Structural basis for HIV-1 neutralization by a gp41 fusion intermediate-directed antibody.

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Luftig, MA; Mattu, M; Di Giovine, P; Geleziunas, R; Hrin, R; Barbato, G; Bianchi, E; Miller, MD; Pessi, A; Carfí, A

Published Date

  • August 2006

Published In

Volume / Issue

  • 13 / 8

Start / End Page

  • 740 - 747

PubMed ID

  • 16862157

International Standard Serial Number (ISSN)

  • 1545-9993

Digital Object Identifier (DOI)

  • 10.1038/nsmb1127


  • eng

Conference Location

  • United States