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

Nature Structural & Molecular Biology volume 13, pages 740–747 (2006)Cite this article

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-Å-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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Figure 1: The structure of the D5–5-helix complex.
Figure 2: Contacts at the D5–5-helix interface.
Figure 3: Comparison of D5 CDR H2 interaction with gp41 hydrophobic pocket to the interactions of other pocket-binding molecules.
Figure 4: D5-derived pocket filled by gp41 N-helix B Trp571 and Leu568.
Figure 5: Model of a D5 IgG molecule accessing the gp41 fusion intermediate.

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Acknowledgements

Help with data collection from the European Synchrotron Radiation Facility staff and the technical assistance and discussions of members of the Carfí laboratory are greatly appreciated. We also thank B. Chen and M. Bottomley for critically reading the manuscript and M. Emili for help with the artwork. SEC-MALS analysis was performed at the W.M. Keck Foundation Biotechnology Resource Laboratory at Yale University. M.L. is the recipient of a European Molecular Biology Organization Postdoctoral Fellowship.

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  1. Romas Geleziunas

    Present address: Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, California, 94404, USA

Authors and Affiliations

  1. Istituto di Ricerche di Biologia Molecolare P. Angeletti, Via Pontina Km 30, 600 I-00040, Pomezia (Rome), Italy

    Micah A Luftig, Marco Mattu, Paolo Di Giovine, Gaetano Barbato, Elisabetta Bianchi, Antonello Pessi & Andrea Carfí

  2. Department of Antiviral Research, Merck Research Laboratories, Sumneytown Pike, P.O. Box 4, West Point, 19486, Pennsylvania, USA

    Romas Geleziunas, Renee Hrin & Michael D Miller

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Supplementary information

Supplementary Fig. 1

Representative electron density. (PDF 272 kb)

Supplementary Fig. 2

D5 CDR H2 insertion into gp41 hydrophobic pocket. (PDF 58 kb)

Supplementary Fig. 3

D5 Fab binding around the gp41 N-peptide trimer. (PDF 60 kb)

Supplementary Table 1

Characterization of D5 CDR loops. (PDF 21 kb)

Supplementary Table 2

Buried surfaces in D5–5-helix and other gp41 inner core complexes. (PDF 11 kb)

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Luftig, M., Mattu, M., Di Giovine, P. et al. Structural basis for HIV-1 neutralization by a gp41 fusion intermediate–directed antibody. Nat Struct Mol Biol 13, 740–747 (2006). https://doi.org/10.1038/nsmb1127

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