Ten years ago, at the University of Agriculture in Vienna, Austria, microbiologist Hermann Katinger isolated an antibody that few had ever seen before. It came in blood from a man who was infected with HIV, the human immunodeficiency virus.
Antibodies, of course, are unleashed against pathogens by the body's immune defenses. Viruses in turn multiply mightily and eventually outnumber and outsmart the antiviral antibodies, and eventually bring AIDS to fruition with lethal consequences.
This maverick, oddball Viennese antibody differed so drastically from run-of-the-mill models that it has set many people in the HIV research community hunting for the ultimate AIDS vaccine.
Molecular immunologist Dennis Burton, a professor at the Scripps Research Institute in La Jolla, Calif., explained what made Katinger's antibody (which he had routinely named 2G12) unique. "If you consider the antibody molecule like the capital letter Y, the Fab domain is either one of the two identical arms. What's unique about this 2G12 antibody," Burton continued, "is the way in which the Fab domains are arranged. Instead of being separate Y-shaped arms, the two arms are intertwined - interdigitated. That's what's unique. Those intertwined arms have never been seen before."
Antibodies exist to recognize or neutralize antigens - their targets. "In this case," Burton went on, "2G12 antibodies recognize a viral sugar molecule called mannose. It normally recognizes single-oligomer mannose chains, but what it really likes to latch onto is an arrangement of these chains, which are found on the HIV. So that's what seems to be its antigen, a particular 3-dimensional arrangement that's unique to the virus surface. That's its epitope."
Mannose Holds Keys To Kingdom
"And mannose is where HIV's key diabolism comes into play. That weird, kooky 2G12 antibody binds to mannose sugars on the surface of HIV and effectively tries to neutralize the virus because of its unparalled ultramicroscopic structure. But that trick is easier said than done. The human body," Burton noted, "makes lots of antibodies against HIV, but they are almost always unable to neutralize the virus. Why? Because much of the viral surface is coated with carbohydrates [sugars]. These are hard for the immune system to attack, because those sugars are made by human cells and attached by human proteins when the virus infects. That's to say, they are self' and should not be recognized by antibodies.
"The Fab [antigen-recognition] arms are interlocked," Burton pointed out. "That is a unique arrangement, good for recognizing a cluster of shapes like sugars on a virus. The 2G12 antibody forms an unusual dimer' [double-molecule] interface where two antibodies create a little-known multivalent binding surface with multiple binding sites that recognizes a deviant arrangement of 2-3 mannose oligomannose' sugars on the surface of protein spikes called glycoprotein 120 that decorate the coat of HIV. This allows the antibody to properly target HIV virions as foreign pathogens."
Burton is one of two senior authors of a paper in today's Science, dated June 27, 2003, and titled "Antibody domain exchange is an immunological solution to carbohydrate cluster recognition." The other senior author, also at Scripps, is X-ray crystallographer Ian Wilson.
"I think there are two findings in this Science article," Burton observed. "One is in relation to vaccine development, which says that antibodies have found the way to recognize or get up the sugar coat on the outside of the virus. Secondly, here's a new antibody structure that is particularly suited to recognizing tight clusters of antigens.
"The novelty of this finding," he added, "was that previously we'd thought that this sugar coat was pretty impregnable, but now I think we can see that it may not be so invincible. But there may be ways to make antibodies to this sugar coat - which is good. It could turn out to be a weakness in the virus where before we always thought it was a strength. Secondly, the structure we describe has not been described before. And that's going to interest quite a few people, I think.
"These results," Burton told BioWorld Today, "are a step in the direction of designing an effective AIDS vaccine because it reveals what these neutralizing antibodies should look like. The next step is to use the structure of the antibody as a template to design a target antigen that would stimulate the human immune system to make 2G12 or similar broadly neutralizing antibodies against HIV."
Scripps Joins Popular AIDS Vaccine Movement
"Here at Scripps," Burton said, "we are interested in deriving a vaccine from the 2G12 antibody. What it will do is react with or neutralize many different strains of HIV. It's been shown to protect monkeys against challenge from HIV in other laboratories. The number of vaccines that are being tried at the moment are mostly based on attempting to induce cellular immunity to HIV. What we're trying to do is induce antibodies, which are one arm of the immune response.
"The antibody arm is at a sort of state that we're at, which is looking to find some things that might elicit good antibodies. And the cellular arm is that they've found some vaccines that elicit apparently quite reasonable cellular responses. So they're trying these out now - beginning to try them out in people. What we'd really like to see is cellular and antibody responses brought together, so you'd have a vaccine that elicited good cellular and good antibody responses.
"The latest statistics are grim," Burton said. "The World Health Organization estimates that about 40 million people worldwide are living with HIV. During 2001 alone, more than 4 million men, women and children succumbed to the disease, and by the end of that year, the disease had made orphans of 14 million children. In the U.S., 40,000 people are infected with HIV each year."
From these data, Burton concluded, that "one of the most compelling medical challenges today is to develop a vaccine that will provide complete prophylactic protection to someone who is later exposed to this virus. An important part of such a vaccine will be a component that elicits or induces effective neutralizing antibodies against HIV in the blood of the vaccinated person."