Journal Article

Arenavirus Glycan Shield Promotes Neutralizing Antibody Evasion and Protracted Infection

Lambert, Paul-Henri, Malinge, Pauline, Architecture et fonction des macromolécules biologiques (AFMB) ; Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Rabah, Nadia, Pinschewer, Daniel D, Meulen, Jan, Ter, Bowden, Thomas A, Remy, Melissa M, This work was supported by the Medical Research Council (grant MR/L009528/1 to TAB), by the European Research Council (ERC grant No. 310962 to DDP), by the European Union Seventh Framework Programme (FP7/ 2007–2013, "European Virus Archive" under the grant agreement n°228292-EVA to DDP), by the Klaus Tschira Stiftung gGmbH (to DDP) and by the Swiss National Science Foundation (No. 310030_149340 to DDP), European Project: 228292,EC:FP7:INFRA,FP7-INFRASTRUCTURES-2008-1,EVA, Siegrist, Claire-Anne, Virologie Structurale - Structural Virology ; Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Université de Bâle = University of Basel (Unibas), Bergthaler, Andr

2015

Overview

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.

• Publisher: HAL CCSD,Public Library of Science,Public Library of Science (PLoS)
• Subject: Animals / Antibodies, Neutralizing - immunology / Antibodies, Viral - immunology / Arenavirus - immunology / Biochemistry, Molecular Biology / Care and treatment / Complications and side effects / Experiments / Health aspects / Hemorrhagic fever / Hemorrhagic Fevers, Viral - immunology / HIV Antibodies - immunology / HIV-1 - immunology / Humans / Immunoglobulins / Infections / Influence / Life Sciences / Mice, Inbred C57BL / Molecular Sequence Data / Monoclonal antibodies / Pathogens / Polysaccharides - immunology / Quantitative Methods / Structural Biology / Vaccines / Viral infections / Viruses