In the continuing search for the Achilles heel of HIV, researchers may finally be enjoying some success.
This week, government researchers at the Vaccine Research Center of the National Institute of Allergy and Infectious Diseases (NIAID) reported the discovery of two naturally occurring antibodies that may block HIV. Describing their work in two separate papers in the journal Science, AIDS experts said that in lab experiments, the antibodies had successfully prevented more than 90% of circulating HIV strains from infecting human cells.
This is not the first discovery of so-called broadly neutralizing antibodies. Last September, scientists at Scripps Research Institute and the International AIDS Vaccine Initiative (IAVI) identified two other antibodies that prevent against infection from 80% of existing HIV strains the most potent known antibodies at the time. The findings were also published in Science.
The two sets of antibodies target different regions of the virus-cell interface together they could help scientists develop a formidable vaccine against AIDS, says Dr. Anthony Fauci, director of NIAID. "The strategy is going to be to put the best antibodies together, and you are going to have a whopper against HIV," he says.
Antibodies are the first-line soldiers of the immune system. Produced by specialized cells in the body that recognize incoming viruses and bacteria, antibodies act as molecular barricades, latching onto and blocking pathogens from infecting healthy cells. This antibody response is the core of all vaccine-based disease prevention.
But HIV is notoriously changeable. The virus continuously alters the makeup of the proteins on its surface, eluding attack from antibodies created by the immune system and from the relatively weak vaccines that have been developed against the virus so far.
The two new antibodies described in the current Science paper work by blocking a protein on the surface of HIV that the virus normally uses like a key to access healthy cells. This key, which tends to remain constant across most strains of the virus, binds to an entry point on a healthy cell surface, called the CD4 receptor site. When antibodies attach to this region of HIV, it cannot interact with CD4 or get inside a host cell.
Because this particular site on HIV is so crucial and rarely mutates, the virus keeps it jealously hidden under convoluted folds of its protein coat, which makes most antibodies designed to latch onto it ineffective. Certain individuals, however, generate antibodies that recognize and bind to the site more easily, so when they are infected with HIV, they are able to fight off infection.
NIAID scientists identified the new antibodies by screening the blood of one HIV-infected African American patient who produced them naturally. By lifting the obstructive protein covering that HIV uses to guard its CD4-binding site, and isolating only those antibodies that were tailor-made to attach to this gate, scientists zeroed in on just two antibodies that were able to neutralize an unprecedented 90% of circulating HIV strains.
Previous experiments on CD4 have identified other naturally occurring antibodies. But these were effective against only 40% to 50% of HIV strains in tests in the lab because they were less precisely targeted, acting on a combination of the actual binding site and the virus's surrounding protein coat.
In the 2009 study led by Dennis Burton of Scripps Research Institute, scientists focused on a different type of antibody involved in the actual process of viral entry. In order to infect a cell once HIV finds an entry point, the virus changes shape, folding itself into a form that allows it to slip inside the healthy cell. Burton's antibodies interrupt that action, blocking about 80% of circulating HIV strains from taking the shape necessary for infection. However, Burton says he and his team are still figuring out exactly how the process works.
Taken together, the recent discoveries boost the prospect of using broadly neutralizing antibodies as the backbone of an HIV vaccine, experts say. In Burton's study, the antibodies were isolated from a blood sample from Africa; in the current study, the antibodies cam from an African American man. In each case, the patients were infected with a different strain of HIV. That's important, Burton says, because it confirms that effective antibodies can be produced by people on different continents carrying different strains of the virus. "The more you see different people making antibodies, the more relaxed you become that different people can do it, and therefore given the right vaccine, that more people can make antibodies against HIV," he says.
So far, the newly discovered antibodies have been tested only in a lab dish. But Burton says he is a few months from beginning animal studies to determine whether his antibodies can prevent HIV infection in a living system as well they do in the lab.
Experts remain hopeful that this line of work will someday lead to the development of an AIDS vaccine than can be tested in humans. "I can guarantee that you're not going to get a vaccine unless you get good antibodies," says Fauci.