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Molecular Approaches to Immunogens able to Elicit Broadly Neutralizing Anti-HIV-1 Antibodies
1D R Burton, 1D A Calarese, 2R A Dwek, 3H Katinger, 1R Pantophlet, 4P W H I Parren, 1P Poignard, 2P M Rudd, 1E O Saphire, 2C N Scanlan, 1R L Stanfield, 1M B Zwick and 1I A Wilson
1The Scripps Res Inst, La Jolla, CA; 2Univ of Oxford, Oxford, UK; 3Univ of Agriculture, Vienna, Austria; 4Genmab, Utrecht, The Netherlands
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Background: The design of immunogens capable of eliciting broadly neutralizing anti-HIV-1 antibodies is proving difficult. Conserved sites on the envelope (Env) trimer on the surface of virions appear to be only weakly immunogenic. However, a small panel of human monoclonal antibodies (m) that do recognize these sites and broadly neutralize HIV-1 have been identified. An understanding of the interaction of these m with HIV-1 Env at the molecular level may promote the design of immunogens capable of eliciting antibodies similar to these m e.g., broadly cross-neutralizing.
Methods: We are attempting to solve the crystal structure of the m in the ence and presence of Env antigens and analyzing the interaction of m with Env by extensive mutagenesis and biochemical studies.
Results: We have solved the structure of the mAb b12 and proposed a docking model for the b12/gp120 complex that has been supported by mutagenesis studies. We have generated gp120 mutant molecules that bind b12 almost exclusively and are interesting immunogens. We have shown that mAb 2G12 recognizes a cluster of oligomannose residues on the silent face of gp120. Crystallography of 2G12 alone and in complex with oligomannose reveals that the antibody has a novel domain-exchanged structure that is uniquely suited to recognition of a carbohydrate cluster. We are designing carbohydrate immunogens based on the structural information.
Conclusions: The broadly neutralizing human m studied to date have many interesting structural features. It remains to be seen if we can exploit the information gained to allow successful immunogen design.
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