A new high-throughput screening technique has uncovered two antibodies that wipe out a wide spectrum of different HIV strains. The targets of these antibodies -- and the method used to find them -- could lead to a much-needed HIV vaccine that confers broad protection against the virus.
"If a vaccine can elicit neutralizing antibodies like the ones discovered here, it would have a strong chance of being effective," says John Mascola, a virologist at the Vaccine Research Center of the National Institute of Allergy and Infectious Diseases in Bethesda, Maryland, who was not involved in the study.
To date, two potential HIV vaccines have been tested -- and failed -- in human clinical trials. The STEP trial, which aimed to elicit a T-cell immune response, was called off in 2007 after the vaccine was found to put participants at greater risk of HIV infection. And a previous attempt, intended to prompt an antibody response, fell through in 2003 after the vaccine failed to trigger any broadly neutralizing antibodies. So the hunt has been on to find other vaccine candidates that recognize and latch on to many forms of the virus.
Now, a team led by Dennis Burton of the Scripps Research Institute in La Jolla, California, has systematically screened blood samples from around 1,800 HIV-positive individuals in five continents looking specifically at the blood's ability to block HIV infection directly. This differs from past screens, in which researchers looked only for antibodies that could bind to tags on the virus's shell. Burton's team found that around 1% of these individuals were 'elite controllers' -- HIV-infected people whose bodies naturally keep the virus at very low levels in the bloodstream without treatment. The researchers then focused on one elite African donor and sifted through the contents of some 30,000 memory B cells -- which produce antibodies quickly by 'remembering' previous infections -- to pinpoint two antibodies with cross-reactive potential.
These two molecules not only interfered with around 75% of all HIV strains tested, but they did so at much lower concentrations than any other previously identified broad-acting antibodies against HIV, the researchers found. "Here we have breadth but also potency," says Burton, who with his team reported the findings online today in Science. As such, future vaccines might not have to induce very high levels of the antibodies to generate a far-reaching protective effect, he says.
Cream of the antibody crop
The two newly discovered HIV-specific antibodies are the first to be identified in more than a decade and the first from an HIV carrier living in the developing world, where most new HIV infections occur. The molecules target a protein on the surface of the virus called gp120 that is used to infect human cells, but at a region of the protein that is conserved among most HIV strains. That's why the antibodies provide wide protection, says Burton. "They're seeing an epitope that's on most viruses."
This epitope, or immune tag, provides a new spot on the virus that could be converted into antigens and incorporated into a vaccine to stimulate similar antibodies, says Dan Barouch, an immunologist at the Beth Israel Deaconess Medical Center in Boston, Massachusetts. "It really expands our thinking in terms of where the chinks in the armour and the vulnerabilities lie."
Applying the same high-throughput screening technique to samples from other elite controllers should turn up more vaccine targets, says Michael Zwick, a molecular immunologist at the Scripps Research Institute who was not involved in the study: "This kind of approach will almost certainly lead to more antibodies."
Burton says that his team has probed around 25 of the top elite controllers from his international panel of donors, and is focusing on characterizing around 10 of the most promising antibodies. "We're almost certain there are a lot more antibodies in there," he says.
But such potent master antibodies might not be all that common, cautions Mascola. Broad protection could also stem from the collective action of many independent antibodies, he says. Earlier this year, Mascola and a research team led by Michel Nussenzweig of The Rockefeller University in New York cloned more than 500 HIV-specific antibodies from 6 elite controllers, and showed that up to 50 antibodies contributed to the overall protective effect. "We don't know which result is more common, or if they both happen," Mascola says.