Friday, September 04, 2009

New Antibodies for HIV: Fresh Hope for a Vaccine?

Scientists probably know more about HIV than any other pathogen, but despite that fact, they have had frustratingly little success in applying their knowledge toward a vaccine against the virus.

Now, after more than 15 years of trial and error in the field, researchers at the Scripps Research Institute and the International AIDS Vaccine Initiative (IAVI) report they have discovered two powerful new antibodies to HIV, which may potentially lead to the development of a way to immunize against the virus. (See TIME's photo essay "Access to Life.")

While the new antibodies are not the first of the so-called broadly neutralizing antibodies that have been isolated from HIV-positive patients, they appear, at least in the lab, to be 10 times more effective at disarming the virus than earlier versions. They are also effective against a broad array of HIV strains that span nearly every continent, from Europe and North America to Asia and Africa. That would make them ideal candidates for a new vaccine — one that could actually protect people from becoming infected with HIV at all.

In a way, it's a back-to-the-future approach. Vaccines, including many of the familiar ones that target childhood diseases such as measles and mumps, work by training the immune system to generate antibodies against a foreign bacteria or virus. Made by immune cells known as B lymphocytes, these antibodies bind to specific portions of a virus and then hamper that virus from infecting healthy cells. Eventually, the piggybacked antibody also tags the invading virus for destruction by other immune cells, known as T cells. (See TIME's AIDS covers.)

"We looked at 162 different [HIV] viruses, and these antibodies neutralized 120 to 130 of strains from all across the world," says Dennis Burton of Scripps, the lead author of the study, published in the Sept. 4 issue of Science. "They certainly don't get everything. But if you are able to get 80% or more of viruses circulating out there with one single antibody, that's terrific. That's really, really good, considering how variable these viruses are."

That variability has been the biggest challenge for HIV vaccinemakers. HIV mutates so rapidly once it finds a new home in an infected patient that it's hard for researchers to keep pace and target the portions of the virus that are conserved. It was a lesson that Merck learned the hard way in 2007, when trials of its promising AIDS-vaccine candidate not only failed to protect people from acquiring HIV but in fact appeared to raise the risk of infection in inoculated people, compared with those who did not get the vaccine. (It's not clear why Merck's compound failed so miserably, but researchers believe it may have to do with the vector, an inactivated cold virus, that was used to ferry the immunity-triggering HIV proteins into the body; some people may have developed enough natural tolerance to the common-cold virus that their immune system did not react to it, or to the viral payload piggybacked on it, at all.)

Given that recent setback, Burton's team decided on a different approach. Instead of trying to identify which portions of HIV elicited the best immune response — a strategy that has been attempted without much success in not just Merck's but other previous vaccine efforts as well — they started with a pool of antibodies they knew could neutralize HIV and then backtracked to determine how to entice the immune system into producing them. To find the most effective antibodies, Burton's team used the latest biological and computational screening techniques, which emerged from genome-sequencing technologies. They collected blood serum from 1,800 HIV-infected people from around the world, then screened these virus-laden samples against B cells to see how many of the HIV strains the immune cells would recognize. To their surprise, the B cells were able to neutralize a fair number of the viruses, but two of the antibodies produced by the cells clearly stood out as more potent than the rest.

"This paper is important because what the authors were able to do is identify many more neutralizing antibodies than what we find in the serum of patients," says Dr. Anthony Fauci, director of the National Institute on Allergy and Infectious Disease, which raises the question, "Why don't people make antibodies to all of these HIV strains? Why isn't their blood naturally loaded with these antibodies?"

One reason may be that HIV is able to hide from B cells, jealously guarding its most conserved, and therefore most vulnerable, portions from view. That would prevent the body from creating the right neutralizing antibodies against the virus. But the two new antibodies reported in Science target a less hidden region of the viral coat, so it may be possible that if a new vaccine is developed, it could stimulate the immune system to marshal a robust enough force of antibodies to stop HIV.

The new discoveries have renewed some AIDS researchers' faith in the vaccine approach. In the lab, says Fauci, scientists know that these antibodies can effectively stop HIV in its tracks, starving it out by preventing it from binding to immune cells that provide it with the nutrients and machinery it needs to grow and reproduce.

The next and perhaps greater challenge is making the right concoction of viral proteins that will stimulate the immune system to churn out these antibodies in large amounts. "Now that we have the antibodies, we have to go back and create the [immune signal] that produces these antibodies," says Seth Berkley, president and CEO of IAVI. After that, the task is to package that immune signal in the form of a usable vaccine. Says Fauci: "And that's a big catch, a second hurdle that we have not gone over yet."


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