학술논문
A gp41 MPER-specific llama VHH requires a hydrophobic CDR3 for neutralization but not for antigen recognition.
Document Type
article
Author
David Lutje Hulsik; Ying-ying Liu; Nika M Strokappe; Simone Battella; Mohamed El Khattabi; Laura E McCoy; Charles Sabin; Andreas Hinz; Miriam Hock; Pauline Macheboeuf; Alexandre M J J Bonvin; Johannes P M Langedijk; David Davis; Anna Forsman Quigley; Marlén M I Aasa-Chapman; Michael S Seaman; Alejandra Ramos; Pascal Poignard; Adrien Favier; Jean-Pierre Simorre; Robin A Weiss; C Theo Verrips; Winfried Weissenhorn; Lucy Rutten
Source
PLoS Pathogens, Vol 9, Iss 3, p e1003202 (2013)
Subject
Language
English
ISSN
1553-7366
1553-7374
1553-7374
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.