Antibody-based inhibition of pathogenic new world hemorrhagic fever mammarenaviruses by steric occlusion of the human transferrin receptor 1 apical domain

Autores
Ferrero, Sol; Flores, Maria D.; Short, Connor; Vázquez, Cecilia Alejandra; Clark, Lars E.; Ziegenbein, James; Zink, Samantha; Fuentes, Daniel; Payés, Cristian; Batto, María V.; Collazo, Michael; García, Cybele C.; Abraham, Jonathan; Cordo, Sandra Myriam; Rodriguez, Jose A.; Helguera, Gustavo Fernando
Año de publicación
2021
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Pathogenic clade B New World mammarenaviruses (NWM) can cause Argentine, Venezuelan, Brazilian, and Bolivian hemorrhagic fevers. Sequence variability among NWM glycoproteins (GP) poses a challenge to the development of broadly neutralizing therapeutics against the entire clade of viruses. However, blockade of their shared binding site on the apical domain of human transferrin receptor 1 (hTfR1/CD71) presents an opportunity for the development of effective and broadly neutralizing therapeutics. Here, we demonstrate that the murine monoclonal antibody OKT9, which targets the apical domain of hTfR1, can sterically block cellular entry by viral particles presenting clade B NWM glycoproteins (GP1-GP2). OKT9 blockade is also effective against viral particles pseudotyped with glycoproteins of a recently identified pathogenic Sabia-like virus. With nanomolar affinity for hTfR1, the OKT9 antigen binding fragment (OKT9-Fab) sterically blocks clade B NWM-GP1s and reduces infectivity of an attenuated strain of Junin virus. Binding of OKT9 to the hTfR1 ectodomain in its soluble, dimeric state produces stable assemblies that are observable by negative-stain electron microscopy. A model of the OKT9-sTfR1 complex, informed by the known crystallographic structure of sTfR1 and a newly determined structure of the OKT9 antigen binding fragment (Fab), suggests that OKT9 and the Machupo virus GP1 share a binding site on the hTfR1 apical domain. The structural basis for this interaction presents a framework for the design and development of high-affinity, broadly acting agents targeting clade B NWMs. IMPORTANCE Pathogenic clade B NWMs cause grave infectious diseases, the South American hemorrhagic fevers. Their etiological agents are Junin (JUNV), Guanarito (GTOV), Sabiá (SABV), Machupo (MACV), Chapare (CHAV), and a new Sabiá-like (SABV-L) virus recently identified in Brazil. These are priority A pathogens due to their high infectivity and mortality, their potential for person-to-person transmission, and the limited availability of effective therapeutics and vaccines to curb their effects. While low homology between surface glycoproteins of NWMs foils efforts to develop broadly neutralizing therapies targeting NWMs, this work provides structural evidence that OKT9, a monoclonal antibody targeting a single NWM glycoprotein binding site on hTfR1, can efficiently prevent their entry into cells.
Fil: Ferrero, Sol. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina
Fil: Flores, Maria D.. University of California at Los Angeles; Estados Unidos
Fil: Short, Connor. University of California at Los Angeles; Estados Unidos
Fil: Vázquez, Cecilia Alejandra. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina
Fil: Clark, Lars E.. Harvard Medical School; Estados Unidos
Fil: Ziegenbein, James. University of California at Los Angeles; Estados Unidos
Fil: Zink, Samantha. University of California at Los Angeles; Estados Unidos
Fil: Fuentes, Daniel. University of California at Los Angeles; Estados Unidos
Fil: Payés, Cristian. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina
Fil: Batto, María V.. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina
Fil: Collazo, Michael. University of California at Los Angeles; Estados Unidos
Fil: García, Cybele C.. Universidad de Buenos Aires; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina
Fil: Abraham, Jonathan. Harvard Medical School; Estados Unidos. Brigham and Women's Hospital; Estados Unidos
Fil: Cordo, Sandra Myriam. Universidad de Buenos Aires; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina
Fil: Rodriguez, Jose A.. University of California at Los Angeles; Estados Unidos
Fil: Helguera, Gustavo Fernando. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina
Materia
ANTIVIRAL AGENTS
ELECTRON MICROSCOPY
JUNIN
MACHUPO
MAMMARENAVIRUS
MONOCLONAL ANTIBODIES
SABIÁ-LIKE
TRANSFERRIN RECEPTOR
X-RAY CRYSTALLOGRAPHY
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/148223

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oai_identifier_str oai:ri.conicet.gov.ar:11336/148223
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Antibody-based inhibition of pathogenic new world hemorrhagic fever mammarenaviruses by steric occlusion of the human transferrin receptor 1 apical domainFerrero, SolFlores, Maria D.Short, ConnorVázquez, Cecilia AlejandraClark, Lars E.Ziegenbein, JamesZink, SamanthaFuentes, DanielPayés, CristianBatto, María V.Collazo, MichaelGarcía, Cybele C.Abraham, JonathanCordo, Sandra MyriamRodriguez, Jose A.Helguera, Gustavo FernandoANTIVIRAL AGENTSELECTRON MICROSCOPYJUNINMACHUPOMAMMARENAVIRUSMONOCLONAL ANTIBODIESSABIÁ-LIKETRANSFERRIN RECEPTORX-RAY CRYSTALLOGRAPHYhttps://purl.org/becyt/ford/3.4https://purl.org/becyt/ford/3Pathogenic clade B New World mammarenaviruses (NWM) can cause Argentine, Venezuelan, Brazilian, and Bolivian hemorrhagic fevers. Sequence variability among NWM glycoproteins (GP) poses a challenge to the development of broadly neutralizing therapeutics against the entire clade of viruses. However, blockade of their shared binding site on the apical domain of human transferrin receptor 1 (hTfR1/CD71) presents an opportunity for the development of effective and broadly neutralizing therapeutics. Here, we demonstrate that the murine monoclonal antibody OKT9, which targets the apical domain of hTfR1, can sterically block cellular entry by viral particles presenting clade B NWM glycoproteins (GP1-GP2). OKT9 blockade is also effective against viral particles pseudotyped with glycoproteins of a recently identified pathogenic Sabia-like virus. With nanomolar affinity for hTfR1, the OKT9 antigen binding fragment (OKT9-Fab) sterically blocks clade B NWM-GP1s and reduces infectivity of an attenuated strain of Junin virus. Binding of OKT9 to the hTfR1 ectodomain in its soluble, dimeric state produces stable assemblies that are observable by negative-stain electron microscopy. A model of the OKT9-sTfR1 complex, informed by the known crystallographic structure of sTfR1 and a newly determined structure of the OKT9 antigen binding fragment (Fab), suggests that OKT9 and the Machupo virus GP1 share a binding site on the hTfR1 apical domain. The structural basis for this interaction presents a framework for the design and development of high-affinity, broadly acting agents targeting clade B NWMs. IMPORTANCE Pathogenic clade B NWMs cause grave infectious diseases, the South American hemorrhagic fevers. Their etiological agents are Junin (JUNV), Guanarito (GTOV), Sabiá (SABV), Machupo (MACV), Chapare (CHAV), and a new Sabiá-like (SABV-L) virus recently identified in Brazil. These are priority A pathogens due to their high infectivity and mortality, their potential for person-to-person transmission, and the limited availability of effective therapeutics and vaccines to curb their effects. While low homology between surface glycoproteins of NWMs foils efforts to develop broadly neutralizing therapies targeting NWMs, this work provides structural evidence that OKT9, a monoclonal antibody targeting a single NWM glycoprotein binding site on hTfR1, can efficiently prevent their entry into cells.Fil: Ferrero, Sol. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Flores, Maria D.. University of California at Los Angeles; Estados UnidosFil: Short, Connor. University of California at Los Angeles; Estados UnidosFil: Vázquez, Cecilia Alejandra. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; ArgentinaFil: Clark, Lars E.. Harvard Medical School; Estados UnidosFil: Ziegenbein, James. University of California at Los Angeles; Estados UnidosFil: Zink, Samantha. University of California at Los Angeles; Estados UnidosFil: Fuentes, Daniel. University of California at Los Angeles; Estados UnidosFil: Payés, Cristian. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Batto, María V.. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Collazo, Michael. University of California at Los Angeles; Estados UnidosFil: García, Cybele C.. Universidad de Buenos Aires; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; ArgentinaFil: Abraham, Jonathan. Harvard Medical School; Estados Unidos. Brigham and Women's Hospital; Estados UnidosFil: Cordo, Sandra Myriam. Universidad de Buenos Aires; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; ArgentinaFil: Rodriguez, Jose A.. University of California at Los Angeles; Estados UnidosFil: Helguera, Gustavo Fernando. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaAmerican Society for Microbiology2021-09info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/148223Ferrero, Sol; Flores, Maria D.; Short, Connor; Vázquez, Cecilia Alejandra; Clark, Lars E.; et al.; Antibody-based inhibition of pathogenic new world hemorrhagic fever mammarenaviruses by steric occlusion of the human transferrin receptor 1 apical domain; American Society for Microbiology; Journal of Virology; 95; 17; 9-20210022-538XCONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://journals.asm.org/doi/10.1128/JVI.01868-20?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmedinfo:eu-repo/semantics/altIdentifier/doi/10.1128/JVI.01868-20info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T10:21:35Zoai:ri.conicet.gov.ar:11336/148223instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-29 10:21:35.622CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Antibody-based inhibition of pathogenic new world hemorrhagic fever mammarenaviruses by steric occlusion of the human transferrin receptor 1 apical domain
title Antibody-based inhibition of pathogenic new world hemorrhagic fever mammarenaviruses by steric occlusion of the human transferrin receptor 1 apical domain
spellingShingle Antibody-based inhibition of pathogenic new world hemorrhagic fever mammarenaviruses by steric occlusion of the human transferrin receptor 1 apical domain
Ferrero, Sol
ANTIVIRAL AGENTS
ELECTRON MICROSCOPY
JUNIN
MACHUPO
MAMMARENAVIRUS
MONOCLONAL ANTIBODIES
SABIÁ-LIKE
TRANSFERRIN RECEPTOR
X-RAY CRYSTALLOGRAPHY
title_short Antibody-based inhibition of pathogenic new world hemorrhagic fever mammarenaviruses by steric occlusion of the human transferrin receptor 1 apical domain
title_full Antibody-based inhibition of pathogenic new world hemorrhagic fever mammarenaviruses by steric occlusion of the human transferrin receptor 1 apical domain
title_fullStr Antibody-based inhibition of pathogenic new world hemorrhagic fever mammarenaviruses by steric occlusion of the human transferrin receptor 1 apical domain
title_full_unstemmed Antibody-based inhibition of pathogenic new world hemorrhagic fever mammarenaviruses by steric occlusion of the human transferrin receptor 1 apical domain
title_sort Antibody-based inhibition of pathogenic new world hemorrhagic fever mammarenaviruses by steric occlusion of the human transferrin receptor 1 apical domain
dc.creator.none.fl_str_mv Ferrero, Sol
Flores, Maria D.
Short, Connor
Vázquez, Cecilia Alejandra
Clark, Lars E.
Ziegenbein, James
Zink, Samantha
Fuentes, Daniel
Payés, Cristian
Batto, María V.
Collazo, Michael
García, Cybele C.
Abraham, Jonathan
Cordo, Sandra Myriam
Rodriguez, Jose A.
Helguera, Gustavo Fernando
author Ferrero, Sol
author_facet Ferrero, Sol
Flores, Maria D.
Short, Connor
Vázquez, Cecilia Alejandra
Clark, Lars E.
Ziegenbein, James
Zink, Samantha
Fuentes, Daniel
Payés, Cristian
Batto, María V.
Collazo, Michael
García, Cybele C.
Abraham, Jonathan
Cordo, Sandra Myriam
Rodriguez, Jose A.
Helguera, Gustavo Fernando
author_role author
author2 Flores, Maria D.
Short, Connor
Vázquez, Cecilia Alejandra
Clark, Lars E.
Ziegenbein, James
Zink, Samantha
Fuentes, Daniel
Payés, Cristian
Batto, María V.
Collazo, Michael
García, Cybele C.
Abraham, Jonathan
Cordo, Sandra Myriam
Rodriguez, Jose A.
Helguera, Gustavo Fernando
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv ANTIVIRAL AGENTS
ELECTRON MICROSCOPY
JUNIN
MACHUPO
MAMMARENAVIRUS
MONOCLONAL ANTIBODIES
SABIÁ-LIKE
TRANSFERRIN RECEPTOR
X-RAY CRYSTALLOGRAPHY
topic ANTIVIRAL AGENTS
ELECTRON MICROSCOPY
JUNIN
MACHUPO
MAMMARENAVIRUS
MONOCLONAL ANTIBODIES
SABIÁ-LIKE
TRANSFERRIN RECEPTOR
X-RAY CRYSTALLOGRAPHY
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.4
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Pathogenic clade B New World mammarenaviruses (NWM) can cause Argentine, Venezuelan, Brazilian, and Bolivian hemorrhagic fevers. Sequence variability among NWM glycoproteins (GP) poses a challenge to the development of broadly neutralizing therapeutics against the entire clade of viruses. However, blockade of their shared binding site on the apical domain of human transferrin receptor 1 (hTfR1/CD71) presents an opportunity for the development of effective and broadly neutralizing therapeutics. Here, we demonstrate that the murine monoclonal antibody OKT9, which targets the apical domain of hTfR1, can sterically block cellular entry by viral particles presenting clade B NWM glycoproteins (GP1-GP2). OKT9 blockade is also effective against viral particles pseudotyped with glycoproteins of a recently identified pathogenic Sabia-like virus. With nanomolar affinity for hTfR1, the OKT9 antigen binding fragment (OKT9-Fab) sterically blocks clade B NWM-GP1s and reduces infectivity of an attenuated strain of Junin virus. Binding of OKT9 to the hTfR1 ectodomain in its soluble, dimeric state produces stable assemblies that are observable by negative-stain electron microscopy. A model of the OKT9-sTfR1 complex, informed by the known crystallographic structure of sTfR1 and a newly determined structure of the OKT9 antigen binding fragment (Fab), suggests that OKT9 and the Machupo virus GP1 share a binding site on the hTfR1 apical domain. The structural basis for this interaction presents a framework for the design and development of high-affinity, broadly acting agents targeting clade B NWMs. IMPORTANCE Pathogenic clade B NWMs cause grave infectious diseases, the South American hemorrhagic fevers. Their etiological agents are Junin (JUNV), Guanarito (GTOV), Sabiá (SABV), Machupo (MACV), Chapare (CHAV), and a new Sabiá-like (SABV-L) virus recently identified in Brazil. These are priority A pathogens due to their high infectivity and mortality, their potential for person-to-person transmission, and the limited availability of effective therapeutics and vaccines to curb their effects. While low homology between surface glycoproteins of NWMs foils efforts to develop broadly neutralizing therapies targeting NWMs, this work provides structural evidence that OKT9, a monoclonal antibody targeting a single NWM glycoprotein binding site on hTfR1, can efficiently prevent their entry into cells.
Fil: Ferrero, Sol. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina
Fil: Flores, Maria D.. University of California at Los Angeles; Estados Unidos
Fil: Short, Connor. University of California at Los Angeles; Estados Unidos
Fil: Vázquez, Cecilia Alejandra. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina
Fil: Clark, Lars E.. Harvard Medical School; Estados Unidos
Fil: Ziegenbein, James. University of California at Los Angeles; Estados Unidos
Fil: Zink, Samantha. University of California at Los Angeles; Estados Unidos
Fil: Fuentes, Daniel. University of California at Los Angeles; Estados Unidos
Fil: Payés, Cristian. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina
Fil: Batto, María V.. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina
Fil: Collazo, Michael. University of California at Los Angeles; Estados Unidos
Fil: García, Cybele C.. Universidad de Buenos Aires; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina
Fil: Abraham, Jonathan. Harvard Medical School; Estados Unidos. Brigham and Women's Hospital; Estados Unidos
Fil: Cordo, Sandra Myriam. Universidad de Buenos Aires; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina
Fil: Rodriguez, Jose A.. University of California at Los Angeles; Estados Unidos
Fil: Helguera, Gustavo Fernando. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina
description Pathogenic clade B New World mammarenaviruses (NWM) can cause Argentine, Venezuelan, Brazilian, and Bolivian hemorrhagic fevers. Sequence variability among NWM glycoproteins (GP) poses a challenge to the development of broadly neutralizing therapeutics against the entire clade of viruses. However, blockade of their shared binding site on the apical domain of human transferrin receptor 1 (hTfR1/CD71) presents an opportunity for the development of effective and broadly neutralizing therapeutics. Here, we demonstrate that the murine monoclonal antibody OKT9, which targets the apical domain of hTfR1, can sterically block cellular entry by viral particles presenting clade B NWM glycoproteins (GP1-GP2). OKT9 blockade is also effective against viral particles pseudotyped with glycoproteins of a recently identified pathogenic Sabia-like virus. With nanomolar affinity for hTfR1, the OKT9 antigen binding fragment (OKT9-Fab) sterically blocks clade B NWM-GP1s and reduces infectivity of an attenuated strain of Junin virus. Binding of OKT9 to the hTfR1 ectodomain in its soluble, dimeric state produces stable assemblies that are observable by negative-stain electron microscopy. A model of the OKT9-sTfR1 complex, informed by the known crystallographic structure of sTfR1 and a newly determined structure of the OKT9 antigen binding fragment (Fab), suggests that OKT9 and the Machupo virus GP1 share a binding site on the hTfR1 apical domain. The structural basis for this interaction presents a framework for the design and development of high-affinity, broadly acting agents targeting clade B NWMs. IMPORTANCE Pathogenic clade B NWMs cause grave infectious diseases, the South American hemorrhagic fevers. Their etiological agents are Junin (JUNV), Guanarito (GTOV), Sabiá (SABV), Machupo (MACV), Chapare (CHAV), and a new Sabiá-like (SABV-L) virus recently identified in Brazil. These are priority A pathogens due to their high infectivity and mortality, their potential for person-to-person transmission, and the limited availability of effective therapeutics and vaccines to curb their effects. While low homology between surface glycoproteins of NWMs foils efforts to develop broadly neutralizing therapies targeting NWMs, this work provides structural evidence that OKT9, a monoclonal antibody targeting a single NWM glycoprotein binding site on hTfR1, can efficiently prevent their entry into cells.
publishDate 2021
dc.date.none.fl_str_mv 2021-09
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/148223
Ferrero, Sol; Flores, Maria D.; Short, Connor; Vázquez, Cecilia Alejandra; Clark, Lars E.; et al.; Antibody-based inhibition of pathogenic new world hemorrhagic fever mammarenaviruses by steric occlusion of the human transferrin receptor 1 apical domain; American Society for Microbiology; Journal of Virology; 95; 17; 9-2021
0022-538X
CONICET Digital
CONICET
url http://hdl.handle.net/11336/148223
identifier_str_mv Ferrero, Sol; Flores, Maria D.; Short, Connor; Vázquez, Cecilia Alejandra; Clark, Lars E.; et al.; Antibody-based inhibition of pathogenic new world hemorrhagic fever mammarenaviruses by steric occlusion of the human transferrin receptor 1 apical domain; American Society for Microbiology; Journal of Virology; 95; 17; 9-2021
0022-538X
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/https://journals.asm.org/doi/10.1128/JVI.01868-20?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed
info:eu-repo/semantics/altIdentifier/doi/10.1128/JVI.01868-20
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv American Society for Microbiology
publisher.none.fl_str_mv American Society for Microbiology
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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