A rapid mutation rate and a protective coating of host-derived sugars seem to have made HIV antibody proof, and in recent years, the neutralizing-antibody approach to HIV vaccine design has taken a back seat. But, neutralizing antibodies are now back in the spotlight, as a recent report in Science shows.

One of the rare neutralizing HIV-specific antibodies that has been isolated from infected patients is the monoclonal antibody 2G12, which binds with high affinity to oligomannose residues on gp120. To find out exactly how 2G12 binds to gp120, two groups, led by Dennis Burton and Ian Wilson at the Scripps Research Institute, La Jolla, USA, determined the crystal structure of the antigen-binding fragment (Fab) of 2G12 together with its carbohydrate ligand. What they discovered was a completely new and unanticipated mode of antigen binding.

Structure of two domain-swapped Fab molecules. Light chains are shown in blue and the heavy chains from Fab1 and Fab2 are shown in red and purple. Reprinted with permission from Calarese et al. © American Association for the Advancement of Science (2003). Credit: Image reproduced with permission from Calarese et al. © American Association for the advancement of Science (2003)

Rather than binding the antigen as a monomer, two 2G12 Fabs interlock, forming a dimer in which their heavy-chain variable (VH) domains are 'swapped'. The result is an extended multivalent antigen-binding site that can recognize the close repeating pattern of sugars that mask the surface of gp120 (see diagram). A conventional antibody could never achieve this due to steric constraints. As Dennis Burton told Nature, “It's an ideal molecular solution to recognizing a tight cluster of repeating patterns”.

Whereas the sugars on the surface of gp120 are closely clustered, on host proteins the same sugars tend to be widely spaced, so the unusual antibody structure allows the recognition of a unique feature of the virus.

Researchers can now start thinking about how to exploit this chink in the armour of HIV. The authors of the paper point out that one possibility is to engineer carbohydrate vaccines that mimic the close array of sugars on gp120.