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The glycoprotein precursor gene of Junin virus determines the virulence of the Romero strain and the attenuation of the Candid #1 strain in a representative animal model of Argentine hemorrhagic fever.
Seregin, Alexey V; Yun, Nadezhda E; Miller, Milagros; Aronson, Judith; Smith, Jennifer K; Walker, Aida G; Smith, Jeanon N; Huang, Cheng; Manning, John T; de la Torre, Juan C; Paessler, Slobodan.
Afiliación
  • Seregin AV; Department of Pathology, University of Texas Medical Branch, Galveston, Texas, USA Galveston National Laboratory, University of Texas Medical Branch, Galveston, Texas, USA.
  • Yun NE; Department of Pathology, University of Texas Medical Branch, Galveston, Texas, USA Galveston National Laboratory, University of Texas Medical Branch, Galveston, Texas, USA Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, Texas, USA.
  • Miller M; Department of Pathology, University of Texas Medical Branch, Galveston, Texas, USA Galveston National Laboratory, University of Texas Medical Branch, Galveston, Texas, USA.
  • Aronson J; Department of Pathology, University of Texas Medical Branch, Galveston, Texas, USA.
  • Smith JK; Department of Pathology, University of Texas Medical Branch, Galveston, Texas, USA.
  • Walker AG; Department of Pathology, University of Texas Medical Branch, Galveston, Texas, USA Galveston National Laboratory, University of Texas Medical Branch, Galveston, Texas, USA.
  • Smith JN; Department of Pathology, University of Texas Medical Branch, Galveston, Texas, USA Galveston National Laboratory, University of Texas Medical Branch, Galveston, Texas, USA.
  • Huang C; Department of Pathology, University of Texas Medical Branch, Galveston, Texas, USA Galveston National Laboratory, University of Texas Medical Branch, Galveston, Texas, USA.
  • Manning JT; Department of Pathology, University of Texas Medical Branch, Galveston, Texas, USA Galveston National Laboratory, University of Texas Medical Branch, Galveston, Texas, USA.
  • de la Torre JC; Department of Immunology and Microbial Science IMM-6, The Scripps Research Institute, La Jolla, California, USA.
  • Paessler S; Department of Pathology, University of Texas Medical Branch, Galveston, Texas, USA Galveston National Laboratory, University of Texas Medical Branch, Galveston, Texas, USA Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, Texas, USA slpaessl@utmb.edu.
J Virol ; 89(11): 5949-56, 2015 Jun.
Article en En | MEDLINE | ID: mdl-25810546
ABSTRACT
UNLABELLED The New World arenavirus Junin virus (JUNV) is the causative agent of Argentine hemorrhagic fever (AHF), a potentially deadly disease endemic to central regions of Argentina. The live-attenuated Candid #1 (Can) strain of JUNV is currently used to vaccinate the human population at risk. However, the mechanism of attenuation of this strain is still largely unknown. Therefore, the identification and functional characterization of viral genetic determinants dictating JUNV virulence or attenuation would significantly improve the understanding of the mechanisms underlying AHF and facilitate the development of novel, more effective, and safer vaccines. Here, we utilized a reverse genetics approach to generate recombinant JUNV (rJUNV) strains encoding different gene combinations of the pathogenic Romero (Rom) and attenuated Can strains of JUNV. All strains of rJUNV exhibited in vitro growth kinetics similar to those of their parental counterparts. Analysis of virulence of the rJUNV in a guinea pig model of lethal infection that closely reproduces the features of AHF identified the envelope glycoproteins (GPs) as the major determinants of pathogenesis and attenuation of JUNV. Accordingly, rJUNV strains expressing the full-length GPs of Rom and Can exhibited virulent and attenuated phenotypes, respectively, in guinea pigs. Mutation F427I in the transmembrane region of JUNV envelope glycoprotein GP2 has been shown to attenuate the neurovirulence of JUNV in suckling mice. We document that in the guinea pig model of AHF, mutation F427I in GP2 is also highly attenuating but insufficient to prevent virus dissemination and development of mild clinical and pathological symptoms, indicating that complete attenuation of JUNV requires additional mutations present in Can glycoprotein precursor (GPC). IMPORTANCE Development of antiviral strategies against viral hemorrhagic fevers, including AHF, is one of the top priorities within the Implementation Plan of the U.S. Department of Health and Human Services Public Health Emergency Medical Countermeasures Enterprise. Live-attenuated Candid #1 strain, derived from the 44th mouse brain passage of the prototype XJ strain of JUNV, has been demonstrated to be safe, immunogenic, and highly protective and is currently licensed for human use in Argentina. However, the bases for the attenuated phenotype of Candid #1 have not been established. Therefore, the identification and functional characterization of viral genetic factors implicated in JUNV pathogenesis and attenuation would significantly improve the understanding of the molecular mechanisms underlying AHF and facilitate the development of novel antiviral strategies.
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Texto completo: 1 Base de datos: MEDLINE Asunto principal: Glicoproteínas / Proteínas del Envoltorio Viral / Virus Junin / Fiebre Hemorrágica Americana Tipo de estudio: Prognostic_studies Límite: Animals País/Región como asunto: America do sul / Argentina Idioma: En Revista: J Virol Año: 2015 Tipo del documento: Article País de afiliación: Estados Unidos
Texto completo
Imprimir
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Buscar en Google

Texto completo: 1 Base de datos: MEDLINE Asunto principal: Glicoproteínas / Proteínas del Envoltorio Viral / Virus Junin / Fiebre Hemorrágica Americana Tipo de estudio: Prognostic_studies Límite: Animals País/Región como asunto: America do sul / Argentina Idioma: En Revista: J Virol Año: 2015 Tipo del documento: Article País de afiliación: Estados Unidos