Protein Finding Bolsters AIDS Vaccine Hopes

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Most important, this molecular target -- a portion of the virus' gp120 surface protein -- does not appear to mutate between strains, the researchers said. It also easily binds to an antibody that's already found in some humans.



The combination of those two elements had eluded AIDS researchers, until now.



"In terms of a vaccine, then, I am cautiously optimistic. I think that instead of being an impossible dream, it's now more about the technical barriers that we need to overcome to get this to work," said the study's lead author, Peter Kwong, a researcher in the Vaccines Research Center at the U.S. National Institute of Allergy and Infectious Diseases' (NIAID).



AIDS research pioneer and NIAID director Dr. Anthony Fauci agreed.



"This is a quantum leap, a big advance in what we can do now vis-a-vis the design of vaccines," he said.



The findings are published in the Feb. 15 issue of the journal Nature.



Vaccines work by pushing the body to generate immune system antibodies that recognize invading pathogens, such as viruses. However, the race for a vaccine against HIV has been particularly tough, because the organism mutates so much and constantly "shape-shifts" its outer sugary coating to elude detection.



The trick, according to Kwong, has been to find a spot that stays the same between different strains and can also be accessed by antibodies that humans could produce in large numbers.



Back in 1998, Kwong's group first captured X-ray images of the gp120 binding site, which HIV uses to hook up with CD4 immune system T-cells, the virus' prime target. The team assumed that the virus protected itself throughout the CD4-gp120 binding process by a kind of molecular-level shape-shifting on its surface, called "conformational masking."



However, closer inspection revealed a surprise. "We found that this binding actually occurs in two steps -- the first step is a kind of 'weak handshake,' or initial attachment, that's not really stable," Kwong said. "Only after that happens is there this shape-shifting change that really locks gp120 onto CD4."



At the same time, the researchers were investigating an immune system antibody called b12. This antibody, while rare, appears to help protect a tiny minority of HIV-exposed people from infection with various strains of the virus. In fact, b12 carriers "neutralize an extremely broad range of HIV isolates (types)," Kwong said.



Further study brought these two strands of research together. The NIAID team, along with experts at the Scripps Institute in La Jolla, Calif., and the Dana-Farber Cancer Institute in Boston, discovered that b12 actually binds to the gp120 site on HIV during that "weak handshake" stage, where it does not change its shape.



Using high-tech crystallography imaging, the researchers actually watched this interaction in detail. "This gives us the resolution to know exactly what's going on," Kwong said.



Because the b12-gp120 hookup does not change its configuration, regardless of the HIV strain it is found on, it's exactly the type of non-mutating "site of vulnerability" that AIDS vaccine researchers have hoped for.



"But we also needed to find that there's no barrier in humans to getting antibodies to go against that site," Kwong said. The fact that b12 is already active in just this way in a few HIV-resistant people suggests that it can be tweaked for wider use in much larger populations, he said.



The next step is to test that notion in animals. "If you get those antibodies to be produced in animals, it should then be straightforward to do something similar in humans," Kwong said.



Fauci stressed, however, that success in AIDS research is never guaranteed.



"There are many steps to go," he said. "You have to make it into a stable form that could immunize people. Then the body has got to recognize (the vaccine) and make a good neutralizing antibody against it. Those are all 'ifs.' On the other hand, we have no reason to believe that all this won't happen."



"I'm sure there are going to be many bumps along the way," Fauci said, "but, nonetheless, this is a major step forward."



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