Structure of broadly neutralizing 4E10 antibody revealed

When it comes to disarming HIV, 4E10 is a champ. The rare human antibody neutralizes nearly 100 strains of HIV-1-a feat no other known anti-HIV antibody can match. Recently, scientists in southern California and Austria determined that the molecule recognizes a helical shape on the virus-a finding that may bring a vaccine to prevent HIV infection one step closer to reality (Immunity 2005; 22:163-173).

Now we have some insight into the structure of the virus at a place where an antibody can get at it, says immunologist Dennis Burton of Scripps Research Institute, who co-led the research. That's a big clue to as to how to design a vaccine to induce broadly neutralizing antibodies like 4E10.

In 2001, Burton and some of the same collaborators showed that 4E10, which was isolated from a HIV-positive individual more than a decade ago in Austria, targets a region on the HIV surface protein gp41 that the virus uses to fuse its membrane with the membrane of the human cell it is infecting. The researchers now suspect the helical structure on gp41 may aid the fusion process by holding the membranes [of the virus and human cell] together in some way, Burton says. Only two other antibodies are known to recognize spiraled antigens.

The team's x-ray crystallography work also revealed a finger-like projection on 4E10 near the site where it binds to the virus. The scientists speculate that this finger, which is hydrophobic, may prod the viral membrane and bring the antibody in contact with the target area. Anchoring it, if you like, into the membrane, Burton says.

If that is the case, he adds, it might be more difficult to make a vaccine to elicit antibodies like this one. Nonetheless, the team is already building helical-shaped proteins that they hope will stimulate 4E10-like antibody response in animals.