Caught in The Act

By Christine Gorman

Stories about AIDS research these days tend to fall into one of three categories: promising treatments, oversold developments or elegant science. This one has elegance written all over it and a rather striking picture to boot. A team of researchers led by scientists at the Dana-Farber Cancer Institute in Boston and Columbia University in New York City reported last week that they had for the first time deciphered the three-dimensional structure of a key portion of the AIDS virus. Their results, which are likely to be the topic of much discussion at the 12th World AIDS Conference in Geneva next week, are so detailed that they could provide a blueprint for new treatments--and possibly even vaccines.

First, some background. Scientists have long known that HIV is devilishly effective at fending off antibodies lobbed at it by the body's immune system. One way the virus does that is by mutating rapidly, changing the various amino acids that make up its outer shell and thus forcing the body to churn out millions of new antibodies, all of which may become ineffective with the next mutation. Some parts of the virus don't change, however; if they did, HIV would rapidly lose its power to infect. If scientists understood more about those parts, they could use them as the basis for designing new drugs.

Similarly, AIDS researchers knew that HIV penetrates healthy immune cells by latching onto two different "locks" on the cells' surface, the so-called chemokine and CD4 receptors, using a protein "key" called gp120. But what those locks looked like and how the HIV key opened them were a mystery.

Not any longer. Using an exacting imaging technique called X-ray crystallography that shows the precise spatial relationship of atoms within a large molecule, the team of scientists was able to lay bare the structure of the gp120 protein and its two favorite receptors.

The result is a detailed, computer-generated snapshot of the HIV infection process that is as starkly beautiful as it is informative. The picture shows, for example, that some of the virus' most stable--and therefore vulnerable--structures are either located at the bottom of crevices, where the relatively bulky antibodies of the immune system can't reach them, or obscured by great forests of sugar molecules. One particularly attractive target comes out of hiding only in that brief moment after gp120 latches onto the CD4 receptor and before it attaches to the chemokine receptor--much too briefly for the immune system to react.

Just because HIV can outfox the immune system, however, doesn't mean it will always outmaneuver drug developers. Most drugs are very small molecules, much smaller than antibodies. Properly designed drugs might be able to infiltrate some of those crevices in HIV's outer walls. There's no guarantee that such an approach will work. But it's certainly easier to try when you have a picture in front of you showing you where to begin.

--Reported by Michelle R. Derrow and Unmesh Kher/New York

With reporting by Michelle R. Derrow and Unmesh Kher/New York