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Ganging Up on HIV

A diverse group of antibodies may work together to neutralize the virus, suggesting a new approach to vaccination.

The human immunodeficiency virus (HIV) is infamous for being a wily opponent, evolving faster than the immune system can keep up with it. Even now, 25 years after the virus was discovered, efforts to create a vaccine against it have fallen flat. While scientists have engineered antibodies that provide broad protection against the virus, vaccines designed to trigger the production of these antibodies work in monkeys but fail to elicit any immunity whatsoever in humans. Now new research shows that vaccines might do better if they could stimulate the body to produce not one of these “super” antibodies but hundreds of milder ones that act, en masse, to take down HIV.

Neutralizing HIV: Shown here are HIV viruses budding from an immune cell.

Researchers from Rockefeller University examined the blood of six “slow progressing” HIV patients–people who can be infected for a long time without getting sick because their bodies are able to sufficiently control the virus. Using a novel technique to identify HIV-antibody-producing cells in the blood, and then another new method to isolate the antibodies themselves, the researchers found 433 different antibodies from these patients that can bind to a particular protein–called gp140–that the virus needs in order to infect immune cells. Many of these human isolated antibodies were capable of neutralizing some strains of HIV in lab tests.

Previous efforts to engineer an HIV vaccine have targeted this protein, but failed to stimulate the human immune system to produce any of the four broadly neutralizing antibodies described to date. The newly discovered group of antibodies, however, provides insight into the body’s natural response to the virus. Unlike the man-made antibodies, none has a great individual impact. But together, they can successfully hold the virus in check. “Not a single one of them is like the ‘fantastic four,’ but the body doesn’t make the fantastic four,” says Michel Nussenzweig, a professor of molecular immunology at Rockefeller University, who led the research. “So maybe what this says is that the kind of vaccine you want is one that will make all these other little guys that, together, will be effective.” The research was published online in the journal Nature on Sunday.

“They essentially rescued the immune memory of six individuals infected with HIV into a test tube,” says Dennis Burton, an immunology professor at the Scripps Research Institute and head of the newly formed HIV Neutralizing Antibody Center. “It’s a major tour de force of immunology.” But he notes that while the study is a great leap forward, there’s still some distance to go before researchers completely understand how people’s immune systems respond to HIV. “There’s still many outstanding problems and issues–we’ve got some of the pieces of the jigsaw puzzle, but there’s a lot of pieces still missing,” Burton says.

Finding such a broad array of antibodies was a huge task that required a novel set of techniques. First, the researchers had to identify the immune cells that bound to gp140 by staining them with HIV proteins. Cells that tested positive were separated out, and the scientists created a “library” of the cells’ DNA fragments. From these fragments, they cloned all the antibodies, expressed them in a new batch of cells, purified out the secreted antibodies, then tested them for their ability to bind to gp140 and to determine whether they inhibited virus replication.

“It’s an impressive amount of work,” says David Montefiori, the director of the Laboratory for AIDS Vaccine Research and Development at Duke University Medical Center. “Nothing of this magnitude has even been attempted before.”

The newly isolated antibodies themselves are unlikely to be an effective protective treatment or therapy. While some of the 433 antibodies can neutralize some strains of HIV, taken together, they cannot broadly neutralize all relevant strains. And the virus would continue to mutate, likely rendering the antibodies’ neutralizing powers less potent over time.

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