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.
Highlights
The HIV-1 envelope protein (Env), a hetero-trimer of non-covalently linked gp120 and gp41 subunits, is the target of broadly neutralizing antibodies [1]
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
Our results indicate that 10E8 interacts with the viral membrane via its light chain and engages membrane proximal external region (MPER) in an upright orientation with respect to the HIV-1 membrane
Summary
The HIV-1 envelope protein (Env), a hetero-trimer of non-covalently linked gp120 and gp subunits, is the target of broadly neutralizing antibodies (bnAbs) [1]. In the presence of MPER antibody 10E8, an 8.8 Å resolution cryo-EM structure illustrated that the three MPER epitope regions within the trimer form a triple helix [20] and the 10E8-bound Env appears to be elevated off the micelles. This elevation in comparison to the pre-fusion form suggested how the MPER may be engaged by 10E8, but the presence of detergent and the lack of a membrane in that study limited the ability to draw definitive conclusions about 10E8 engagement of native Env on virions. Due to the proximity of MPER to the membrane, MPER binding antibodies are thought to interact with the membrane and, some have been shown to interact with lipids [21,22,23,24]
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