AIDS Study Shows
HIV Is A Shape-Shifting
"Viral Houdini"
By Maggie Fox
Health and Science Correspondent
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.
``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.''

Sightings HomePage