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

Alexey V. Seregin, Nadezhda E. Yun, Milagros Miller, Judith Aronson, Jennifer K. Smith, Aida G. Walker, Jeanon N. Smith, Cheng Huang, John Manning, Juan C. de la Torre, Slobodan Paessler

Research output: Contribution to journalArticle

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Abstract

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).

Original languageEnglish (US)
Pages (from-to)5949-5956
Number of pages8
JournalJournal of Virology
Volume89
Issue number11
DOIs
StatePublished - 2015

Fingerprint

Junin virus
Virulence
glycoproteins
Glycoproteins
Fever
virulence
Animal Models
animal models
Genes
genes
guinea pigs
Guinea Pigs
mutation
Mutation
New World Arenaviruses
Arenavirus
microbial genetics
Argentine hemorrhagic fever
Reverse Genetics
Endemic Diseases

ASJC Scopus subject areas

  • Immunology
  • Virology

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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; de la Torre, Juan C.; Paessler, Slobodan.

In: Journal of Virology, Vol. 89, No. 11, 2015, p. 5949-5956.

Research output: Contribution to journalArticle

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abstract = "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).",
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