protect humans against the avian virus known as H5N1 (left). According to the Centers for Disease Control and Prevention, research studies to test a vaccine to protect humans against H5N1, which is known to have infected people in southeast Asia, began in April 2005. Image: James Cavallini / Photo Researchers, Inc.

In the case of the H5N1 avian flu strain, waves of genetic reassortment have pushed the virus from geese into chickens, then ducks, and beyond. What are the molecular mechanics behind these interspecies jumps? Scientists are beginning to find out. In the past year, researchers have published several studies of mammals in Asia infected with H5N1—including humans, tigers in a Thai zoo, and mice. Each case appears to harbor the same mutation: a single amino acid substitution, glutamine to lysine, in position 627 of the virus's PB2 protein, a polymerase protein that renders the virus more pathogenic by helping it replicate. The specific cause of the jump from one species to another remains something of a mystery, but many researchers believe it has to do with changes in the HA protein, which is responsible for recognizing receptors on the cells the virus infects.

Although pathogenicity is a key influenza feature, it's only part of the health equation. Equally important, scientists say, is transmissibility within a species. Peter Palese, a virologist at Mount Sinai School of Medicine, in New York, has lots of questions in that regard: "What makes an influenza virus transmissible from human to human? What are influenza's rules for this transmission? And how can we study it in the lab, using animal models?" He acknowledges that "we just don't have good answers right now."

HHMI investigator Stephen Harrison, a structural biologist at Harvard Medical School, adds that these questions require scientists to blend different approaches. "To understand influenza's molecular evolution, we must rephrase natural history questions in molecular terms," Harrison says. "In other words, we have to capture that moment when a virus jumps to a new species, and learn the detailed dynamics of viral infection."

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