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

TY - JOUR

T1 - Antibody mechanics on a membrane-bound HIV segment essential for GP41-targeted viral neutralization

AU - Kim, Mikyung

AU - Sun, Zhen-Yu J

AU - Rand, Kasper Dyrberg

AU - Shi, Xiaomeng

AU - Song, Likai

AU - Cheng, Yuxing

AU - Fahmy, Amr F

AU - Majumdar, Shreoshi

AU - Ofek, Gilad

AU - Yang, Yongping

AU - Kwong, Peter D

AU - Wang, Jia-Huai

AU - Engen, John R

AU - Wagner, Gerhard

AU - Reinherz, Ellis L

PY - 2011/11

Y1 - 2011/11

N2 - 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.

AB - 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.

U2 - 10.1038/nsmb.2154

DO - 10.1038/nsmb.2154

M3 - Journal article

C2 - 22002224

SN - 1545-9993

VL - 18

SP - 1235

EP - 1243

JO - Nature Structural and Molecular Biology

JF - Nature Structural and Molecular Biology

IS - 11

ER -