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, 13 (2), e1006212

Lipid Interactions and Angle of Approach to the HIV-1 Viral Membrane of Broadly Neutralizing Antibody 10E8: Insights for Vaccine and Therapeutic Design


Lipid Interactions and Angle of Approach to the HIV-1 Viral Membrane of Broadly Neutralizing Antibody 10E8: Insights for Vaccine and Therapeutic Design

Adriana Irimia et al. PLoS Pathog.


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.

Conflict of interest statement

WRS is a co-founder and stock holder in Compuvax, Inc. which has programs in non-HIV vaccine design that might benefit indirectly from this research.


Fig 1
Fig 1. 10E8 lipid-binding site.
(A) Crystal structure of the 10E8-T117v2 complex bound to 06:0 PG (sticks; red, glycerol and phosphate moieties of the head group; cyan, head group region linked to the lipid tails). The 10E8 light chain (LC) is shown in beige, heavy chain (HC) in violet, and T117v2 scaffold containing the MPER epitope (pink) in gray. This color scheme is used throughout. (B) All potential hydrogen-bond interactions (within ~3.5 Å) of the 06:0 PG fragment (colored by atoms) with 10E8 residues of CDRL1 (beige) and CDRH3 (violet) are shown as dashed lines. (C) All potential hydrogen-bond interactions (within ~3.5 Å) of the 06:0 PA fragment (colored by atoms) with CDRL1 (beige) and CDRH3 (violet) residues of 10E8. (D) All potential hydrogen-bond interactions (within ~3.5 Å) of a glycerol found in the lipid-binding site in the 10E8-T117v2 structure in the absence of added lipids.
Fig 2
Fig 2. Design of 10E8 light-chain mutants.
(A) Several light chain (LC; beige) basic residues (Arg and Lys shown as sticks) are in the same plane with the lipid head group (red and cyan sticks) and Lys683 (red sticks) of the gp41 MPER epitope (red). The heavy chain (HC) is shown in violet. (B) Light-chain surface residues (beige) that are presumed to face the viral membrane. The heavy-chain residues at the tip of CDRH3 are shown as violet sticks. The 10E8 peptide epitope (pink) from the T117v2 scaffold is shown up to Lys683 (pink; last residue of gp41 ectodomain). (C) Alignment of the amino-acid sequence of the five 10E8 light-chain mutants compared to wild-type 10E8. Only the variable region of the 10E8 light-chain variants are shown with the Kabat numbering scheme on top of the alignment. The mutations are highlighted in red.
Fig 3
Fig 3. Distribution of charge on the surfaces of the 10E8 light-chain variants.
The electrostatic solvent accessible surface (contoured at ±5 kT/e) of the light-chain region presumed to bind the viral membrane is shown for: (A) wild-type mature 10E8; (B) 10E8 mutant 1; (C) 10E8 mutant 2; (D) 10E8 mutant 3; (E) 10E8 mutant 5. Negative and positive charges are indicated in red and blue colored surfaces, respectively. The ligands bound in the lipid-binding site are shown as dark cyan sticks and the epitope scaffold is shown in gray. The underlined superscript letters designate the original residues in the 10E8 wild type.
Fig 4
Fig 4. Integration of experimental data into a 10E8-MPER epitope-viral membrane model.
(A) Surface rendering of the 10E8 Fab (beige, light chain; violet, heavy chain) showing the PG lipid fragment (red-dark cyan sticks) bound in a cavity formed between CDRL1, FRL3 and CDRH3 in the 10E8-T117v2-PG crystal structure. The helical 10E8 epitope residues in the T117v2 scaffold protein (gray) are shown in dark pink and the light-chain surface interacting with the viral membrane is colored by atom type. (B) Model of the 10E8 angle of approach with respect to MPER epitope-viral membrane during antibody engagement. (C) Model of the 4E10 angle of approach with respect to MPER epitope-viral membrane [23] for comparison. In both (B) and (C), the light and heavy chains are shown in beige and violet, respectively. The helical MPER epitope is shown in red and the lipid bilayer as thin green lines. The experimental bound lipids are shown as thicker dark cyan sticks in both structures. (D) and (E) Fitting our models of the viral membrane with 4E10 and 10E8 in the experimental EM map of the CD4-bound Env (EMDB-5455 [40]). The light and heavy chains are shown as yellow and blue cartoons. The lipid bilayers are shown in green and the MPER epitope as dark red helices.

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