Scientists Learn How AIDS Virus Blocks Vaccines
After more than 15 years of effort, researchers have finally been able to puzzle out the three-dimensional structure of a key protein on the surface of the AIDS virus, a feat that provides the first good explanation of why an infected person’s immune system is unable to fight off the virus and why attempts to produce AIDS vaccines have been unsuccessful.
In particular, the studies show that the site targeted by most vaccines--including the Vaxgen AIDS vaccine approved for large-scale testing only two weeks ago--is shielded by a structure similar to the movable roofs on many athletic stadiums.
While the virus circulates through the blood, it is protected from the immune system by the shield. But when the virus is ready to enter white blood cells, the shield rolls back, allowing the virus to penetrate the cell.
The structural studies, reported in two papers in today’s Nature and one in tomorrow’s Science, show that the protein has other defenses as well, making HIV “a viral Houdini” that can not be kept bottled up by the immune system, said Dr. Joseph Sadroski of the Dana-Farber Cancer Institute in Boston, one of the authors.
But the studies also suggest that there may be ways to circumvent those defenses with vaccines or drugs.
“This is a major step forward,” said molecular biologist David Baltimore, president of Caltech and head of the federal government’s advisory panel on AIDS vaccines. “It gives us a better idea about why [the Vaxgen vaccine] is unlikely to give us the kind of antibodies we need to protect people” and points toward approaches that might eventually be more successful.
“We now have specific target sites on which to focus in developing new drugs and vaccines,” added Dr. Anthony S. Fauci, director of the National Institute of Allergy and Infectious Diseases.
The protein in question is called gp120. Its function is much like the front-door key of a house. Dangling from the surface of HIV, gp120 must slip into a cavity on another protein on the surface of a white blood cell, called CD4, to trigger the ultimately deadly infection process.
Many of the potential AIDS vaccines that immunologists are now studying, including the Vaxgen product, are made from gp120 molecules produced by genetic engineering techniques in bacteria. Scientists had hoped that vaccinating people with gp120 would stimulate the immune system to recognize it and prevent it from binding to CD4.
But that approach has not been very successful, and the new pictures of the molecule show why.
Researchers use a process called X-ray crystallography to determine the precise position of every atom in the molecule. As the technique’s name implies, however, the scientists must have the molecule in a crystalline form not unlike the salt or sugar crystals on a kitchen table.
That has been the bugaboo with gp120. Other proteins have a rigid structure, so it is relatively easy to induce them to condense into regular crystalline arrays. But gp120 has many long, flexible sugar molecules on its surface that interfere with this stacking. Getting the molecules to line up in a regular manner is rather like trying to construct a neat cube with beanbag chairs.
To get around the problem, Sadroski and his colleagues snipped off sections of the gp120 that they didn’t think were important to its function. Crystallographers Peter Kwong and Wayne Hendrickson of Columbia University were then able to bind the remaining core of the molecule with CD4 and crystallize the complex to determine its structure.
“It’s a technological tour de force,” said AIDS researcher Dani Bolognesi of the Duke University Medical Center.
Studying the X-ray structure quickly showed several ways in which the virus evades detection. The portion of gp120 that actually binds to CD4 is protected from immune attack by dome-like loops of protein. When the protein is ready to bind, the loops collapse out of the way.
This receptor also has what the researchers call an “icing” of carbohydrate molecules that further protect it from antibodies. An effective attack on HIV might require some technique to remove this icing, researchers said.
Another large portion of gp120 has no characteristics that would allow the immune system to recognize and attack it, making it what they term a “silent face.” “We didn’t realize before that there are whole regions [of the molecule] that the immune system never sees,” Sadroski said.
The structure also reveals some potential targets for attack.
In particular, Kwong said, the large cavity at the interface of gp120 and CD4 “is a drug designer’s dream. The deep cavity at the heart of the interaction is just begging to be filled” with a drug that would block the binding in the same way that a broken key in a lock prevents an intact key from entering.
Baltimore and others cautioned that new drugs and vaccines against AIDS will not come overnight. In the longer term, however, they are confident that further study of the molecule will produce a new battle plan against the disease and a variety of new weapons to use in that war.
(BEGIN TEXT OF INFOBOX / INFOGRAPHIC)
View of a Virus
Computer-generated image illustrating how the AIDS virus, top, enters a white blood cell, below, via protein molecules.
In blue gp 120 is the key that fits into the lock, CD4, in red, to trigger the infection. The green-colored molecule represents a second receptor that the virus must also bind to.
Source: Science
Computer-generated image by R. Wyatt and J. Sodroski; enhanced by K. Sutliff
