Vaccine-elicited receptor-binding site antibodies neutralize two New World hemorrhagic fever arenaviruses

Clark, Lars; Mahmutovic, Selma; Raymond, D.D.; Dilanyan, Taleen; Koma, Takaaki; Manning, John T.; Shankar, Sundaresh; Levis, Silvana; Briggiler, Ana M.; Enría, Delia; Wucherpfennig, Kai W.; Paessler, Slobodan; Abraham, Jonathan

doi:10.1038/s41467-018-04271-z

Cited by 44 publications

(65 citation statements)

References 63 publications

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“…Hence, such conformational switches may serve to form immunological decoys, in addition to priming the spike complexes for switching to secondary receptors. Receptor-binding sites are known vulnerabilities of viral glycoproteins (19,32,(36)(37)(38). In the case of GP1 LASV , a complete map of the ␣-DG binding site is still not available, but several residues that contribute to ␣-DG binding were previously identified (39,40).…”

Section: Resultsmentioning

confidence: 99%

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

Borenstein-Katz

Shulman

Hamawi

et al. 2019

J Virol

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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.

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Section: Resultsmentioning

confidence: 99%

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

Borenstein-Katz

Shulman

Hamawi

et al. 2019

J Virol

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“…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).…”

Section: Discrete Structural and Functional States Of The Arenaviral Gp1mentioning

confidence: 99%

“…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).…”

Section: Discrete Structural and Functional States Of The Arenaviral Gp1mentioning

confidence: 99%

Unraveling virus relationships by structure-based phylogenetic classification

Stelfox

Bowden

2020

Virus Evolution

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Delineation of the intricacies of protein function from macromolecular structure constitutes a continual obstacle in the study of cell and pathogen biology. Structure-based phylogenetic analysis has emerged as a powerful tool for addressing this challenge, allowing the detection and quantification of conserved architectural properties between proteins, including those with low or no detectable sequence homology. With a focus on viral protein structure, we highlight how a number of investigations have utilized this powerful method to infer common functionality and ancestry.

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“…MAbs targeting sequence-conserved GP2 are considered very promising, while antibodies that cross-react with both NW and Old World arenaviruses neutralize neither (Amanat et al, 2018). NAbs for JUNV simply targeting GP1 have not been reported to have cross-neutralization capabilities against the five arenaviruses except for one elicited by Candid#1 that neutralizes both JUNV and MACV with varying efficiency in vitro (Clark et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

“…Several monoclonal antibodies (mAbs) against JUNV have been reported in recent years, including human-mouse chimaera mAbs modified by Zeitlin et al (2016), vaccine-elicited human mAbs discovered by Clark et al (2018), and a series of mouse mAbs identified by our group (Pan et al, 2018). These mAbs target the envelope glycoprotein complex (GPC) for neutralization, which consists of trimeric noncovalently bound subunits: receptor recognition subunit glycoprotein 1 (GP1), membrane-fusion subunit glycoprotein 2 (GP2), and stable signal peptide (SSP) (Radoshitzky et al, 2007;Wang et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Development of horse neutralizing immunoglobulin and immunoglobulin fragments against Junín virus

Pan

Wang

et al. 2020

Antiviral Research

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Argentine haemorrhagic fever (AHF) is a rodent-borne disease with a lethality as high as~30%, which is caused by the New World arenavirus, Junín virus (JUNV). It was once a major epidemic in South America and puts millions of people in Argentina at risk. Here, we aimed to develop horse antibodies or antibody fragments against JUNV. Before preparing the horse antibodies, a strategy to efficiently generate horse antisera was established based on comparisons among immunogens and immunization methods in both mice and horses. Antisera against JUNV were finally obtained by vaccinating horses with vesicular stomatitis virus pseudotypes bearing JUNV GP. The horse antibodies IgG and F(ab') 2 were subsequently demonstrated to effectively neutralize vesicular stomatitis virus pseudotypes bearing JUNV GP and to show some cross-neutralization against pathogenic New World arenaviruses. Further research revealed that Asp123 on GP1 is an important site for the binding of antibodies targeting mainly JUNV GP1 for neutralization. Collectively, this study presents an efficient strategy to develop horse antisera against JUNV and provides GP1-specific horse antibodies as potential therapeutics for AHF.

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Vaccine-elicited receptor-binding site antibodies neutralize two New World hemorrhagic fever arenaviruses

Cited by 44 publications

References 63 publications

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

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

Unraveling virus relationships by structure-based phylogenetic classification

Development of horse neutralizing immunoglobulin and immunoglobulin fragments against Junín virus

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