Researchers are inching their way toward a new HIV vaccine strategy by studying the cells of people who have naturally strong immune defenses against the virus.

Researchers are inching their way toward a new HIV vaccine strategy by studying the cells of people who have naturally—and bafflingly—strong immune defenses against the virus.

Last year, Howard Hughes Medical Institute investigator Michel C. Nussenzweig's team figured out how to isolate key immune cells from rare individuals who are HIV-positive but carry very low levels of the virus in their blood and have only mild, if any, symptoms.

Antibodies increase their stickiness to their antigen because they use both arms to grab. With HIV, an antibody can only hold on with one arm.

Michel C. Nussenzweig

That study found that these individuals produce a diverse army of antibodies—blood proteins that go after foreign invaders—to target HIV particles from multiple angles.

Now, the team has discovered that some of these so-called 'broadly neutralizing antibodies' are versatile in another way: a single antibody can bind to two structurally distinct sites on an HIV particle at once. The findings are published in the September 29, 2010 issue of the journal Nature.

Although neutralizing antibodies cannot cure HIV once an individual is infected, experiments in primates have suggested they could ward off the initial infection. "That's why people are so interested in them—it’s believed, although not proven, that if you could get people to make these antibodies de novo, that you would be able to prevent HIV," says Nussenzweig, professor of molecular immunology at The Rockefeller University in New York.

Drawing from the blood of six patients, Nussenzweig and colleagues—including fellow HHMI investigator Bruce D. Walker—analyzed 134 neutralizing antibodies that target a the spike of the HIV particle, dubbed gp140, which the virus uses to invade immune cells. Although the spike mutates, the antibodies are directed toward critical portions that are shared by most if not all virions.

Antibodies have two arms, and they typically work by attaching each arm to identical and nearby copies of a foreign antigen. "Antibodies increase their stickiness to their antigen because they use both arms to grab," Nussenzweig explains. Antibodies can't use this approach with gp140, however, because the spikes are sparse—only about 15 per particle—and often far apart. "With HIV, an antibody can only hold on with one arm," he says.

The new experiments reveal how certain neutralizing antibodies manage to get a better grip. Three-quarters of the antibodies drawn from the six patients are 'polyreactive': meaning one arm of the antibody binds strongly to gp140, whereas the other can bind more loosely to a variety of other types of molecules. "We believe that the antibodies that we see are selected to have this additional property so that they can hang on better," Nussenzweig says.

This non-specific stickiness is not usually a good thing: if an antibody could bind to many different structures, then it could more easily latch on to host cells, increasing the risk of autoimmune disease. In fact, as Nussenzweig reported in Science in 2003, only about five percent of antibodies in the mature immune system are polyreactive.

No one knows how or why some people, like these six patients, make swarms of polyreactive antibodies. Researchers do know that it takes about three years for people to develop these super fighters—and the new work gives a potential explanation.

Broadly neutralizing antibodies carry a host of genetic mutations that they have acquired over time, presumably in response to the actions of co-evolving viral particles. When the researchers engineered the gp140 antibodies so that they no longer had the mutations, they lost the ability to bind and neutralize HIV.

This suggests that a vaccine that triggers this process might take years to take full effect. Still, this 'natural' approach to vaccine development might be an effective alternative to the more traditional strategy, Nussenzweig says.

So far, most attempts at designing HIV vaccines have relied on 'reverse immunology': exposing an individual to unnaturally high levels of an engineered HIV antigen to spur their immune system to produce a particular kind of antibody. But this method has not been able to induce individuals to make broadly neutralizing antibodies.

An alternative approach might be to expose individuals to low levels of viral antigens, mimicking what happens in a real infection. "What I'd love to be able to try, is to allow the immune system to see essentially what it would see during the infection, but without an infection," Nussenzweig says. "That's how most successful vaccines are made."

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