Structural basis for the antibody neutralization of herpes simplex virus

Area of Science:

• Structural Biology
• Virology
• Immunology

Background:

• Herpes simplex virus (HSV) entry into host cells is mediated by Glycoprotein D (gD) binding to cellular receptors.
• gD is a validated target for developing anti-HSV therapies, with monoclonal antibodies like E317 showing high inhibitory potential.
• Understanding the structural basis of antibody-mediated neutralization is crucial for therapeutic antibody development.

Purpose of the Study:

• To elucidate the structural basis of neutralization by the human monoclonal antibody E317 against HSV Glycoprotein D (gD).
• To correlate virus-neutralizing epitopes with gD's receptor-binding regions.
• To further validate the therapeutic and diagnostic potential of mAb E317.

Main Methods:

• Crystallization of the gD ectodomain in complex with the E317 Fab domain.
• Determination of the complex's three-dimensional structure using X-ray crystallography.
• Analysis of epitope mapping and comparison with known receptor-binding sites and neutralizing antigenic sites.

Main Results:

• The crystal structure reveals E317 primarily interacts with gD via its heavy chain, covering a significant epitope area.
• The E317 epitope on gD overlaps with the binding sites for host receptors herpesvirus entry mediator (HVEM) and nectin-1.
• E317 binding blocks gD's interaction with both HVEM and nectin-1, and prevents the formation of the N-terminal hairpin required for HVEM recognition. Epitopes are conserved across HSV-1 and HSV-2.

Conclusions:

• The E317 antibody neutralizes HSV by directly interfering with gD's interaction with its cellular receptors, HVEM and nectin-1.
• The study provides a structural basis for E317's potent antiviral activity, highlighting conserved neutralizing epitopes.
• These findings reinforce the therapeutic and diagnostic utility of the E317 antibody for combating HSV infections.