Solving the Viral Spike

Even though the envelope glycoprotein is antigenic, the immune response is still unable to control the virus. Researchers had known for some time that the viral protein envelope undergoes a conformational change as it binds to the CD4 receptor. Using X-ray crystallography, they tried to root out the moment in shape-shifting when the virus might expose a soft spot - that is, a place where an antibody could move in and block infection.

However, in a study published in 2002, Kwong and his colleagues discovered that the shape change happens too late for any antibody to interfere (Nature, 420:678-82, 2002). "By the time you get antibodies to react, the virus has [entered] the cell," Kwong says. "That was disappointing."

Kwong and others refocused their attention on filling in the incomplete picture of virus invasion that had been forming for nearly a decade. In 1998, using X-ray crystallography, Kwong had solved the structure of the gp120 bound to the receptor. (Nature, 393:648-59, 1998) In 2005, Stephen Harrison's group at Harvard Medical School solved the unbound structure of simian gp120 - that is, elements of the binding protein before they fused with the receptor, and the best glimpse so far at what the virus "looks like" to the immune system. (Nature, 433:834-41, 2005) Because HIV is such an unstable virus - its changeable form is difficult to force into a rigid lattice, which is part of its invasion strategy - getting enough crystals to solve the structure of the complete viral spike continues to elude researchers.

While understanding how b12 interacts with HIV may be a crucial step in formulating a vaccine, the complete structure of the viral spike needs to be resolved to expose any other sites of vulnerability, Burton says. A truly effective vaccine may have to wait until that piece falls into place, says Kwong. Unlike other vaccines that use inactivated pathogen to mimic how living pathogens trigger the immune response, HIV vaccine development has had to take a somewhat backwards approach, starting with virus and antibody atomic structure, Burton says.

Designing drugs that interfere with T cells to block the binding of the gp120 may be dangerous, says Stephanie Tristram-Nagle, researcher at Carnegie Mellon University. Tristram-Nagle showed this month in Biophysical Journal that HIV's fusion peptide reduces the bending energy at the receptor membrane, making it less energetically costly for fusion to happen there (Biophys J, 93, Sept. 2007).

Even if successful vaccines were designed, the virus mutates frequently, perhaps assuming new structural characteristics that make the vaccine irrelevant.

Understanding the structure that allows HIV to both evade and invade is critical, says Burton. More broadly neutralizing antibodies are likely to be developed in the near future that are able to kick off the approaching HIV spikes from the receptor binding sites, he adds - tactics that couldn't be manipulated without the crystallography. For Burton, using the structural biology of HIV will become even more important as the technology advances. "It's crucial," he says. Solving and preventing the virus' invasion strategies is "a matter of time."