Comprehensive Assessment of the Antigenic Impact of Human Papillomavirus Lineage Variation on Recognition by Neutralizing Monoclonal Antibodies Raised against Lineage A Major Capsid Proteins of Vaccine-Related Genotypes

Anna Godi, Dolcibella Boampong, Busayo Elegunde, Kavita Panwar, Maxime Fleury, Shaowei Li, Qinjian Zhao, Ningshao Xia, Neil D. Christensen, Simon Beddows*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

7 Citations (Scopus)

Abstract

Human papillomavirus (HPV) is the causative agent of cervical and other epithelial cancers. Naturally occurring variants of HPV have been classified into lineages and sublineages based on their whole-genome sequences, but little is known about the impact of this diversity on the structure and function of viral gene products. The HPV capsid is an icosahedral lattice comprising 72 pentamers of the major capsid protein (L1) and the associated minor capsid protein (L2). We investigated the potential impact of this genome variation on the capsid antigenicity of lineage and sublineage variants of seven vaccine-relevant, oncogenic HPV genotypes by using a large panel of monoclonal antibodies (MAbs) raised against the L1 proteins of lineage A antigens. Each genotype had at least one variant that displayed a ≥4-fold reduced neutralizing antibody sensitivity against at least one MAb, demonstrating that naturally occurring variation can affect one or more functional antigenic determinants on the HPV capsid. For HPV16, HPV18, HPV31, and HPV45, the overall impact was of a low magnitude. For HPV33 (sublineages A2 and A3 and lineages B and C), HPV52 (lineage D), and HPV58 (lineage C), however, variant residues in the indicated lineages and sublineages reduced their sensitivity to neutralization by all MAbs by up to 1,000-fold, suggesting the presence of key antigenic determinants on the surface of these capsids. These determinants were resolved further by site-directed mutagenesis. These data improve our understanding of the impact of naturally occurring variation on the antigenicity of the HPV capsid of vaccine-relevant oncogenic HPV genotypes. IMPORTANCE Human papillomavirus (HPV) is the causative agent of cervical and some other epithelial cancers. HPV vaccines generate functional (neutralizing) antibodies that target the virus particles (or capsids) of the most common HPV cancer-causing genotypes. Each genotype comprises variant forms that have arisen over millennia and which include changes within the capsid proteins. In this study, we explored the potential for these naturally occurring variant capsids to impact recognition by neutralizing monoclonal antibodies. All genotypes included at least one variant form that exhibited reduced recognition by at least one antibody, with some genotypes affected more than others. These data highlight the impact of naturally occurring variation on the structure of the HPV capsid proteins of vaccine-relevant oncogenic HPV genotypes.

Original languageEnglish
Article numbere01236-20
JournalJournal of Virology
Volume94
Issue number24
DOIs
Publication statusPublished - Dec 2020

Bibliographical note

Funding Information:
This work was supported by Public Health England. This work did not receive a specific grant from any funding agency in the public, commercial, or not-for-profit sectors. We declare no conflicts of interest.

Funding Information:
We are indebted to John T. Schiller and Christopher Buck (National Cancer Institute, Bethesda, MD, USA) for access to the psheLL backbone used for the pseudovirus clones. We thank Dhanraj Samuel, Lenesha Warrener, and Sara L. Bissett from Public Health England for generation of some of the HPV18-specific MAbs used in this study. Some of this work was conducted as part of an MSc Biomedical Science (Queen Mary University of London) project (D.B.). This work was supported by Public Health England. This work did not receive a specific grant from any funding agency in the public, commercial, or not-for-profit sectors. We declare no conflicts of interest.

Publisher Copyright:
© Crown copyright 2020.

Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.

Keywords

  • Antigenicity
  • Human papillomavirus
  • Lineage
  • Monoclonal antibodies
  • Neutralization
  • Variant

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