Antibody Discovered for 91% of HIV Strains

[TampaYankee]

Antibody Discovered for 91% of HIV Strains

By MARK SCHOOFS

http://online.wsj.com/article/SB10001424052748703609004575355072271264394.html

U.S. government scientists have discovered three powerful antibodies, the strongest of which neutralizes 91% of HIV strains, more than any AIDS antibody yet discovered.

Looking closely at the strongest antibody, they have detailed exactly what part of the virus it targets and how it attacks that site. Together with recent research into how to make animals produce antibodies, the new findings constitute a significant step toward an AIDS vaccine.

The antibodies were discovered in the cells of a 60-year-old African-American gay man, known in the scientific literature as Donor 45, whose body made the antibodies naturally. Researchers screened 25 million of his cells to find 12 that produced the antibodies.

Now the trick will be for scientists to develop a vaccine or other methods to make anyone's body produce them.

That effort "will require work," said Gary Nabel, director of the Vaccine Research Center at the National Institute of Allergy and Infectious Diseases, who was a leader of the research. "We're going to be at this for a while" before any benefit is seen in the clinic, he said.

The research was published Thursday in two papers in the online edition of the journal Science, 10 days before the opening of the large International AIDS Conference in Vienna, where prevention science is expected to take center stage.

More than 33 million people were living with HIV at the end of 2008, and about 2.7 million contracted the virus that year, according to United Nations estimates. Vaccines, which are believed to work by activating the body's ability to produce antibodies, eliminated or curtailed smallpox, polio and other once-feared viral diseases, so they have been the holy grail of AIDS research.

Last year, following a trial in Thailand, results of the first HIV vaccine to show any efficacy were announced. But that vaccine reduced the chances of infection by only about 30%, and controversy erupted because in one common analysis the results were not statistically significant. The vaccine was not designed to elicit the new antibodies.

The new discovery is part of what Wayne Koff, head of research and development at the nonprofit International AIDS Vaccine Initiative, calls a "renaissance" in HIV vaccine research.

Antibodies that are utterly ineffective, or that disable just one or two strains, are common. Until last year, only a handful of "broadly neutralizing antibodies," those that efficiently disable a large swath of HIV strains, had been discovered, and none of them neutralized more than about 40% of known HIV variants.

In the last year, thanks to efficient new detection methods, at least a half dozen broadly neutralizing antibodies, including the three latest ones, have been identified in peer-reviewed journals. Most of the new antibodies are also more potent, able to knock out HIV at far lower concentrations than their previously known counterparts.

Dennis Burton of the Scripps Institute in La Jolla, Calif., led a team that discovered two broadly neutralizing antibodies last year; he says his team has identified additional, unpublished ones.

Some of the new antibodies attack different points on the virus, raising hopes that they could work synergistically. In unpublished research, John Mascola, deputy director of the Vaccine Research Center, has shown that one of Dr. Burton's antibodies neutralizes virtually all the strains that are resistant to the strongest new antibody, called VRC01, and vice versa. Only one strain out of 95 tested was resistant to both antibodies, he said. Dr. Mascola is one of the authors of Thursday's papers.

In the latest research, the antibodies were found to attack a key site on a spike on the virus that attaches to cells the virus infects. Because this site has to attach to a specific molecule on the cell surface, it is one of the few parts of HIV that don't mutate much.

Scientists tested 32 patients to see which ones had sera—clear fluid in the blood—that neutralized HIV. The sera contained unknown antibodies. Donor 45 had promising sera, so they focused on him.

Researchers say they plan to test the new antibodies, likely blended together in a cocktail, in three broad ways.

First, they could be given to people in their raw form, somewhat like a drug, to prevent transmission of the virus. However, they would likely be expensive and persist in the body only for a limited time, perhaps weeks, making that method impractical for all but specialized cases, such as to prevent mother-to-child transmission during childbirth.

The antibody could also be tested in a "microbicide," a gel that women and receptive partners in gay male pairings could apply before sex to prevent infection.

The antibodies might even be tried as a treatment for people who are already infected. While the antibodies are unlikely to completely suppress HIV on their own, say scientists, they might boost the efficacy of current antiretroviral drugs.

Dr. Nabel said that the Vaccine Research Center has contracted with a company to produce an antibody suitable for use in humans so that testing in people could begin.

The second way to use the new research is to deploy classical vaccine approaches. Traditional vaccines work by using a weakened or dead virus, or a viral fragment, to train the immune system to recognize the invader and produce antibodies. Because the new HIV antibodies are extremely specific, attaching tightly to particular parts of the virus, scientists have to show the immune system an exact replica of the parts of the virus that the antibodies attack.

That's a tall order—for example, it can be hard for such a replica to hold the correct shape—but different teams are trying different ways to achieve this goal.

In a little-noticed study published earlier this year in the Proceedings of the National Academy of Sciences, scientists at Merck & Co. provided what Dr. Koff calls a "proof of principle" that other researchers can build on. Starting with an old antibody—one that is much weaker than the newly found ones—the Merck researchers created replicas of its target site. It was a painstaking, iterative process, requiring the researchers to add chemical bonds to stabilize the replica so that it wouldn't collapse.

Eventually, Merck was able to produce experimental vaccine candidates capable of stimulating guinea pigs and rabbits to produce the antibody. John Shiver, head of Merck's vaccine research, said he believes similar vaccine candidates could be "engineered using one of these new antibodies."

There are other potential pitfalls. There is evidence that Donor 45's cells took months or possibly even years to create the powerful antibodies. That means scientists might have to give repeated booster shots or devise other ways to speed up this process.

Finally, there are experimental methods that employ tactics such as gene therapy. Nobel laureate David Baltimore, with funding from the Bill and Melinda Gates Foundation, is working on one such approach.

His team at the California Institute of Technology in Pasadena, Calif., has stitched genes that code for antibodies into a harmless virus, which they then inject into mice. The virus infects mouse cells, turning them into factories that produce the antibodies.

Using one of the old antibodies, Dr. Baltimore said his team was able to protect mice from getting infected when injected with live HIV. Those experiments are not published. Recently, his lab has begun working with Dr. Burton's antibodies and the strongest antibody from Donor 45. Even if it proves successful, this strategy is years away from the clinic, Dr. Baltimore cautioned.

Write to Mark Schoofs at mark.schoofs@wsj.com

[MsGuy]

Read this article, came here to post a link but find TY already on the ball.

Maybe the medical boffins are finally getting a good hold on this damned virus.