- WASHINGTON (Reuters) - Researchers said Wednesday they had gotten their
first good look at the physical structure of a key protein used by the
AIDS virus, and found it is a ``viral Houdini'' that shifts shape to evade
the body's defenses. They managed to image the crystalline structure of
the gp120 protein the virus uses to break into the immune system cells
it attack -- an important step toward designing new drugs and vaccines
to fight it. Dr. Joseph Sodroski and colleagues at Harvard's Dana-Farber
Cancer Institute and New York's Columbia University said they found some
surprises, including some formidable defenses and an ability to change
shape to elude the body's defenses. ``We discovered that a large part of
the gp120 surface is protected against attack by a dense army of carbohydrates
and by an amazing capacity to change shape,'' Sodroski said in a statement.
``HIV is a viral Houdini.''
-
- He added in a telephone interview: ``It's
probably changing shape as part of its natural function. We also know that
different strains vary ... so it is a quick-change artist in that sense.''
The findings, published in both the science journal Nature and the journal
Science this week, show that gp120 uses loop-shaped regions to mask its
critical locking elements until the last minute. It also has a coating
of sugar molecules that act as a shield against antibodies -- immune system
proteins that attack invaders.
-
- But the structure also reveals some potential
weaknesses that could be targeted by drugs or vaccines, including the structure
that HIV uses to attach to CCR5, one of the receptors or cellular doorways
the virus uses to enter cells. Blocking this structure could stop HIV from
infecting cells. The protein gp120 is one of the main targets of vaccines
against the virus, and knowing about its structure can help scientists
physically design a version of gp120 that will stimulate the body's immune
system better.
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- ``Studying the gp120 crystal's structure
can tell us a lot more about how the virus locks on to immune system cells,''
Dr. Anthony Fauci, director of the National Institute of Allergies and
Infectious Diseases (NIAID), said in a statement. ``We now have specific
target sites on which to focus in developing new drugs and vaccines.''
Advanced equipment lets scientists ``see'' exactly what drugs look like
physically, as well as the microbes or natural body substances they act
on. They can match the physical structures of the drugs to the physical
structures of the microbes, so they fit together perfectly. The NIAID said
the research could indicate that some of the vaccines under development
against HIV might not work. For example, South San Francisco-based VaxGen
Inc.'s vaccine -- the first HIV vaccine to enter final clinical trials
in people -- uses gp120.
-
- ``Gp120, which is this VaxGen approach,
has been tried before and it has been very disappointing and I think that
is something we can expect,'' Sodroski said. He said it took the teams
five years to make the protein form a crystal structure that could then
be imaged using X-ray crystallography. ``It's easy to build crystals out
of molecules that are uniformly shaped, but gp120 has all these sugars
on it,'' he said. ``It has these variable loops on the surface that are
probably moving all over the place. It's like trying to build a house
out of bricks that aren't square. Gp120 was terrible in terms of getting
it to crystallize.''
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