In the quest to develop a vaccine to prevent AIDS, the optimal weapon may be not a sniper rifle but a shotgun. Scientists have discovered that patients who fight off HIV more effectively than others possess a broad range of antibodies that attack many different parts of the deadly virus instead of a single vulnerable point.
Thus far, HIV has proved notoriously resistant to any potential vaccine or cure. One reason is that it directly attacks the immune system. But it also mutates rapidly; many of the proteins that make up the virus’s outer capsule can change too fast for the immune system to keep up.
To get around this problem, scientists have tried injecting into the blood snippets of proteins that don’t alter as quickly—most notably the so-called CD4 binding site of the gp120 protein. This simple strategy, used in the first vaccines against smallpox and most others since, would in theory create circulating antibodies that neutralize the virus before it has a chance to establish a foothold in the body. But for HIV, the strategy so far has failed in clinical trials—for instance, the aborted study of Merck’s experimental vaccine V520 in 2007.
The new research—which also offers the first near-complete census of anti-HIV antibodies—suggests that vaccinologists may be off-base in attempting to create a single, highly effective antibody against HIV. A better strategy might be to generate many different antibodies or even to induce a greater response from the entire immune system after infection, researchers say.
“For the first time, we know how the natural immune response makes very potent antibodies, and from this hopefully we can make a vaccine,” says study author John Mascola, deputy director of the Vaccine Research Center at the National Institute of Allergy and Infectious Diseases.
New attack sites
Previous knowledge of the HIV immune response came from extracting and analyzing circulating antibodies in the blood serum of infected patients, but these studies painted an incomplete picture.
The new study, on the other hand, used a more sophisticated technique to study six rare, “slow-progressing” HIV patients—people who have higher antibody levels and therefore reduced amounts of virus circulating in their blood. Developed in the past few years, the method involves running blood past tiny bits of virus, which allows scientists to pull out not just circulating antibodies but the actual memory B cells that produce those antibodies.
“Once we have identified the cell, we can pick it out, produce a library copy and clone the antibody genes,” says the study’s principal investigator, Michel Nussenzweig of Rockefeller University. This in turn allows the scientists to produce large batches of pure antibodies, as well as finding out exactly where the antibodies bind on the virus and how effective they are at stopping it from infecting additional cells.
There were many surprises in the findings, published online in Nature on March 15, he says. One was the sheer diversity of antibodies—some people in the study produced as many as 50 different kinds. Researchers also found that some antibodies attacked sites on the virus that weren’t known to be vulnerable, including another spot on gp120 close to the CD4 binding site.
None of these sites, though, was “immunodominant,” or significantly more susceptible than any other. “No single antibody accounts for the serum-neutralizing activity,” Nussenzweig says. “Only a combination of antibodies seems to be broadly neutralizing.”
These results suggest that, with some help, the body could mount an effective attack against HIV, although perhaps not strong enough to erase the virus after it has damaged a person’s immune system. Rather, Nussenzweig says, scientists hope that by using a cocktail of multiple proteins, they can stimulate a vaccine response similar to the body’s natural response but starting earlier and acting faster, preventing infection completely.
“We want to know the minimum number of antibodies that can be broadly neutralizing,” he says.
Treating, not preventing
Not everyone shares such optimism about a preventive vaccine. Some experts in the field say that the immune system is fundamentally flawed in its response to HIV and that experimental vaccines resulting from the current research approach do not stand a chance.
“It looks like it is beyond the reach of the natural immune system,” says Sudhir Paul, a professor of pathology at the University of Texas Medical School at Houston who was not involved in the new research paper. “To fight HIV, we need to engineer new kinds of vaccines.”
But the new research is important because it takes one step forward toward an immunotherapeutic vaccine—one that can be used for someone who has already contracted the virus, he says.
“This study shows that infected individuals have an immunological memory for certain important parts of the virus,” Paul says. “If we can stimulate that memory, we can get an explosive response to HIV.”
That approach may ultimately be quite important, as many people already suffer from the virus. “There is hope,” he says. “If we had a compound that could stimulate immunological memory, we could vaccinate people already infected” to cure them.