Format

Send to

Choose Destination
PLoS Pathog. 2015 Nov 20;11(11):e1005276. doi: 10.1371/journal.ppat.1005276. eCollection 2015 Nov.

Arenavirus Glycan Shield Promotes Neutralizing Antibody Evasion and Protracted Infection.

Author information

1
Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland.
2
World Health Organization Collaborating Centre for Vaccine Immunology, University of Geneva, Geneva, Switzerland.
3
Division of Experimental Virology, Department of Biomedicine, University of Basel, Basel, Switzerland.
4
Novimmune SA, Plan-Les-Ouates, Switzerland.
5
Institut Pasteur, Département de Virologie, Unité de Virologie Structurale and CNRS UMR 3569 Virologie, Paris, France.
6
Institute of Virology, Philipps University Marburg, Marburg, Germany.
7
Department of Cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland.
8
AFMB, UMR7257 CNRS/Aix Marseille Université, Marseille, France.
9
Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.

Abstract

Arenaviruses such as Lassa virus (LASV) can cause severe hemorrhagic fever in humans. As a major impediment to vaccine development, delayed and weak neutralizing antibody (nAb) responses represent a unifying characteristic of both natural infection and all vaccine candidates tested to date. To investigate the mechanisms underlying arenavirus nAb evasion we engineered several arenavirus envelope-chimeric viruses and glycan-deficient variants thereof. We performed neutralization tests with sera from experimentally infected mice and from LASV-convalescent human patients. NAb response kinetics in mice correlated inversely with the N-linked glycan density in the arenavirus envelope protein's globular head. Additionally and most intriguingly, infection with fully glycosylated viruses elicited antibodies, which neutralized predominantly their glycan-deficient variants, both in mice and humans. Binding studies with monoclonal antibodies indicated that envelope glycans reduced nAb on-rate, occupancy and thereby counteracted virus neutralization. In infected mice, the envelope glycan shield promoted protracted viral infection by preventing its timely elimination by the ensuing antibody response. Thus, arenavirus envelope glycosylation impairs the protective efficacy rather than the induction of nAbs, and thereby prevents efficient antibody-mediated virus control. This immune evasion mechanism imposes limitations on antibody-based vaccination and convalescent serum therapy.

PMID:
26587982
PMCID:
PMC4654586
DOI:
10.1371/journal.ppat.1005276
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Public Library of Science Icon for PubMed Central
Loading ...
Support Center