Differential Antibody-Based Immune Response against Isolated GP1 Receptor-Binding Domains from Lassa and Junín Viruses

Abstract

There are two predominant subgroups in the Arenaviridae family of viruses, the Old World and the New World viruses, that use distinct cellular receptors for entry. While New World viruses typically elicit good neutralizing antibody responses, the Old World viruses generally evade such responses. Antibody-based immune responses are directed against the glycoprotein spike complexes that decorate the viruses. A thick coat of glycans reduces the accessibility of antibodies to the surface of spike complexes from Old World viruses, but other mechanisms may further hamper the development of efficient humoral responses. Specifically, it was suggested that the GP1 receptor-binding module of the Old World Lassa virus might help with evasion of the humoral response. Here we investigated the immunogenicity of the GP1 domain from Lassa virus and compared it to that of the GP1 domain from the New World Junín virus. We found striking differences in the ability of antibodies that were developed against these immunogens to target the same GP1 receptor-binding domains in the context of the native spike complexes. Whereas GP1 from Junín virus elicited productive neutralizing responses, GP1 from Lassa virus elicited only nonproductive responses. These differences can be rationalized by the conformational changes that GP1 from Lassa virus but not GP1 from Junín virus undergoes after dissociating from the trimeric spike complex. Hence, shedding of GP1 in the case of Lassa virus can indeed serve as a mechanism to subvert the humoral immune response. Moreover, the realization that a recombinant protein may be used to elicit a productive response against the New World Junín virus may suggest a novel and safe way to design future vaccines. IMPORTANCE Some viruses that belong to the Arenaviridae family, like Lassa and Junín viruses, are notorious human pathogens, which may lead to fatal outcomes when they infect people. It is thus important to develop means to combat these viruses. For developing effective vaccines, it is vital to understand the basic mechanisms that these viruses utilize in order to evade or overcome host immune responses. It was previously noted that the GP1 receptor-binding domain from Lassa virus is shed and accumulates in the serum of infected individuals. This raised the possibility that Lassa virus GP1 may function as an immunological decoy. Here we demonstrate that mice develop nonproductive immune responses against GP1 from Lassa virus, which is in contrast to the effective neutralizing responses that GP1 from Junín virus elicits. Thus, GP1 from Lassa virus is indeed an immunological decoy and GP1 from Junín virus may serve as a constituent of a future vaccine.

Contrasting Modes of New World Arenavirus Neutralization by Immunization-Elicited Monoclonal Antibodies

“…Our and other NAbs recognize recombinantly produced NW GP1 ( Fig. 1 to 5 ) ( 27 – 29 ), consistent with a previous study demonstrating that recombinant NW GP1 is immunogenic and capable of eliciting NAbs ( 43 ). Further, given that recombinant NW GP1 recognizes TfR1 ( 23 , 44 ), these combined observations are consistent with the hypothesis that the conformations of monomeric JUNV and MACV GP1 are likely to resemble that existing on the mature trimeric NW arenaviral GP ( 1 ).…”

Recent Advances in Bunyavirus Glycoprotein Research: Precursor Processing, Receptor Binding and Structure

“…While a NW GP1-GP2 structure has yet to be reported, the NW GP1 from Machupo virus (MACV) [ 209 , 210 ], Junín virus (JUNV), and Whitewater Arroyo virus (WWAV), solved alone, and in complex with the TfR1 receptor and Fab fragments of neutralizing mAbs, have revealed only a single conformation, which may resemble the GP2-bound pre-fusion state [ 207 , 209 , 210 , 211 , 212 , 213 , 214 ]. The observation that the OW arenavirus GP1 undergoes conformational changes provides a structure-based hypothesis for how it may constitute an immunological decoy following release from the pre-fusion GP complex during infection [ 202 , 215 , 216 , 217 ] and is consistent with a study showing that recombinantly-derived NW GP1 is more effective at raising a neutralizing antibody response than OW GP1 [ 217 ]. Interestingly, crystallographic analysis of receptor-bound Lujo virus (LUJV) GP1 revealed a structure that contrasts known OW and NW GP1 structures [ 218 ], an observation that likely reflects its unique usage of the NRP2 host cell molecule ( Table 1 ) [ 103 ].…”

Adjuvant formulated virus-like particles expressing native-like forms of the Lassa virus envelope surface glycoprotein are immunogenic and induce antibodies with broadly neutralizing activity

“…Most human antibodies that neutralize LASV bind to quaternary structure epitopes containing regions from both GP1 and GP2. LASV VLPs display a correctly folded and conformationally relevant GP, which means that they have advantages over GP-subunit vaccines that lack higher-order protein structures and epitopes displayed on the intact virus 64,65 . As hyperimmunized serum contains a mixed population of antibodies, polyclonal antibody preparations can bind and neutralize multiple epitopes on GP, which may also reduce the emergence of viral escape mutants.…”