Interactions between Anti-HIV Antibodies and their Lipid-Embedded Epitopes Defined by EPR Spectroscopy

Abstract

A vaccine capable of stimulating protective anti-viral antibodies is needed to curtail the global AIDS epidemic. The membrane proximal ectodomain region (MPER) of the HIV envelope protein gp41 is the target of human neutralizing antibodies 4E10, 2F5, Z13e1 and 10E8. How these antibodies bind to their membrane-immersed epitopes and mediate anti-viral activity are unclear. Here, electron paramagnetic resonance (EPR) techniques were used to define the manner in which these antibodies recognize the L-shaped helix-hinge-helix MPER segment. Both 4E10 and 2F5 induce large conformational changes in the MPER relative to the membrane, and extracts buried residues from the lipids. The interaction is a stepwise and dynamic rearrangement through an apparent scoop-like movement of the antibodies' long and unique CDRH3 segments. Mutations of the CDRH3 segments reduced the ability of the antibodies to extract MPER peptides from membranes. These findings and others currently under investigation have significant implications for structure-aided vaccine design.