Lipid interactions and angle of approach to the HIV-1 viral membrane of broadly neutralizing antibody 10E8: Insights for vaccine and therapeutic design

Abstract

Among broadly neutralizing antibodies to HIV, 10E8 exhibits greater neutralizing breadth than most. Consequently, this antibody is the focus of prophylactic/therapeutic development. The 10E8 epitope has been identified as the conserved membrane proximal external region (MPER) of gp41 subunit of the envelope (Env) viral glycoprotein and is a major vaccine target. However, the MPER is proximal to the viral membrane and may be laterally inserted into the membrane in the Env prefusion form. Nevertheless, 10E8 has not been reported to have significant lipid-binding reactivity. Here we report x-ray structures of lipid complexes with 10E8 and a scaffolded MPER construct and mutagenesis studies that provide evidence that the 10E8 epitope is composed of both MPER and lipid. 10E8 engages lipids through a specific lipid head group interaction site and a basic and polar surface on the light chain. In the model that we constructed, the MPER would then be essentially perpendicular to the virion membrane during 10E8 neutralization of HIV-1. As the viral membrane likely also plays a role in selecting for the germline antibody as well as size and residue composition of MPER antibody complementarity determining regions, the identification of lipid interaction sites and the MPER orientation with regard to the viral membrane surface during 10E8 engagement can be of great utility for immunogen and therapeutic design.

Author summary

The trimeric Env glycoprotein located on HIV surface is the target of broadly neutralizing antibodies and is the focus of vaccine and therapeutic approaches to prevent HIV infection. Structural studies with HIV Env trimers have shed light on the complete epitopes of several broadly neutralizing antibodies. However, structural determination of the complete epitopes of the highly cross-reactive MPER antibodies has been technically difficult due to the viral membrane component and that these epitopes are probably only exposed transiently after Env engages CD4. In this study, we structurally characterize the interaction of the broadest and most potent MPER-targeting antibody, 10E8, with viral membrane lipids and scaffolded MPER and propose how 10E8 approaches the MPER-viral membrane epitope during neutralization. Our results indicate that 10E8 interacts with the viral membrane via its light chain and engages MPER in an upright orientation with respect to the HIV-1 membrane. These findings are of interest for design of HIV-1 vaccines and therapeutics.