Download Antibody Kills 91% of HIV Strains

Antibody Kills 91% of HIV Strains
JULY 8, 2010,
By MARK SCHOOFS
In a significant step toward an AIDS vaccine, 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.
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. That vaccine was not designed to elicit the new antibodies.
The new discovery is the latest in 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.
But 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 antibody was found to attack a spike on the virus that attaches
to cells the virus infects. Because this spike 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 potent
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.
One potential pitfall: 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 [email protected]