In 1998, Dr. Kwong and colleagues published the first X-ray snapshot of the core of HIV gp120 as it attaches to a cellular receptor known as CD4. That image gave researchers a glimpse of some sites on the virus that could be targets of drugs or vaccines, but it also revealed the extent of HIV's overlapping defenses. For example, scientists subsequently learned that CD4-gp120 contact causes gp120 to change shape, a viral feint known as conformational masking, which acts to further shield HIV from immune system attack.
While the earlier study provided a picture of the CD4-gp120 complex, the new finding delineates the precise stepwise engagement between gp120 and CD4. The researchers found that the gp120-CD4 encounter starts with a highly focused contact and then expands to a broader surface that stabilizes the interaction.
"The first contact is like a cautious handshake, which then becomes a hearty bear hug," says Gary Nabel, M.D., Ph.D., director of NIAID's VRC and co-author of the new paper.
An effective HIV vaccine likely needs to induce antibodies that can sense and destroy multiple HIV strains. Scientists have sought such broadly neutralizing antibodies by studying the blood of people whose immune systems appear to hold the virus at bay for long periods of time—b12 is one of these rare, broadly neutralizing antibodies.
Until now, no one had succeeded in determining the detailed structure of b12 in complex with gp120. It was extremely difficult to crystallize b12 bound to gp120, says Dr. Kwong, in part due to the inherently flexible nature of the chemical bonds in gp120. To overcome the problem, the investigators created a variety of gp120s and eventually made the pro
Source:NIH/National Institute of Allergy and Infectious Diseases