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.

Convergent immunological solutions to Argentine hemorrhagic fever virus neutralization

“…Although glycans do not appear to play a role in eOD01-JUNV GP1 complex formation, the presence of glycosylation on the GP1 does affect the potency of antibody-mediated neutralization. For example, OD01 and GD01 neutralize rLCMV displaying an XJ Clone 3 JUNV vaccine strain glycoprotein, which lacks the Asn166 glycosylation motif, more potently than the autologous virus, in which this glycosylation motif has been restored (28). Considering the proximity of Asn166 to the JUNV GP1-antibody interface (Fig.…”

A study of genetic variability of human parainfluenza virus type 1 in Croatia, 2011–2014

“…Glycosylation of surface proteins is a presumed mechanism for helping virus to evade the host immune response (Palomo et al, 1991(Palomo et al, , 2000Sommerstein et al, 2015;Suptawiwat et al, 2015). Variation in the number of specific glycosylation sites can influence the expression of viral protein epitopes and, consequently, the type of produced specific antibodies.…”

“…Potential N-and O-glycosylated sites in Croatian F and HN protein sequences were determined using NetNGlyc 1.0 and NetOGlyc 4.0 servers (Steentoft et al, 2013).…”

Development of novel replication-defective lymphocytic choriomeningitis virus vectors expressing SIV antigens

“…This is, at least in part, due to glycosylation of the LCMV surface protein (GP), which impairs the capacity of GP specific antibodies to neutralize the virus [13]. Moreover, rLCMV vectors do not encode the GP gene, and the vaccinee’s immune system is therefore only exposed to the minute amounts of viral GP present in the vector particle preparations, while de novo synthesis of GP as immunogen in the vaccinee is excluded.…”