Receptor determinants of zoonotic transmission of New World hemorrhagic fever arenaviruses

Radoshitzky, Sheli R.; Kuhn, Jens H.; Spiropoulou, Christina F.; Albariño, César G.; Nguyen, Dan P.; Salazar‐Bravo, Jorge; Dorfman, Tatyana; Lee, Amy; Wang, Enxiu; Ross, Susan R.; Choe, Hyeryun; Farzan, Michael

doi:10.1073/pnas.0709254105

Cited by 125 publications

(220 citation statements)

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“…2 C and D), the only clade B arenavirus glycoprotein-receptor structure reported to date. Tyr211 is a key residue in the GP1-hTfR1 interface (22) and conserved across all TfR1 orthologs that support NW arenavirus entry (23,30,31). Although we note that sequence and structural variation between the MACV GP1 and JUNV GP1 RBS exist, the colocalization of Tyr30B eOD01 and Tyr98 GD01 at the Tyr211 hTfR1 recognition site indicates that both nAbs effectively mimic TfR1-mediated arenaviral attachment.…”

Section: Resultsmentioning

confidence: 63%

Convergent immunological solutions to Argentine hemorrhagic fever virus neutralization

Zeltina

Krumm

Mehmet

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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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...

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Section: Resultsmentioning

confidence: 63%

Convergent immunological solutions to Argentine hemorrhagic fever virus neutralization

Zeltina

Krumm

Mehmet

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…The anti-human TfR1 antibody used in our blocking experiments has been shown to recognize a mouse-human TfR1 chimera containing human residues 187-383, but not a mouse-human TfR1 chimera containing human residues 187-207 or 213-383 (34), suggesting the epitope recognized may be contained within residues 208-212. Hence this apical domain would be a promising place to begin initial mapping studies.…”

Section: Discussionmentioning

confidence: 87%

Identification of transferrin receptor 1 as a hepatitis C virus entry factor

Martin

Uprichard

2013

Proc. Natl. Acad. Sci. U.S.A.

193

175

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Hepatitis C virus (HCV) is a liver tropic pathogen that affects ∼170 million people worldwide and causes liver pathologies including fibrosis, cirrhosis, steatosis, iron overload, and hepatocellular carcinoma. As part of a project initially directed at understanding how HCV may disrupt cellular iron homeostasis, we found that HCV alters expression of the iron uptake receptor transferrin receptor 1 (TfR1). After further investigation, we found that TfR1 mediates HCV entry. Specifically, functional studies showed that TfR1 knockdown and antibody blocking inhibit HCV cell culture (HCVcc) infection. Blocking cell surface TfR1 also inhibited HCV pseudoparticle (HCVpp) infection, demonstrating that TfR1 acts at the level of HCV glycoprotein-dependent entry. Likewise, a TfR1 small-molecule inhibitor that causes internalization of surface TfR1 resulted in a decrease in HCVcc and HCVpp infection. In kinetic studies, TfR1 antibody blocking lost its inhibitory activity after anti-CD81 blocking, suggesting that TfR1 acts during HCV entry at a postbinding step after CD81. In contrast, viral spread assays indicated that HCV cellto-cell spread is less dependent on TfR1. Interestingly, silencing of the TfR1 trafficking protein, a TfR-1 specific adaptor protein required for TfR1 internalization, also inhibited HCVcc infection. On the basis of these results, we conclude that TfR1 plays a role in HCV infection at the level of glycoprotein-mediated entry, acts after CD81, and possibly is involved in HCV particle internalization.hepatic iron overload | viral entry factor H epatitis C virus (HCV) infects more than 170 million people worldwide. Approximately 80% of infections persist to chronicity and can lead to liver pathologies including fibrosis, cirrhosis, steatosis, hepatic iron overload, and hepatocellular carcinoma. At this time, however, no vaccine is available to protect against infection, and current IFN-based treatment options, including those that include the HCV protease inhibitors recently approved for genotype 1 patients, are associated with toxic side effects and are only effective in a subset of patients (1, 2). As a result, in the United States, chronic HCV infection is the leading cause of hepatocellular carcinoma and the most common indication for liver transplantation. Importantly, identifying host factors and pathways involved in HCV infection could provide insight into HCVmediated liver disease and possibly lead to the discovery of novel therapeutic targets.Previous studies have reported that a disproportionate number of HCV patients develop hepatic iron overload, suggesting that iron metabolic pathways are deregulated during HCV infection (3-6). Consistent with this hypothesis, changes in the expression of iron metabolic genes have been reported in infected patients and in one HCV replicon cell clone (7,8). Following up on those studies, we initially observed that TfR1 mRNA and protein levels were down-regulated in human hepatoma Huh7 cells in response to HCV infection.TfR1 is the main receptor for cellular ir...

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“…Former comparisons of different arenaviruses and isolate behavior emphasized the crucial importance of the GP-1 subunit in virus entry and subsequent establishment of a persistent infection (35)(36)(37). Despite GP-2 being key for SSP/Z interaction (6) and GPC processing (32), only very recently, a GP-2 mutation was shown to be responsible for the in vivo attenuation of an arenavirus member, namely, the Junin virus vaccine strain Candid1 (38).…”

Section: Discussionmentioning

confidence: 99%

Evolution of Recombinant Lymphocytic Choriomeningitis Virus/Lassa Virus In Vivo Highlights the Importance of the GPC Cytosolic Tail in Viral Fitness

Sommerstein¹,

Palma

Ölschläger

et al. 2014

J Virol

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A key characteristic of arenaviruses is their ability to establish persistent infection in their natural host. Different factors like host age, viral dose strain, and route of infection may contribute to the establishment of persistence. However, the molecular mechanisms governing persistence are not fully understood. Here, we describe gain-of-function mutations of lymphocytic choriomeningitis virus (LCMV) expressing Lassa virus (LASV) GP, which can prolong viremia in mice depending on the sequences in the GP-2 cytoplasmic tail. The initial mutant variant (rLCMV/LASV mut GP) carried a point mutation in the cytosolic tail of the LASV glycoprotein GP corresponding to a K461G substitution. Unlike what occurred with the original rLCMV/LASV wild-type (wt) GP, infection of C57BL/6 mice with the mutated recombinant virus led to a detectable viremia of 2 weeks' duration. Further replacement of the entire sequence of the cytosolic tail from LASV to LCMV GP resulted in increased viral titers and delayed clearance of the viruses. Biosynthesis and cell surface localization of LASV wt and mut GPs were comparable. IMPORTANCEStarting from an emerging virus in a wild-type mouse, we engineered a panel of chimeric Lassa/lymphocytic choriomeningitis viruses. Mutants carrying a viral envelope with the cytosolic tail from the closely related mouse-adapted LCMV were able to achieve a productive viral infection lasting up to 27 days in wild-type mice. Biochemical assays showed a comparable biosynthesis and cell surface localization of LASV wt and mut GPs. These recombinant chimeric viruses could allow the study of immune responses and antivirals targeting the LASV GP.T he prototypic arenavirus lymphocytic choriomeningitis virus (LCMV) represents a powerful experimental model used to study the virus-host interaction of noncytopathic viruses and the role of T cells in clearing viral infections in mouse models (1). Infection with several existing strains results in different outcomes causing either transient, acute infection with virus-specific protective immunity or protracted, chronic infection with persisting viremia and immunosuppression (2). LCMV is an enveloped virus comprising two segments (S and L) of ambisense singlestranded RNA. The S RNA encodes the nucleoprotein (NP) and the envelope glycoprotein precursor (GPC) that is posttranslationally cleaved by signal peptidase and the cellular proprotein convertase SKI-1/S1P into the mature virion glycoprotein complex SSP/GP-1/GP-2 (GPs). The L RNA encodes the RNA-dependent RNA polymerase (L) and a small RING finger protein (Z). The GP mediates cell target attachment and fusion. NP and Z cover several functions, including inhibition of the innate immune response and viral particle budding, respectively. NP and L assemble with the two ambisense segments to form the ribonucleoprotein complexes (RNPs), which serve as the templates for transcription and replication. It has been shown that in LCMV the viral polymerase L and GP-1 of the glycoprotein are important determinants for the...

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Receptor determinants of zoonotic transmission of New World hemorrhagic fever arenaviruses

Cited by 125 publications

References 50 publications

Convergent immunological solutions to Argentine hemorrhagic fever virus neutralization

Convergent immunological solutions to Argentine hemorrhagic fever virus neutralization

Identification of transferrin receptor 1 as a hepatitis C virus entry factor

Evolution of Recombinant Lymphocytic Choriomeningitis Virus/Lassa Virus In Vivo Highlights the Importance of the GPC Cytosolic Tail in Viral Fitness

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