PMID- 25810546 OWN - NLM STAT- MEDLINE DCOM- 20150727 LR - 20181113 IS - 1098-5514 (Electronic) IS - 0022-538X (Print) IS - 0022-538X (Linking) VI - 89 IP - 11 DP - 2015 Jun TI - 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. PG - 5949-56 LID - 10.1128/JVI.00104-15 [doi] AB - 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. CI - Copyright (c) 2015, American Society for Microbiology. All Rights Reserved. FAU - Seregin, Alexey V AU - Seregin AV AD - Department of Pathology, University of Texas Medical Branch, Galveston, Texas, USA Galveston National Laboratory, University of Texas Medical Branch, Galveston, Texas, USA. FAU - Yun, Nadezhda E AU - Yun NE AD - 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. FAU - Miller, Milagros AU - Miller M AD - Department of Pathology, University of Texas Medical Branch, Galveston, Texas, USA Galveston National Laboratory, University of Texas Medical Branch, Galveston, Texas, USA. FAU - Aronson, Judith AU - Aronson J AD - Department of Pathology, University of Texas Medical Branch, Galveston, Texas, USA. FAU - Smith, Jennifer K AU - Smith JK AD - Department of Pathology, University of Texas Medical Branch, Galveston, Texas, USA. FAU - Walker, Aida G AU - Walker AG AD - Department of Pathology, University of Texas Medical Branch, Galveston, Texas, USA Galveston National Laboratory, University of Texas Medical Branch, Galveston, Texas, USA. FAU - Smith, Jeanon N AU - Smith JN AD - Department of Pathology, University of Texas Medical Branch, Galveston, Texas, USA Galveston National Laboratory, University of Texas Medical Branch, Galveston, Texas, USA. FAU - Huang, Cheng AU - Huang C AD - Department of Pathology, University of Texas Medical Branch, Galveston, Texas, USA Galveston National Laboratory, University of Texas Medical Branch, Galveston, Texas, USA. FAU - Manning, John T AU - Manning JT AD - Department of Pathology, University of Texas Medical Branch, Galveston, Texas, USA Galveston National Laboratory, University of Texas Medical Branch, Galveston, Texas, USA. FAU - de la Torre, Juan C AU - de la Torre JC AD - Department of Immunology and Microbial Science IMM-6, The Scripps Research Institute, La Jolla, California, USA. FAU - Paessler, Slobodan AU - Paessler S AD - 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. LA - eng GR - R01 AI093445/AI/NIAID NIH HHS/United States GR - T32 AI060549/AI/NIAID NIH HHS/United States GR - R01AI093445/AI/NIAID NIH HHS/United States GR - T32-AI060549/AI/NIAID NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20150325 PL - United States TA - J Virol JT - Journal of virology JID - 0113724 RN - 0 (Glycoproteins) RN - 0 (Viral Envelope Proteins) RN - 0 (Virulence Factors) SB - IM MH - Animals MH - Disease Models, Animal MH - Glycoproteins/genetics/*metabolism MH - Guinea Pigs MH - Hemorrhagic Fever, American/pathology/*virology MH - Junin virus/genetics/*physiology MH - Reverse Genetics MH - Viral Envelope Proteins/genetics/*metabolism MH - Virulence MH - Virulence Factors PMC - PMC4442433 EDAT- 2015/03/27 06:00 MHDA- 2015/07/28 06:00 PMCR- 2015/12/01 CRDT- 2015/03/27 06:00 PHST- 2015/01/13 00:00 [received] PHST- 2015/03/13 00:00 [accepted] PHST- 2015/03/27 06:00 [entrez] PHST- 2015/03/27 06:00 [pubmed] PHST- 2015/07/28 06:00 [medline] PHST- 2015/12/01 00:00 [pmc-release] AID - JVI.00104-15 [pii] AID - 00104-15 [pii] AID - 10.1128/JVI.00104-15 [doi] PST - ppublish SO - J Virol. 2015 Jun;89(11):5949-56. doi: 10.1128/JVI.00104-15. Epub 2015 Mar 25.