Crystal structure and size-dependent neutralization properties of HK20, a human monoclonal antibody binding to the highly conserved heptad repeat 1 of gp41
- Sabin, Charles Unit of Virus Host Cell Interactions (UVHCI) UMI 3265, Universite´ Joseph Fourier-EMBL-CNRS, Grenoble, France
- Corti, Davide Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
- Buzon, Victor Unit of Virus Host Cell Interactions (UVHCI) UMI 3265, Universite´ Joseph Fourier-EMBL-CNRS, Grenoble, France
- Seaman, Mike S. Division of Viral Pathogenesis, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States of America
- Hulsik, David Lutje Unit of Virus Host Cell Interactions (UVHCI) UMI 3265, Universite´ Joseph Fourier-EMBL-CNRS, Grenoble, France
- Hinz, Andreas Unit of Virus Host Cell Interactions (UVHCI) UMI 3265, Universite´ Joseph Fourier-EMBL-CNRS, Grenoble, France
- Vanzetta, Fabrizia Humabs SAGL, Bellinzona,Switzerland
- Agatic, Gloria Humabs SAGL, Bellinzona,Switzerland
- Silacci, Chiara Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
- Mainetti, Lara Viral Evolution and Transmission Unit, Division of Immunology, Transplant and Infectious Diseases, San Raffaele Scientific Institute, Milan, Italy
- Scarlatti, Gabriella Viral Evolution and Transmission Unit, Division of Immunology, Transplant and Infectious Diseases, San Raffaele Scientific Institute, Milan, Italy
- Sallusto, Federica Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
- Weiss, Robin Division of Infection and Immunity, University College London, London, United Kingdom
- Lanzavecchia, Antonio Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland - Institute of Microbiology, Swiss Federal Institute of Technology, Zurich, Switzerland
- Weissenhorn, Winfried Unit of Virus Host Cell Interactions (UVHCI) UMI 3265, Universite´ Joseph Fourier-EMBL-CNRS, Grenoble, France
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18.11.2010
Published in:
- Plos pathogens. - 2010, vol. 6, no. 11, p. e1001195
English
The human monoclonal antibody (mAb) HK20 neutralizes a broad spectrum of primary HIV-1 isolates by targeting the highly conserved heptad repeat 1 (HR1) of gp41, which is transiently exposed during HIV-1 entry. Here we present the crystal structure of the HK20 Fab in complex with a gp41 mimetic 5-Helix at 2.3 A° resolution. HK20 employs its heavy chain CDR H2 and H3 loops to bind into a conserved hydrophobic HR1 pocket that is occupied by HR2 residues in the gp41 post fusion conformation. Compared to the previously described HR1-specific mAb D5, HK20 approaches its epitope with a different angle which might favor epitope access and thus contribute to its higher neutralization breadth and potency. Comparison of the neutralization activities of HK20 IgG, Fab and scFv employing both single cycle and multiple cycle neutralization assays revealed much higher potencies for the smaller Fab and scFv over IgG, implying that the target site is difficult to access for complete antibodies. Nevertheless, two thirds of sera from HIV-1 infected individuals contain significant titers of HK20-inhibiting antibodies. The breadth of neutralization of primary isolates across all clades, the higher potencies for Cclade viruses and the targeting of a distinct site as compared to the fusion inhibitor T-20 demonstrate the potential of HK20 scFv as a therapeutic tool.
- Language
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- English
- Classification
- Medicine
- License
- License undefined
- Identifiers
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- RERO DOC 326628
- DOI 10.1371/journal.ppat.1001195
- ARK ark:/12658/srd1318932
- Persistent URL
- https://n2t.net/ark:/12658/srd1318932
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