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; Corti, Davide; Buzon, Victor; Seaman, Mike S.; Hulsik, David Lutje; Hinz, Andreas; Vanzetta, Fabrizia; Agatic, Gloria; Silacci, Chiara; Mainetti, Lara; Scarlatti, Gabriella; Sallusto, Federica; Weiss, Robin; Lanzavecchia, Antonio; Weissenhorn, Winfried

doi:10.1371/journal.ppat.1001195

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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

18.11.2010

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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.

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