Antibody mechanics on a membrane-bound HIV segment essential for GP41-targeted viral neutralization.

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TitleAntibody mechanics on a membrane-bound HIV segment essential for GP41-targeted viral neutralization.
Publication TypeJournal Article
Year of Publication2011
AuthorsKim, M, Sun, Z-YJ, Rand, KD, Shi, X, Song, L, Cheng, Y, Fahmy, AF, Majumdar, S, Ofek, GA, Yang, Y, Kwong, PD, Wang, J-H, Engen, JR, Wagner, G, Reinherz, EL
JournalNat Struct Mol Biol
Volume18
Issue11
Pagination1235-43
Date Published2011 Nov
ISSN1545-9985
KeywordsAmino Acid Sequence, Antibodies, Neutralizing, Binding Sites, Epitopes, HIV Antibodies, HIV Envelope Protein gp41, HIV-1, Humans, Membrane Lipids, Models, Molecular, Molecular Sequence Data, Neutralization Tests, Protein Binding, Protein Conformation
Abstract

Broadly neutralizing antibodies such as 2F5 are directed against the membrane-proximal external region (MPER) of HIV-1 GP41 and recognize well-defined linear core sequences. These epitopes can be engrafted onto protein scaffolds to serve as immunogens with high structural fidelity. Although antibodies that bind to this core GP41 epitope can be elicited, they lack neutralizing activity. To understand this paradox, we used biophysical methods to investigate the binding of human 2F5 to the MPER in a membrane environment, where it resides in vivo. Recognition is stepwise, through a paratope more extensive than core binding site contacts alone, and dynamic rearrangement through an apparent scoop-like movement of heavy chain complementarity-determining region 3 (CDRH3) is essential for MPER extraction from the viral membrane. Core-epitope recognition on the virus requires the induction of conformational changes in both the MPER and the paratope. Hence, target neutralization through this lipid-embedded viral segment places stringent requirements on the plasticity of the antibody combining site.

DOI10.1038/nsmb.2154
Alternate JournalNat. Struct. Mol. Biol.
PubMed ID22002224
PubMed Central IDPMC3253551
Grant ListP30 AI060354 / AI / NIAID NIH HHS / United States
R01 AI084785 / AI / NIAID NIH HHS / United States
R01 AI084785-03 / AI / NIAID NIH HHS / United States
R01 GM086507 / GM / NIGMS NIH HHS / United States
R01 GM086507-03 / GM / NIGMS NIH HHS / United States
R01-GM086507 / GM / NIGMS NIH HHS / United States
R01AI84785 / AI / NIAID NIH HHS / United States
U19 AI091693 / AI / NIAID NIH HHS / United States
U19 AI091693-02 / AI / NIAID NIH HHS / United States
U19AI91693 / AI / NIAID NIH HHS / United States