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A gp41 MPER-specific Llama VHH Requires a Hydrophobic CDR3 for Neutralization but not for Antigen Recognition

Hulsik, DL; Liu, Y-Y; Strokappe, NM; Battella, S; El Khattabi, M; McCoy, LE; Sabin, C; ... Rutten, L; + view all (2013) A gp41 MPER-specific Llama VHH Requires a Hydrophobic CDR3 for Neutralization but not for Antigen Recognition. PLOS PATHOGENS , 9 (3) , Article e1003202. 10.1371/journal.ppat.1003202. Green open access

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Abstract

The membrane proximal external region (MPER) of the HIV-1 glycoprotein gp41 is targeted by the broadly neutralizing antibodies 2F5 and 4E10. To date, no immunization regimen in animals or humans has produced HIV-1 neutralizing MPER-specific antibodies. We immunized llamas with gp41-MPER proteoliposomes and selected a MPER-specific single chain antibody (VHH), 2H10, whose epitope overlaps with that of mAb 2F5. Bi-2H10, a bivalent form of 2H10, which displayed an approximately 20-fold increased affinity compared to the monovalent 2H10, neutralized various sensitive and resistant HIV-1 strains, as well as SHIV strains in TZM-bl cells. X-ray and NMR analyses combined with mutagenesis and modeling revealed that 2H10 recognizes its gp41 epitope in a helical conformation. Notably, tryptophan 100 at the tip of the long CDR3 is not required for gp41 interaction but essential for neutralization. Thus bi-2H10 is an anti-MPER antibody generated by immunization that requires hydrophobic CDR3 determinants in addition to epitope recognition for neutralization similar to the mode of neutralization employed by mAbs 2F5 and 4E10.

Type: Article
Title: A gp41 MPER-specific Llama VHH Requires a Hydrophobic CDR3 for Neutralization but not for Antigen Recognition
Open access status: An open access version is available from UCL Discovery
DOI: 10.1371/journal.ppat.1003202
Publisher version: http://dx.doi.org/10.1371/journal.ppat.1003202
Language: English
Additional information: © 2013 Lutje Hulsik et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. This work was supported by the Bill & Melinda Gates Foundation as part of the Collaboration for AIDS Vaccine Discovery (CAVD grant 38637), Combined Highly Active Anti- Retroviral Microbicides (CHAARM:http://chaarm.eu/), the Dutch Foundation for Scientific Research (NWO) through a VICI grant (no. 700.56.442) (AMJJB), the TGE RMN THC Fr3050 (JPS) and the LabEX GRAL (WW). MH is supported by a post-doctoral fellowship from Sidaction and WW is supported by the Institut Universitaire de France. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Infection and Immunity
URI: https://discovery.ucl.ac.uk/id/eprint/1392947
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