By William J. Cromie

Gazette Staff

The AIDS virus uses an ingenious spring-powered micro-harpoon to infect white blood cells, Harvard researchers have discovered. Two years ago, they found that the flu virus launches the same type of weapon.

"It's a dramatic thing to see," says Don Wiley, professor of biochemistry and biophysics. "It hints at a general mechanism used by many different viruses to infect host cells. We know enough now to be pretty sure that Ebola, measles, and other viruses do the same thing."

Knowing how a virus infects cells takes scientists halfway to designing or discovering ways to fling micro-monkey wrenches into the harpoon mechanisms. "We never thought about being able to treat viral diseases this way until we discovered these details," notes Wiley, who is also an investigator at the Howard Hughes Medical Institute, cosponsor of the research with the National Institutes of Health.

The AIDS virus, called HIV, is studded with hundreds of small, rounded projections which fit snugly into pockets in the surface of certain white blood cells. A lack of fit keeps the virus from docking with any other cells.

Wiley compares the post-docking stage to two balloons touching each other. "Ever try to fuse two balloons together?" he asks. "They touch and bounce off each other but they don't fuse together, a condition necessary for infection."

The contact, however, arms a harpoon that consists of six helices. Three of then wind together to form a single rod; the three others zip upward along the outside of that rod. This fires the harpoon into the cell's skin. A no-leak fusion occurs and the virus empties its genes into the cell. These genes take over the cell and use it to produce more viruses, which get released into the blood.

"This sort of fusion is ubiquitous in nature," Wiley remarks. "It occurs when a sperm and egg unite and a chemical message is passed from nerve to nerve in your brain. It's very basic."

Slow Progress

While researching fusion in the mid-1970s, Wiley first came upon biological harpoons. By 1981, he and his collaborators had isolated a flu-virus harpoon in an unfired position. By 1994, his team knew what the flu's weapon looks like after it fires.

"Progress is slow in this business," he says wryly, referring to the long intervals between steps to discoveries.

To be studied, harpoons and other proteins on the viral surface have to be crystallized, that is, turned into a solid crystal. Otherwise the tiny proteins vibrate, rotate, and twist. The crystal is bombarded with x-rays which are scattered by its atoms. The scatter pattern is unique for each protein and enables biologists to locate each atom in the protein. The process takes years.

Once Wiley became intimately acquainted with the flu virus, his knowledge and intuition told him that the AIDS virus must operate in a similar way.

"We were surprised when we found that it was more like the flu virus than we ever imagined," he says. That "we" includes research associate Winfried Weissenhorn, Andrea Dressen, a postdoctoral fellow, and Stephen Harrison, professor of biochemistry and molecular biology

Five years ago, Wiley gave Weissenhorn the task of investigating those humps on the surface of HIV. "He's the real hero, the risk taker," Wiley says of Weissenhorn. "Working pretty much alone, he dangled over the abyss for a long time before he learned enough for the rest of us to join him. If things hadn't worked out, we had other research to go back to but Winfried had put all his time and effort into this project."

Wiley also worked with an old flu colleague, John Skehel, director of the National Institute of Medical Research in England. They would decide what to do on the phone, then one or the other would do it. "We're scientifically joined at the hip," Wiley remarks.

A Race Is Run

Meanwhile, across Cambridge at the Whitehead Institute of Biomedical Research, Peter Kim and his colleagues worked on the same problem. They also had mapped portions of the flu virus and suspected that HIV would be similar. Within the same week in April, both teams solved the structure of the HIV harpoon.

Kim's group reported its discovery last month in the journal Cell. Wiley's team describes its work in today's issue of Nature.

Asked about the intensity of the race, Wiley says, "it's not just competition, it's also community. Everyone in the scientific community builds on the work of others. One group sees thing that the other doesn't. And there's plenty of room for two groups to work on ways to inhibit the fusion and infection process."

They already have an idea where to start. In 1990, John Wild of Duke University made a small piece of a HIV harpoon coil, which he used to jam the mechanism. The piece was made of protein, however. It worked well in a laboratory dish, but people digest such proteins as food.

Wiley thinks it may be possible to design a pill to do the job. "We may even be able to discover a molecule already in existence that we can use," he says.

As you can imagine, getting a molecule into a springlike coil in a protrusion on an invisibly small virus will not be done quickly or easily. Of course, once it is done once, that would open the door to wrecking the action of other viruses.

"You start off with a very basic problem like fusion," Wiley muses. "Fusion is easiest to study in viruses, so you start to investigate a particular one. Then you realize what you have learned has practical applications to another important virus and, perhaps, to many disease-causing viruses. I think that demonstrates how basic research yields unexpected and useful consequences."

This specific line of work won't lead to the AIDS vaccine that President Clinton made a national goal last Sunday, but the general process of pursuing knowledge for its own sake could do it.