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. 2017 Jun 2;356(6341):923-928.
doi: 10.1126/science.aam7260.

Structural Basis for Antibody-Mediated Neutralization of Lassa Virus

Free PMC article

Structural Basis for Antibody-Mediated Neutralization of Lassa Virus

Kathryn M Hastie et al. Science. .
Free PMC article


The arenavirus Lassa causes severe hemorrhagic fever and a significant disease burden in West Africa every year. The glycoprotein, GPC, is the sole antigen expressed on the viral surface and the critical target for antibody-mediated neutralization. Here we present the crystal structure of the trimeric, prefusion ectodomain of Lassa GP bound to a neutralizing antibody from a human survivor at 3.2-angstrom resolution. The antibody extensively anchors two monomers together at the base of the trimer, and biochemical analysis suggests that it neutralizes by inhibiting conformational changes required for entry. This work illuminates pH-driven conformational changes in both receptor-binding and fusion subunits of Lassa virus, illustrates the unique assembly of the arenavirus glycoprotein spike, and provides a much-needed template for vaccine design against these threats to global health.


Fig. 1
Fig. 1. Organization and glycosylation of the LASV trimer
(A) Cartoon representation of the trimer from the front, side, and top. The GP1 subunit of each monomer is in a light shade and the GP2 subunit in a dark shade. In the top view, spheres indicate positions of the C terminus of GP1 and the N terminus of GP2 at the trimeric interface. (B) The crystal structure of the LASV GP trimer (cartoon) docked into the tomographic reconstruction of the LASV GPC spike from fixed virions (surface, EMD-3290), in the same orientations as shown in (A). (C) GP monomer A is shown in cartoon representation and is colored by domain as in fig. S3. Structural elements involved in trimerization are indicated. GP monomers B and C are shown as surfaces. (D) The glycans visible in the crystal structure are illustrated as atomic spheres, with those glycans attached to GP1 illustrated in light shades and those attached to GP2 illustrated in dark shades.
Fig. 2
Fig. 2. Receptor binding in the context of the LASV GP trimer
(A) The crystal structure of one monomer of the LASV GP trimer (GP1 and GP2 colored light and dark orange, respectively) is superimposed on one monomer of the LCMV GP dimer (GP1 and GP2 colored light and dark blue). Residues known to confer high-affinity binding to α-DG by LCMV are shown with LCMV numbering. (B) View of the LASV GP trimer from the top. The locations of the residues important for α-DG binding are shown and numbered according to LASV, with the equivalent residues in LCMV noted as subscript. Note: R190 in LCMV is required for α-DG binding. This residue is G186 in LASV but is modeled here as arginine (in cyan).
Fig. 3
Fig. 3. Conformational changes and receptor binding by LASV GP
(A) Comparison of the crystal structure of the isolated GP1 subunit of LASV, at pH 5, to the GP1 subunit of the LASV GP trimer, at neutral pH. Positions of the histidine triad involved in LAMP1 binding are shown. Structural elements of LASV GP1 that vary between the low- and neutral-pH forms are indicated. Spheres indicate the N- and C-terminal residues visible in the low-pH GP1 structure and the location of the equivalent residues in the LASV GP trimer structure. (B) Detailed view of the histidine triad. Glycan N89 is shown as orange ball-and-stick. The hydrogen bond between H92 and the backbone oxygen of N90 is shown as a dotted line.
Fig. 4
Fig. 4. Structural definition of the 37.7H epitope
(A) The GP trimer bound to three 37.7H Fabs from the top (left) and side (right). Cartoon representations of the 37.7H Fab heavy and light chains are shown in dark and light gray, respectively. Each Fab binds to two GP monomers, shown as surface representations, near the base of the trimer. (B) Monomers A and C are shown as surface representations, with the heavy- and light-chain CDRs shown as dark and light gray tubes, respectively. The footprint of the antibody is colored yellow, with the binding site indicated. Side-chain interactions at the GP-37.7H interface are magnified in the inset boxes. GP elements are colored as indicated in fig. S3. Note that only selected residues are shown for clarity.
Fig. 5
Fig. 5. Effect of antibodies on rVSV-LASV GP infection and fusion
Antibody-mediated neutralization of (A) rVSV-LASV GP or (B) rVSV-VSV-G. The antibody 9.7A is non-neutralizing and in the same competition group as 37.7H (GPC-B); 13.4E binds to a linear epitope in the T-loop of GP2; 12.1F binds to the GP1 subunit of LASV. Error bars indicate the standard deviation of at least six (two biological replicates, each having three or more technical replicates). (C) Antibody-mediated inhibition of rVSV-LASV GP fusion at the cell surface. Error bars indicate the standard error of the mean of six (except 37.7H, where N = 9). (D) Fab 37.7H reduces binding of a LAMP1-Fc fusion protein to LASV GPCysR4. Error bars indicate the standard deviation of six and three technical replicates.

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