title: Arenavirus Glycan Shield Promotes Neutralizing Antibody Evasion and Protracted Infection.
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.
authors.affiliation: Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland.|World Health Organization Collaborating Centre for Vaccine Immunology, University of Geneva, Geneva, Switzerland.
authors.forename: Rami
authors.initials: R
authors.lastname: Sommerstein
authors.affiliation: Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland.
authors.forename: Lukas
authors.initials: L
authors.lastname: Flatz
authors.affiliation: Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland.|Division of Experimental Virology, Department of Biomedicine, University of Basel, Basel, Switzerland.
authors.forename: Melissa M
authors.initials: MM
authors.lastname: Remy
authors.affiliation: Novimmune SA, Plan-Les-Ouates, Switzerland.
authors.forename: Pauline
authors.initials: P
authors.lastname: Malinge
authors.affiliation: Novimmune SA, Plan-Les-Ouates, Switzerland.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Magistrelli
authors.affiliation: Novimmune SA, Plan-Les-Ouates, Switzerland.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Fischer
authors.affiliation: Division of Experimental Virology, Department of Biomedicine, University of Basel, Basel, Switzerland.
authors.forename: Mehmet
authors.initials: M
authors.lastname: Sahin
authors.affiliation: Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland.
authors.forename: Andreas
authors.initials: A
authors.lastname: Bergthaler
authors.affiliation: Institut Pasteur, Département de Virologie, Unité de Virologie Structurale and CNRS UMR 3569 Virologie, Paris, France.
authors.forename: Sebastien
authors.initials: S
authors.lastname: Igonet
authors.affiliation: Institute of Virology, Philipps University Marburg, Marburg, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Ter Meulen
authors.affiliation: Department of Cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland.
authors.forename: Dorothée
authors.initials: D
authors.lastname: Rigo
authors.affiliation: Department of Cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland.
authors.forename: Paolo
authors.initials: P
authors.lastname: Meda
authors.affiliation: AFMB, UMR7257 CNRS/Aix Marseille Université, Marseille, France.
authors.forename: Nadia
authors.initials: N
authors.lastname: Rabah
authors.affiliation: AFMB, UMR7257 CNRS/Aix Marseille Université, Marseille, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Coutard
authors.affiliation: Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Bowden
authors.affiliation: Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland.|World Health Organization Collaborating Centre for Vaccine Immunology, University of Geneva, Geneva, Switzerland.
authors.forename: Paul-Henri
authors.initials: PH
authors.lastname: Lambert
authors.affiliation: Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland.|World Health Organization Collaborating Centre for Vaccine Immunology, University of Geneva, Geneva, Switzerland.
authors.forename: Claire-Anne
authors.initials: CA
authors.lastname: Siegrist
authors.affiliation: Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland.|World Health Organization Collaborating Centre for Vaccine Immunology, University of Geneva, Geneva, Switzerland.|Division of Experimental Virology, Department of Biomedicine, University of Basel, Basel, Switzerland.
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Pinschewer
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology*; D000914:Antibodies, Viral / Q000276:immunology*; D018050:Arenavirus / Q000276:immunology*; D015483:HIV Antibodies / Q000276:immunology; D015497:HIV-1 / Q000276:immunology; D006482:Hemorrhagic Fevers, Viral / Q000276:immunology*; D006801:Humans; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D011134:Polysaccharides / Q000276:immunology*
chemical_list: D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D015483:HIV Antibodies; D011134:Polysaccharides