Convergent immunological solutions to Argentine hemorrhagic fever virus neutralization

Abstract

Transmission of hemorrhagic fever New World arenaviruses from their rodent reservoirs to human populations poses substantial public health and economic dangers. These zoonotic events are enabled by the specific interaction between the New World arenaviral attachment glycoprotein, GP1, and cell surface human transferrin receptor (hTfR1). Here, we present the structural basis for how a mouse-derived neutralizing antibody (nAb), OD01, disrupts this interaction by targeting the receptor-binding surface of the GP1 glycoprotein from Junín virus (JUNV), a hemorrhagic fever arenavirus endemic in central Argentina. Comparison of our structure with that of a previously reported nAb complex (JUNV GP1-GD01) reveals largely overlapping epitopes but highly distinct antibody-binding modes. Despite differences in GP1 recognition, we find that both antibodies present a key tyrosine residue, albeit on different chains, that inserts into a central pocket on JUNV GP1 and effectively mimics the contacts made by the host TfR1. These data provide a molecular-level description of how antibodies derived from different germline origins arrive at equivalent immunological solutions to virus neutralization. . These viruses are endemic to rodent populations in rural areas of Argentina, Bolivia, and Venezuela, respectively, and viral spillover into human populations can result in severe hemorrhagic fever (HF) (3). Novel pathogenic NW arenaviruses continue to be identified (4-6), underscoring a wide-scale need for effective vaccines and therapeutics.JUNV, the etiological agent of Argentine hemorrhagic fever (AHF), constitutes one of the most dangerous NW arenaviruses, putting an estimated 5 million people at risk (7,8). JUNV infection typically exhibits a rapid onset of disease (7-14 d) and high mortality rates (15-30%) (7, 9, 10). There are no internationally approved drugs for preventing or treating NW arenavirus HF. However, the successful development of a live, attenuated JUNV vaccine, Candid#1, has proven that AHF can be controlled (11). Similarly, virus-neutralizing immune plasma from convalescent individuals has been successfully used for the treatment of AHF (10, 12).The JUNV envelope surface is decorated by trimeric multifunctional glycoprotein complex (GPC) spikes. Each protomer in the trimer consists of: a myristoylated (13) stable signal peptide, an attachment subunit (GP1), and a transmembrane fusion subunit (GP2) (14-19). Host-cell entry of JUNV and other clade B arenaviruses is initiated by the interaction between the arenaviral GP1 and the host transferrin receptor (TfR1) (20). The GP1 subunit interacts with the apical domain of TfR1, distal from natural transferrin and hereditary hemochromatosis protein recognition sites (21, 22). A primary determinant of zoonotic spread of clade B arenaviruses is the ability of the GP1 to recognize the human TfR1 ortholog (20, 23).The JUNV GPC spike comprises the primary target for neutralizing immune responses (24) and three GPC-specific mousederived nAbs-GD01, OD01, and GB03-have shown prom...

Unraveling virus relationships by structure-based phylogenetic classification

“…Interestingly, although henipaviral G RBPs and morbilliviral H RBPs both bind proteinaceous receptors (ephrin and SLAMF1/nectin-4, respectively), they occupy unique branches. This observation is consistent with the contrasting modes of henipaviral and morbilliviral receptor recognition (Zeltina, Bowden, and Lee 2016) and supports the hypothesis that the departure of an ancestral virus from sialic acid to protein receptor specificity may have occurred more than once during paramyxovirus evolution (Bowden et al 2008).…”

“…2B). This observation is in-line with the absence of ephrin, SLAMF1, and sialic acid-binding motifs in MojV-G RBP (Zeltina, Bowden, and Lee 2016) and in vitro studies, which demonstrated that MojV undergoes a distinct host cell entry pathway (Rissanen et al 2017). Similarly, the zoonotic paramyxovirus, Sosuga virus (SosV) (Albarino et al 2014), also displays a distinct RBP structure, despite presenting some of the conserved residues known to be integral for sialic acid binding and hydrolysis.…”

“…Both OW and NW arenaviruses display a glycoprotein complex, GPC, which is composed of a retained stable signal peptide, GP1 attachment glycoprotein, and membrane-anchored GP2 fusion glycoprotein. Structural studies have shown that the arenaviral GP1 presents a compact a/b fold, and the GP2 forms a class I type fusion architecture (Bowden et al 2009;Abraham et al 2010;Igonet et al 2011;Parsy et al 2013;Cohen-Dvashi et al 2015;Mahmutovic et al 2015;Hastie et al 2016Hastie et al , 2017Li et al 2016;Israeli et al 2017;Shimon, Shani, and Diskin 2017;Zeltina et al 2017;Clark et al 2018; Pryce et al 2018) (Fig. 1F).…”

“…Due to the current paucity of GP2-bound NW GP1 structures, it is unknown whether the NW GP1 exhibits the same structural plasticity as OW GP1s. However, this has been hypothesized to be unlikely as GP2-free NW GP1 elicits a neutralizing antibody immune response following immunization in animal models, is recognized by vaccine-elicited neutralizing antibodies, and recognizes the host transferrin receptor 1 (Abraham et al 2010;Mahmutovic et al 2015;Zeltina et al 2017;Clark et al 2018;Borenstein-Katz et al 2019). A/Maryland H13 (4KPQ), A/Astrakhan H14 (3EYJ), A/Western Australia H15 (5TG8), A/Sweden H16 (4FIU), A/Guatemala HL17 (4I78), and A/Peru HL18 (4MC5).…”

Development of horse neutralizing immunoglobulin and immunoglobulin fragments against Junín virus

“…In comparison, residual IgG weakly bound to these peptides, reflecting little nonspecific binding. In fact, P5 overlapped with the neutralizing epitopes of GD01 reported by Mahmutovic et al (2015) and with those of eOD01 reported by Zeltina et al (2017) at Y122 and D123 on GP1 (Fig. 6B).…”