Arenavirus Glycan Shield Promotes Neutralizing Antibody Evasion and Protracted Infection

PLoS Pathogens

Thomas A. Bowden¹  Paul-Henri Lambert¹  Nadia Rabah²  Bruno Coutard²  Pauline Malinge³  Rami Sommerstein³  Jan ter Meulen³  Daniel D. Pinschewer³  Melissa M. Remy³  Giovanni Magistrelli⁴  Sebastien Igonet⁴  Claire-Anne Siegrist⁵  Dorothée Rigo⁶  Paolo Meda⁷  Nicolas Fischer⁸  Mehmet Sahin⁸  Andreas Bergthaler⁸  Lukas Flatz⁹ 

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

关键词: Antibodies;    Glycosylation;    Sequence alignment;    Sequence motif analysis;    Junin virus;    Machupo virus;    Guanarito virus;    Arenaviruses;   

DOI  :  10.1371/journal.ppat.1005276

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY