title: Antibody mechanics on a membrane-bound HIV segment essential for GP41-targeted viral neutralization.
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.
authors: Laboratory of Immunobiology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
authors: Mikyung
authors: M
authors: Kim
authors: Zhen-Yu J
authors: ZY
authors: Sun
authors: Kasper D
authors: KD
authors: Rand
authors: Xiaomeng
authors: X
authors: Shi
authors: Likai
authors: L
authors: Song
authors: Yuxing
authors: Y
authors: Cheng
authors: Amr F
authors: AF
authors: Fahmy
authors: Shreoshi
authors: S
authors: Majumdar
authors: Gilad
authors: G
authors: Ofek
authors: Yongping
authors: Y
authors: Yang
authors: Peter D
authors: PD
authors: Kwong
authors: Jia-Huai
authors: JH
authors: Wang
authors: John R
authors: JR
authors: Engen
authors: Gerhard
authors: G
authors: Wagner
authors: Ellis L
authors: EL
authors: Reinherz
mesh_terms: D000595:Amino Acid Sequence; D057134:Antibodies, Neutralizing / Q000737:chemistry* / Q000276:immunology*; D001665:Binding Sites; D000939:Epitopes / Q000737:chemistry / Q000276:immunology; D015483:HIV Antibodies / Q000737:chemistry / Q000276:immunology*; D015700:HIV Envelope Protein gp41 / Q000737:chemistry* / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D008563:Membrane Lipids / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009500:Neutralization Tests; D011485:Protein Binding; D011487:Protein Conformation
chemical_list: D057134:Antibodies, Neutralizing; D000939:Epitopes; D015483:HIV Antibodies; D015700:HIV Envelope Protein gp41; D008563:Membrane Lipids