Virus' parts a clue to cure

Medicine & Science

January 26, 2004|By Gareth Cook | Gareth Cook,NEW YORK TIMES NEWS SERVICE

Scientists have discovered how a family of dangerous viruses invades healthy cells, a finding that promises new treatments for dengue fever, West Nile and other diseases that infect more than 50 million people every year.

The dengue virus, which sparks severe fevers and can cause internal bleeding, and the West Nile virus, carried across the United States by birds, are both emerging diseases in the Americas.

But scientists have not understood how they infect cells once they invade the body. Using advanced imaging equipment, researchers at Children's Hospital Boston have found the microscopic machinery the viruses use to rip through the cell's protective wall.

The discovery, described in last week's journal Nature, gives scientists a blueprint to design drugs to block the viruses - a strategy that has been successful at combating the virus that causes AIDS.

"This is a very significant breakthrough," said Richard J. Kuhn, a virus specialist who is a professor of biological sciences at Purdue University.

In a field dominated by the quest to understand genetics, this research marks a success for a very different approach: uncovering the raw mechanics of cells.

It is part of a growing field of research that looks at biology's physical structures - microscopic whips, protective walls and spring-loaded hooks - and how they clash in every cell's battle to survive. This winter, Harvard University launched a Center for Molecular and Cellular Dynamic, to pursue the subject.

"If you want to intervene, we have to understand how all the parts work," said Stephen C. Harrison, a co-author of the paper and director of the new center, which is a part of Harvard Medical School. "We are generating masses of genomics data now, but the two approaches can't live without each other."

The work last week involved the virus that causes dengue fever, but scientists said that it could lead to treatments for a variety of similar viruses, including West Nile, yellow fever and hepatitis C. All have similar structures, so it is likely that they use the same machinery to invade.

A virus' entry into the cell is a crucial, and potentially vulnerable, point in its life cycle. Viruses work by entering and then hijacking healthy cells, releasing instructions to the cell to build more of the virus.

The principle has led to at least one drug currently in use: Fuzeon, approved by the Food and Drug Administration last year, which combats AIDS by interfering with HIV's ability to fuse with cell membranes and pass through.

In the new research, Harvard researcher Yorgo Modis isolated the protein used by the dengue virus when it invades and took images of it, before and after it is deployed, using X-ray crystallography. This gave him detailed three-dimensional snapshots of the protein's structure.

By combining these images with elaborate biochemical sleuthing, the team uncovered a story in which the dengue virus behaves like a pirate ship, pulling alongside an unsuspecting cell and then forcing itself aboard.

When a healthy cell first encounters the virus, it surrounds it with a membrane and then draws it into the cell, leaving the virus trapped in a kind of bubble. Inside this bubble, called an "endosome," the environment becomes more acidic as the cell attempts to break down whatever is inside.

This, the paper reports, is when the virus moves into action. Long proteins reach out from the virus and hook themselves into the cell membrane. When these are locked into place, they snap back, slamming the virus through the membrane and freeing it to do its damage.

To treat dengue fever, a drug could be created that would interfere with these protein hooks.

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