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

Yi Xing; Stefan L Oliver; TuongVi Nguyen; Claudio Ciferri; Avishek Nandi; Julie Hickman; Cinzia Giovani; Edward Yang; Giuseppe Palladino; Charles Grose; Yasushi Uematsu; Anders E Lilja; Ann M Arvin; Andrea Carfí

doi:10.1073/pnas.1501176112

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

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

Yi Xing, Stefan L Oliver, TuongVi Nguyen, Claudio Ciferri, Avishek Nandi, Julie Hickman, Cinzia Giovani, Edward Yang, Giuseppe Palladino, Charles Grose, …

Proceedings of the National Academy of Sciences - PNAS, Vol.112(19), pp.6056-6061

05/12/2015

DOI: 10.1073/pnas.1501176112

PMCID: PMC4434712

PMID: 25918416

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Abstract

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.

Protein Structure, Tertiary

Surface Plasmon Resonance

Immunoglobulin Fragments - chemistry

Protein Structure, Secondary

Humans

Models, Molecular

Crystallography, X-Ray

Herpesvirus 3, Human - immunology

Neutralization Tests

Animals

Antibodies, Neutralizing - chemistry

Viral Envelope Proteins - chemistry

Protein Binding

Antibodies, Viral - immunology

Epitopes - chemistry

Mice

Glycoproteins - chemistry

Antibodies, Monoclonal - chemistry

Details

Title: Subtitle: A site of varicella-zoster virus vulnerability identified by structural studies of neutralizing antibodies bound to the glycoprotein complex gHgL
Creators: Yi Xing - GlaxoSmithKline (GSK) Vaccines, Cambridge, MA 02139; andrea.x.carfi@gsk.com yi.x.xing@gsk.com
Stefan L Oliver - Stanford University School of Medicine, Stanford, CA 94305
TuongVi Nguyen - GlaxoSmithKline (GSK) Vaccines, Cambridge, MA 02139
Claudio Ciferri - GlaxoSmithKline (GSK) Vaccines, Cambridge, MA 02139
Avishek Nandi - GlaxoSmithKline (GSK) Vaccines, Cambridge, MA 02139
Julie Hickman - GlaxoSmithKline (GSK) Vaccines, Cambridge, MA 02139
Cinzia Giovani - GSK Vaccines, Siena 53100, Italy
Edward Yang - Stanford University School of Medicine, Stanford, CA 94305
Giuseppe Palladino - Novartis Vaccines, Cambridge, MA 02139; and
Charles Grose - Virology Laboratory, University of Iowa Children's Hospital, Iowa City, IA 52242
Yasushi Uematsu - GSK Vaccines, Siena 53100, Italy
Anders E Lilja - GlaxoSmithKline (GSK) Vaccines, Cambridge, MA 02139
Ann M Arvin - Stanford University School of Medicine, Stanford, CA 94305
Andrea Carfí - GlaxoSmithKline (GSK) Vaccines, Cambridge, MA 02139; andrea.x.carfi@gsk.com yi.x.xing@gsk.com
Resource Type: Journal article
Publication Details: Proceedings of the National Academy of Sciences - PNAS, Vol.112(19), pp.6056-6061
DOI: 10.1073/pnas.1501176112
PMID: 25918416
PMCID: PMC4434712
NLM abbreviation: Proc Natl Acad Sci U S A
ISSN: 0027-8424
eISSN: 1091-6490
Publisher: National Academy of Sciences
Grant note: AI081994 / NIAID NIH HHS R01 AI053846 / NIAID NIH HHS R21 AI081994 / NIAID NIH HHS R01 AI089716 / NIAID NIH HHS R01 AI102546 / NIAID NIH HHS AI53846 / NIAID NIH HHS
Language: English
Date published: 05/12/2015
Academic Unit: Stead Family Department of Pediatrics; Infectious Disease (Pediatrics)
Record Identifier: 9984093501302771

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