nice article from NYT 6/18/98, on solving the structure of GP120 ...
X-RAYS SHOW HOW AIDS VIRUS ATTACKS
New York Times News Service
June 18, 1998
Scientists using a powerful X-ray technique have taken the first
snapshot of the contact made by the AIDS virus as it snares its two
target sites on the surface of a human cell. The pictures show the
intricacy of the virus' methods for dodging the human immune system and
confirm some researchers' view that the AIDS vaccine recently approved
for testing is unlikely to work.
At the same time, the sight of the virus' defenses brings to light
certain weak points against which new drugs and perhaps vaccines could
be designed.
The visualization of the virus' attack, a computer-generated image based
on X-rays, is the fruit of eight years of research at Columbia
University in New York City and the Dana-Farber Cancer Institute in
Boston.
It depended on a technique powered by X-rays from the particle
accelerator at the Brookhaven National Laboratory on Long Island, N.Y.
The results are being published in this week's issues of Nature and
Science.
The new work is important because it captures the critical moment of
infection when one of the probes that stud the surface of the virus
makes contact with the outer membrane of a target cell.
David Baltimore, president of the California Institute of Technology and
chairman of a committee that advises the government on AIDS research,
described the finding as a landmark, arrived at by "great engineering
and superb crystallography."
Although researchers understood the process of infection in a general
way, they can now see what happens with the precision of an atom's eye
view.
"It's the difference between being blind and being sighted," said Joseph
Sodroski, one of the authors of the new report.
"You can immediately visualize the conserved elements of the protein,
which make attractive targets for drugs or vaccines," he said, referring
to the regions of the probe that the virus does not change by mutation.
The X-ray pictures show that the probe latches on to one site, then
changes its shape to reveal another, previously hidden grapple that
snags the second site. Because the grapple is hidden until the last
moment, it is largely invisible to the immune system.
Another reason for the virus' ability to evade immune detection, the new
pictures show, is that the surface of the initial probe is swathed in
sugar molecules, which the immune system does not recognize as foreign
since many of the body's own proteins also are cloaked with sugar.
The X-ray pictures of the viral probe are a long-sought prize that have
eluded detection hitherto. The features that make the virus so
changeable and barely visible to the immune system also make it
extremely hard to X-ray
These obstacles have now been overcome by making stripped-down versions
of the viral probe and the two sites it attacks. The stripped down
versions were synthesized by Sodroski and Richard Wyatt and the
Dana-Farber Institute. The X-ray analyses were made by Wayne Hendrickson
and Peter Kwong at Columbia University.
"It's a very innovative and imaginative solution. It will be hard to
find another AIDS paper this year that will have a bigger impact," said
John Moore, an AIDS researcher at Rockefeller University in New York
City.
Peter Kim, an X-ray crystallographer at the Whitehead Institute in
Boston, said that many laboratories in industry and universities had
tried to crystallize the virus' probe protein. "It's a testimony to
their perseverance that they succeeded," he said.
The X-ray pictures show the precise shape of the probe as it interacts
with its targets, two antenna-like projections from the cell's surface
that receive chemical signals from other cells. The structures are known
to researchers as the CD4 receptor and the chemokine receptor.
One notable feature seen in the new pictures is that part of the CD4
receptor pokes into a large cavity inside the probe. "When I first saw
that I said, 'My God, that's the cure for AIDS,' " said Kwong, meaning
that the cavity is an obvious target for drugs.
The possibilities for a vaccine seem less promising, however, because of
the virus' two-target strategy. The real target, it seems, is the
chemokine receptor, but to decoy the immune system the virus first
latches on to the CD4 receptor. The first interaction triggers the
opening up of its grapple for the chemokine receptor. Once it is open,
the grapple is vulnerable to immune attack but by this time it is
already poised above its target, giving the antibodies of the immune
system little time or space to attack.
Devising a vaccine "is certainly a long shot," Hendrickson said, "but
the better we understand this culprit the more likely it is that
effective agents can be designed."
"Having the binding site for CD4 is a great plus because it could give
an idea of a site for an inhibitor of binding," Baltimore said,
referring to the possibility of a drug to attack the site.
Some scientists are skeptical that current candidate vaccines, based on
the probe protein, will be successful, a view they say is confirmed by
the new X-rays.
Don Francis, the president of VaxGen, the company now testing one of the
vaccines, responded that tests in chimpanzees show the vaccines protect
the animals from very high doses of virus.
"It works in a chimp, it's safe in humans and it produces a better
immune response in humans than in chimps. To sit back and wait for more
lab tests would, I think, be unconscionable," Francis said.
The work in Hendrickson's laboratory was funded by the Howard Hughes
Medical Institute in Bethesda, Md., which also spent $10 million on the
device that collects X-rays from the Brookhaven accelerator. |
