Research Article: Arenavirus Glycan Shield Promotes Neutralizing Antibody Evasion and Protracted Infection

Date Published: November 20, 2015

Publisher: Public Library of Science

Author(s): Rami Sommerstein, Lukas Flatz, Melissa M. Remy, Pauline Malinge, Giovanni Magistrelli, Nicolas Fischer, Mehmet Sahin, Andreas Bergthaler, Sebastien Igonet, Jan ter Meulen, Dorothée Rigo, Paolo Meda, Nadia Rabah, Bruno Coutard, Thomas A. Bowden, Paul-Henri Lambert, Claire-Anne Siegrist, Daniel D. Pinschewer, Ted C. Pierson.

http://doi.org/10.1371/journal.ppat.1005276

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.

Partial Text

For most viral vaccines in clinical use today, neutralizing antibodies (nAbs) represent the main correlate of protection [1, 2]. However, viral immune evasion strategies such as antigenic variation and so-called “glycan shields” on viral envelope proteins [3–8] can undermine the protective, neutralizing capacity of antibody immunity. An understanding of the mechanisms underlying viral interference with the host’s antibody defense is, therefore, of pivotal importance to refine vaccination strategies.

Glycan shielding of arenavirus GPs provides an explanation for the consistent failure to induce potent LASV-specific antibody immunity by either vaccination or natural infection [14, 15, 17, 18, 56–59]. In both circumstances, specific ELISA titers were high while neutralizing activity remained modest at best [56–58]. In line with these observations, our data suggest that glycosylation does not primarily prevent GP-1-specific antibody induction, but it impairs the capacity of these antibodies to neutralize. This shielding mechanism we propose differs from previous concepts such as the supposed “hole” in the arenavirus GP-1-specific B cell repertoire [25]. Neither would the arenavirus GP-1 represent the equivalent of an “immunologically silent face” in HIV-1 [60], i.e. GP-1 does not seem to lack immunogenicity owing to glycan resemblance to “self”. Our observations are more reminiscent of the “glycan shield” concept for HIV-1 [3], proposing that glycans impair antibody access to neutralizing epitopes on gp120. In stark contrast to HIV-1, however, the available sequence data suggest that arenavirus GP-1 glycans are invariable between isolates. Conversely, the difference in glycan density between the GP-1 of JUNV and LASV represents a likely reason why the excellent therapeutic success of convalescent serum in Argentine hemorrhagic fever does not find a parallel in Lassa fever [17, 21]. The presence of comparably fewer glycans in JUNV-GP-1 also is likely to facilitate the induction of antibody-mediated protection by the live-attenuated JUNV vaccine Candid#1 [11, 41]. In contrast, our data indicate that glycan-deficient LASV-GPs as immunogens will not overcome these structural hurdles.

 

Source:

http://doi.org/10.1371/journal.ppat.1005276

 

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