Researchers Discover New Insights into Influenza Virus

MILWAUKEE _ The manner in which the influenza virus packages its cell-invading missiles, called virions, is highly selective and not random, as many virologists had previously thought.

The new insights, reported Thursday in the journal Nature by a team of University of Wisconsin-Madison and international researchers, may enable scientists to speed up the development of medicines and vaccines to thwart the virus and prevent its spread.

“This looks like an exceedingly pretty piece of work,” said William Schaffner, a flu expert and head of the preventive medicine department at Vanderbilt University Medical Center in Nashville, Tenn., who was not involved in the study.

“What this group of investigators has done is used the laws of nature to understand what leads to the building of a new influenza virus,” and they have documented “how the virus’ architectural parts are ordered in the sequence of construction,” he said.

This information could prove vital as health officials across the globe scramble to deal with the prospect of a potentially looming avian flu pandemic.

Yoshihiro Kawaoka, a researcher at the School of Veterinary Medicine at UW-Madison, and a team of researchers from Japan, Sweden and California dissected the influenza virus to see what was inside.

Using an electron microscope and a technique known as electron tomography _ which works like a CT scan by visually slicing and dicing very small particles _ they were able to see how the virus was put together and how it organizes its strains of RNA, the strings of genetic material that tell the virus how to exit and attack new cells.

They discovered that if the spherical virion _ the complete viral form that exists outside a cell _ was sliced transversely, a unique pattern appeared. What they saw was something that resembled an orderly, radially symmetric pepperoni pizza, with a circular slice of pepperoni in the middle, encircled by seven other evenly spaced slices.

If they then sliced the virion the other way, along a longitudinal plane, they saw long, rodlike structures of differing lengths.

In every virion they dissected, they found the same pattern.

At first they thought the pattern was unique to the strain they were investigating _ an H1N1 influenza A virus that is commonly used in laboratory studies.

They checked out other strains that had been isolated from people (an H3N2 and H1N1), ducks (an H3N1 and H2N2) and pigs (an H1N2), and found the same pattern in each virus.

“In all strains tested,” the authors wrote, “the virions showed the same organization of rod-like structures, in which a central dot was surrounded by seven dots.”

But because not all influenza A viruses are spherical in shape, they decided to broaden their data pool. They examined a “filamentous” shaped strain, the shape that many newly isolated strains seem to take.

This task was more difficult because many of the virions lacked the density required to clearly see the inner structures with the electron microscope. But in the samples they could see, the same pattern appeared.

“We’ve found that the influenza virus has a specific mechanism that permits it to package its genetic materials,” said Kawaoka, who is also a professor at the University of Tokyo.

And now that researchers know the genome instructs the particles to form in an organized fashion, said Kawaoka, that means “one can find a way to disrupt” the genome to prevent it from forming the virus.

Adolfo Garcia-Sastre, a microbiologist at Mount Sinai School of Medicine in New York, agreed.

“It’s a beautiful publication,” he said, that uses “very sophisticated electron microscopy to reconstruct the genomic complex of the influenza virus.”

He said the work will enable researchers to possibly “make the virus do what they want it to do,” either by making benign forms that could be used for vaccinations, or by stopping the virus from reproducing, thereby creating a new kind of anti-viral drug.

But, he said, “there’s still a lot of things that are not well understood.” For instance, how the virus selects which RNA rods go where, and which codes they will hold, is still not known.

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