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  • Title: Structural basis for HIV-1 neutralization by a gp41 fusion intermediate-directed antibody.
    Author: Luftig MA, Mattu M, Di Giovine P, Geleziunas R, Hrin R, Barbato G, Bianchi E, Miller MD, Pessi A, Carfí A.
    Journal: Nat Struct Mol Biol; 2006 Aug; 13(8):740-7. PubMed ID: 16862157.
    Abstract:
    Elicitation of potent and broadly neutralizing antibodies is an important goal in designing an effective human immunodeficiency virus-1 (HIV-1) vaccine. The HIV-1 gp41 inner-core trimer represents a functionally and structurally conserved target for therapeutics. Here we report the 2.0-A-resolution crystal structure of the complex between the antigen-binding fragment of D5, an HIV-1 cross-neutralizing antibody, and 5-helix, a gp41 inner-core mimetic. Both binding and neutralization depend on residues in the D5 CDR H2 loop protruding into the conserved gp41 hydrophobic pocket, as well as a large pocket in D5 surrounding core gp41 residues. Kinetic analysis of D5 mutants with perturbed D5-gp41 interactions suggests that D5 persistence at the fusion intermediate is crucial for neutralization. Thus, our data validate the gp41 N-peptide trimer fusion intermediate as a target for neutralizing antibodies and provide a template for identification of more potent and broadly neutralizing molecules.
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