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HIV's Stealth Located in Key Discovery - 2002-12-12

U.S. biologists have discovered a key reason why the AIDS virus, HIV, outwits human disease defenses. The virus engages in a novel method of deception against the immune system. Understanding how HIV changes itself could lead to a vaccine against it.

HIV has puzzled scientists for years. They know that its presence attracts swarming hordes of immune system warrior cells called antibodies. Antibodies are an important early defense against disease. They normally ambush microbes to block them before other types of immune cells break them up and devour them. But somehow, antibodies fail to neutralize HIV. This is all the more mystifying because HIV particles display certain proteins that are large and clear signals, like battle flags telling antibodies that the enemy is present and to attack.

A team of biologists led by Peter Kwong of the U.S. government's National Institutes of Health wanted to know what caused antibodies to stall. "What is the peculiar nature of the virus that has allowed it to exist in the way it has and to create this enormous pandemic? What is unique about it that allows it to remain resistant to neutralization?"

After studying the lack of interaction between HIV and several types of antibodies, Mr. Kwong and colleagues have an answer. The deceptive HIV changes its surface proteins in a way that antibodies cannot lock onto. According to research team member Joseph Sodroski of Harvard Medical School in Boston, the virus uses a fixed surface protein called GP120 as a signal to elicit antibodies, but then alters it so that it becomes an elusive moving target, discouraging the continuing antibody production that ultimately defeats a microbe. "We think that the GP120 is broken up into parts and those parts are moving with respect to one another," says Mr. Sodroski. "All of these antibodies have to lock GP120 into a very rigid state when they bind, and that is something that is difficult for an antibody to do."

Forging an effective antibody response is crucial to a successful vaccine against any virus because antibodies are one of the first immune actors. A vaccine is simply a method of introducing a disease safely into a person to train the immune system for the real onslaught.

Because antibodies have proven ineffective against HIV, experimental AIDS vaccines currently in human testing do not even try to trigger them. Instead, they seek to teach the immune system to rouse other types of defensive cells to act.

But the new research offers hope that an HIV vaccine might eventually activate antibodies. In other experiments, the scientists have partially reduced the mobility of the HIV GP120 surface protein. Mr. Sodroski says it is important to get a vaccine to do so. "If we can rigidify those regions, make them a little less flexible, and present them to the immune system in a vaccine, then we could make a more effective antibody response.," he says. "Now, the virus we can't change. The virus is still going to have this flexibility. But we do know that some of these antibodies, once they are made, can be reasonably effective against some of the viruses."

Even if an HIV vaccine could incorporate an antibody defense, it is far too soon to know whether it would turn the tide against the virus. Biologist Theodore Jardetzky of Northwestern University in Chicago says the virus uses several tactics to evade the immune system, and the antibody deception is just one of them. "These researchers have really defined a new concept for us to try to understand," he says. "Now the big question is whether or not we can prove that this mechanism is a dominant effect in preventing the generation of a protective immune response and if we can actually engineer ways of bypassing this escape mechanism. That has yet to be determined."

The research appears in the December 12 issue of the journal "Nature."