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Research Laboratories
Structural Biology Laboratory
Peter Kwong, Ph.D.

Description of Research Program (2001):
The Structural Biology Laboratory seeks to apply structural biology to the design of an effective HIV vaccine. One contribution that structural biology can make is as an unparalleled source of information. Following the paradigm that in order to conquer the enemy, one must first understand or "see" the enemy, we have sought to reveal the actual HIV molecules that confound the humoral immune system: the envelope glycoproteins gp120 and gp41. The gp120 glycoprotein resides on the outer surface of the virus and is the primary target of neutralizing antibodies, but in a manner not fully understood, manages to evade being neutralized by the human immune response.

The HIV-1 gp120 envelope glycoprotein (depicted here in pink and red) is shown, caught in the act of binding to the cellular CD4 receptor (yellow), by a neutralizing antibody (blue/purple), which extends off the left edge of the picture.

By using innovative crystallographic techniques, we have determined the structure of gp120 at atomic resolution, visualizing directly numerous overlapping mechanisms of immune evasion. These include conformational change, steric occlusion, islands of variation and a carbohydrate cloak, all of which serve to disguise the gp120 surface from immune detection. This information shows how difficult it is to elicit neutralizing antibodies against HIV.

Given the ability of structural biology to determine the atomic structure of gp120, the question arises: is structural information merely another source of information, the same as any other biochemical or biophysical technique-or is it in some way special? Does knowing the precise atomic coordinates, and thus having access to the underlying chemistry of gp120, permit the precise design of a vaccine?

While structure based drug design has revolutionalized drug design, accounting for example for the rapid development of the HIV protease inhibitors, vaccine design has in the past, placed almost no reliance on structural information. Partly this is because the antigen/immune system interactions are much more complex than drug/target interactions. Nonetheless, given the availability of the atomic structure of gp120, the failures of natural gp120 to elicit a protective immune response, and a large receptor binding region on the surface of gp120 itself, we have proposed a novel approach to vaccine development using functional constraints coupled with structural information to design modified gp120 molecules.

Our approach combines hypothesis driven iterative optimization with structural analysis and protein design principles. The goal is to disable the numerous mechanisms of gp120 immune evasion, and thereby produce a modified gp120 that elicits a broadly neutralizing response. This novel approach, if successful against HIV, has the potential of being useful against other pathogenic viruses.

Description of Research Program (2007)