title: Assessment of Inhibitors of Pathogenic Crimean-Congo Hemorrhagic Fever Virus Strains Using Virus-Like Particles.
abstract: Crimean-Congo hemorrhagic fever (CCHF) is an often lethal, acute inflammatory illness that affects a large geographic area. The disease is caused by infection with CCHF virus (CCHFV), a nairovirus from the Bunyaviridae family. Basic research on CCHFV has been severely hampered by biosafety requirements and lack of available strains and molecular tools. We report the development of a CCHF transcription- and entry-competent virus-like particle (tecVLP) system that can be used to study cell entry and viral transcription/replication over a broad dynamic range (~4 orders of magnitude). The tecVLPs are morphologically similar to authentic CCHFV. Incubation of immortalized and primary human cells with tecVLPs results in a strong reporter signal that is sensitive to treatment with neutralizing monoclonal antibodies and by small molecule inhibitors of CCHFV. We used glycoproteins and minigenomes from divergent CCHFV strains to generate tecVLPs, and in doing so, we identified a monoclonal antibody that can prevent cell entry of tecVLPs containing glycoproteins from 3 pathogenic CCHFV strains. In addition, our data suggest that different glycoprotein moieties confer different cellular entry efficiencies, and that glycoproteins from the commonly used strain IbAr10200 have up to 100-fold lower ability to enter primary human cells compared to glycoproteins from pathogenic CCHFV strains.
authors.affiliation: Viral Special Pathogens Branch, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia, United States of America.
authors.forename: Marko
authors.initials: M
authors.lastname: Zivcec
authors.affiliation: Infectious Disease Pathology Branch, Division of High Consequence Pathogens and Pathology, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia, United States of America.
authors.forename: Maureen G
authors.initials: MG
authors.lastname: Metcalfe
authors.affiliation: Viral Special Pathogens Branch, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia, United States of America.
authors.forename: César G
authors.initials: CG
authors.lastname: Albariño
authors.affiliation: Viral Special Pathogens Branch, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia, United States of America.
authors.forename: Lisa W
authors.initials: LW
authors.lastname: Guerrero
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, University of Georgia, Athens, Georgia, United States of America.
authors.forename: Scott D
authors.initials: SD
authors.lastname: Pegan
authors.affiliation: Viral Special Pathogens Branch, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia, United States of America.
authors.forename: Christina F
authors.initials: CF
authors.lastname: Spiropoulou
authors.affiliation: Viral Special Pathogens Branch, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia, United States of America.
authors.forename: Éric
authors.initials: É
authors.lastname: Bergeron
mesh_terms: D000911:Antibodies, Monoclonal / Q000378:metabolism; D057134:Antibodies, Neutralizing / Q000378:metabolism; D000914:Antibodies, Viral / Q000378:metabolism; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D017930:Genes, Reporter; D003225:Hemorrhagic Fever Virus, Crimean-Congo / Q000235:genetics / Q000302:isolation & purification / Q000502:physiology*; D008969:Molecular Sequence Data; D017422:Sequence Analysis, DNA; D014158:Transcription, Genetic / Q000187:drug effects*; D014771:Virion / Q000235:genetics / Q000502:physiology / Q000648:ultrastructure; D053586:Virus Internalization / Q000187:drug effects*; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral