site of varicella-zoster virus vulnerability identified by structural studies of neutralizing antibodies bound to the glycoprotein complex gHgL

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 112; no. 19; pp. 6056 - 6061
• Main Authors: Xing, Yi, Oliver, Stefan L., Nguyen, TuongVi, Ciferri, Claudio, Nandi, Avishek, Hickman, Julie, Giovani, Cinzia, Yang, Edward, Palladino, Giuseppe, Grose, Charles, Uematsu, Yasushi, Lilja, Anders E., Arvin, Ann M., Carfí, Andrea
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 12.05.2015; National Acad Sciences
• Subjects: Alphaherpesvirinae; Animals; Antibodies, Monoclonal - chemistry; Antibodies, Neutralizing - chemistry; Antibodies, Viral - immunology; binding sites; Biological Sciences; Cells; Crystallography, X-Ray; epitopes; Epitopes - chemistry; Glycoproteins; Glycoproteins - chemistry; Herpesvirus; Herpesvirus 3, Human - immunology; Human alphaherpesvirus 3; Humans; Immunization; Immunoglobulin Fragments - chemistry; membrane fusion; Membranes; Mice; Microscopy; Models, Molecular; Monoclonal antibodies; Neutralization; Neutralization Tests; neutralizing antibodies; Protein Binding; Protein Structure, Secondary; Protein Structure, Tertiary; Surface Plasmon Resonance; vaccines; Varicella-zoster virus; Viral Envelope Proteins - chemistry; Viruses; Young adults; electron microscopy; gHgL; neutralizing antibodies; VZV; crystal structures
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1501176112

Varicella-zoster virus (VZV), of the family Alphaherpesvirinae , causes varicella in children and young adults, potentially leading to herpes zoster later in life on reactivation from latency. The conserved herpesvirus glycoprotein gB and the heterodimer gHgL mediate virion envelope fusion with cell membranes during virus entry. Naturally occurring neutralizing antibodies against herpesviruses target these entry proteins. To determine the molecular basis for VZV neutralization, crystal structures of gHgL were determined in complex with fragments of antigen binding (Fabs) from two human monoclonal antibodies, IgG-94 and IgG-RC, isolated from seropositive subjects. These structures reveal that the antibodies target the same site, composed of residues from both gH and gL, distinct from two other neutralizing epitopes identified by negative-stain electron microscopy and mutational analysis. Inhibition of gB/gHgL-mediated membrane fusion and structural comparisons with herpesvirus homologs suggest that the IgG-RC/94 epitope is in proximity to the site on VZV gHgL that activates gB. Immunization studies proved that the anti-gHgL IgG-RC/94 epitope is a critical target for antibodies that neutralize VZV. Thus, the gHgL/Fab structures delineate a site of herpesvirus vulnerability targeted by natural immunity. Significance Mapping neutralizing epitopes on viral entry glycoproteins allows the identification of potentially important functional regions. The structure of varicella-zoster virus (VZV) gHgL bound to two antibodies isolated from immune donors reveals a common binding site. Functional experiments demonstrate that the two antibodies neutralize VZV infection and inhibit glycoprotein gB/glycoprotein complex gHgL-mediated membrane fusion. Immunization experiments in mice demonstrate that VZV gHgL elicits potently neutralizing antibodies and confirm the key role of this antigenic site in antibody-mediated virus neutralization. This manuscript sheds light on the molecular mechanism of herpesvirus cell entry and will guide the design of subunit-based vaccines against VZV.