Potential and action mechanism of favipiravir as an antiviral against Junin virus

2021 ◽  
Author(s):  
Vahid Rajabali Zadeh ◽  
Shuzo Urata ◽  
Tosin Oladipo Afowowe ◽  
Jiro Yasuda
Keyword(s):  
Hemorrhagic Fever ◽  
Resistant Mutant ◽  
Polymerase Activity ◽  
Activity Levels ◽  
Glycoprotein Precursor ◽  
Virus Growth ◽  
Junin Virus ◽  
Argentine Hemorrhagic Fever ◽  
Drug Resistant Mutant ◽  
Junín Virus

Favipiravir is a nucleoside analogue that inhibits the replication and transcription of a broad spectrum of RNA viruses, including pathogenic arenaviruses. In this study, we isolated a favipiravir-resistant mutant of Junin virus (JUNV), which is the causative agent of Argentine hemorrhagic fever, and analyzed the antiviral mechanism of favipiravir against JUNV. Two amino acid substitutions, N462D in the RNA-dependent RNA polymerase (RdRp) and A168T in the glycoprotein precursor GPC, were identified in the mutant. GPC-A168T substitution enhanced the efficiency of JUNV internalization, which explains the robust replication kinetics of the mutant in the virus growth analysis. Although RdRp-N462D substitution did not affect polymerase activity levels in a minigenome system, comparisons of RdRp error frequencies showed that the virus with RdRp-D462 possessed a significantly higher fidelity. We also provided experimental evidence for the first time that favipiravir inhibited JUNV through the accumulation of transition mutations, confirming its role as a purine analogue against arenaviruses. Moreover, we showed that treatment with a combination of favipiravir and either ribavirin or remdesivir inhibited JUNV replication in a synergistic manner, blocking the generation of the drug-resistant mutant. Our findings provide new insights for the clinical management and treatment of Argentine hemorrhagic fever.

scholarly journals 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

2015 ◽  
Vol 89 (11) ◽  
pp. 5949-5956 ◽  
Author(s):  
Alexey V. Seregin ◽  
Nadezhda E. Yun ◽  
Milagros Miller ◽  
Judith Aronson ◽  
Jennifer K. Smith ◽  
...  
Keyword(s):  
Guinea Pig ◽  
Functional Characterization ◽  
Hemorrhagic Fever ◽  
Pig Model ◽  
Glycoprotein Precursor ◽  
Junin Virus ◽  
Argentine Hemorrhagic Fever ◽  
Guinea Pig Model ◽  
Junín Virus

ABSTRACTThe 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 exhibitedin vitrogrowth 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).IMPORTANCEDevelopment 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.

Junin virus activity in two rural populations of the Argentine hemorrhagic fever (AHF) endemic area

1983 ◽  
Vol 12 (4) ◽  
pp. 273-280 ◽  
Author(s):  
Mercedes C. Weissenbacher ◽  
Marta S. Sabattini ◽  
María M. Avila ◽  
Patricia M. Sangiorgio ◽  
María R. F. De Sensi ◽  
...  
Keyword(s):  
Endemic Area ◽  
Hemorrhagic Fever ◽  
Rural Populations ◽  
Junin Virus ◽  
Argentine Hemorrhagic Fever ◽  
Virus Activity ◽  
Junín Virus

scholarly journals Novel Arenavirus Entry Inhibitors Discovered by Using a Minigenome Rescue System for High-Throughput Drug Screening

2015 ◽  
Vol 89 (16) ◽  
pp. 8428-8443 ◽  
Author(s):  
Jessica Y. Rathbun ◽  
Magali E. Droniou ◽  
Robert Damoiseaux ◽  
Kevin G. Haworth ◽  
Jill E. Henley ◽  
...  
Keyword(s):  
High Throughput ◽  
Causative Agent ◽  
High Throughput Screening ◽  
Hemorrhagic Fever ◽  
Human Pathogens ◽  
Junin Virus ◽  
Hemorrhagic Fevers ◽  
Argentine Hemorrhagic Fever ◽  
Rescue System ◽  
Junín Virus

ABSTRACTCertain members of theArenaviridaefamily are category A agents capable of causing severe hemorrhagic fevers in humans. Specific antiviral treatments do not exist, and the only commonly used drug, ribavirin, has limited efficacy and can cause severe side effects. The discovery and development of new antivirals are inhibited by the biohazardous nature of the viruses, making them a relatively poorly understood group of human pathogens. We therefore adapted a reverse-genetics minigenome (MG) rescue system based on Junin virus, the causative agent of Argentine hemorrhagic fever, for high-throughput screening (HTS). The MG rescue system recapitulates all stages of the virus life cycle and enables screening of small-molecule libraries under biosafety containment level 2 (BSL2) conditions. The HTS resulted in the identification of four candidate compounds with potent activity against a broad panel of arenaviruses, three of which were completely novel. The target for all 4 compounds was the stage of viral entry, which positions the compounds as potentially important leads for future development.IMPORTANCEThe arenavirus family includes several members that are highly pathogenic, causing acute viral hemorrhagic fevers with high mortality rates. No specific effective treatments exist, and although a vaccine is available for Junin virus, the causative agent of Argentine hemorrhagic fever, it is licensed for use only in areas where Argentine hemorrhagic fever is endemic. For these reasons, it is important to identify specific compounds that could be developed as antivirals against these deadly viruses.

scholarly journals Junín Virus Promotes Autophagy To Facilitate the Virus Life Cycle

2019 ◽  
Vol 93 (15) ◽  
Author(s):  
Julieta S. Roldán ◽  
Nélida A. Candurra ◽  
María I. Colombo ◽  
Laura R. Delgui
Keyword(s):  
Hemorrhagic Fever ◽  
Replication Capacity ◽  
Epidemic Disease ◽  
Junin Virus ◽  
Hemorrhagic Fevers ◽  
Argentine Hemorrhagic Fever ◽  
The Family ◽  
Infected Cells ◽  
Junín Virus

ABSTRACTJunín virus (JUNV), a member of the familyArenaviridae, is the etiological agent of Argentine hemorrhagic fever (AHF), a potentially deadly endemic-epidemic disease affecting the population of the most fertile farming land of Argentina. Autophagy is a degradative process with a crucial antiviral role; however, several viruses subvert the pathway to their benefit. We determined the role of autophagy in JUNV-infected cells by analyzing LC3, a cytoplasmic protein (LC3-I) that becomes vesicle membrane associated (LC3-II) upon induction of autophagy. Cells overexpressing enhanced green fluorescent protein (EGFP)-LC3 and infected with JUNV showed an increased number of LC3 punctate structures, similar to those obtained after starvation or bafilomycin A1 treatment, which leads to autophagosome induction or accumulation, respectively. We also monitored the conversion of LC3-I to LC3-II, observing LC3-II levels in JUNV-infected cells similar to those observed in starved cells. Additionally, we kinetically studied the number of LC3 dots after JUNV infection and found that the virus activated the pathway as early as 2 h postinfection (p.i.), whereas the UV-inactivated virus did not induce the pathway. Cells subjected to starvation or pretreated with rapamycin, a pharmacological autophagy inductor, enhanced virus yield. Also, we assayed the replication capacity of JUNV in Atg5 knockout or Beclin 1 knockdown cells (both critical components of the autophagic pathway) and found a significant decrease in JUNV replication. Taken together, our results constitute the first study indicating that JUNV infection induces an autophagic response, which is functionally required by the virus for efficient propagation.IMPORTANCEMammalian arenaviruses are zoonotic viruses that cause asymptomatic and persistent infections in their rodent hosts but may produce severe and lethal hemorrhagic fevers in humans. Currently, there are neither effective therapeutic options nor effective vaccines for viral hemorrhagic fevers caused by human-pathogenic arenaviruses, except the vaccine Candid no. 1 against Argentine hemorrhagic fever (AHF), licensed for human use in areas of endemicity in Argentina. Since arenaviruses remain a severe threat to global public health, more in-depth knowledge of their replication mechanisms would improve our ability to fight these viruses. Autophagy is a lysosomal degradative pathway involved in maintaining cellular homeostasis, representing powerful anti-infective machinery. We show, for the first time for a member of the familyArenaviridae, a proviral role of autophagy in JUNV infection, providing new knowledge in the field of host-virus interaction. Therefore, modulation of virus-induced autophagy could be used as a strategy to block arenavirus infections.

ChemInform Abstract: Imidazo[2,1-b]thiazole Carbohydrate Derivatives: Synthesis and Antiviral Activity Against Junin Virus, Agent of Argentine Hemorrhagic Fever.

ChemInform ◽  
2011 ◽  
Vol 42 (22) ◽  
pp. no-no
Author(s):  
Jose Sebastian Barradas ◽  
Maria Ines Errea ◽  
Norma B. D'Accorso ◽  
Claudia Soledad Sepulveda ◽  
Elsa Beatriz Damonte
Keyword(s):  
Antiviral Activity ◽  
Hemorrhagic Fever ◽  
Junin Virus ◽  
Argentine Hemorrhagic Fever ◽  
Junín Virus

Prevalence of Infection with Junin Virus in Rodent Populations in the Epidemic Area of Argentine Hemorrhagic Fever

1994 ◽  
Vol 51 (5) ◽  
pp. 554-562 ◽  
Author(s):  
James N. Mills ◽  
C. J. Peters ◽  
James E. Childs ◽  
Kelly T. McKee ◽  
Thomas G. Ksiazek ◽  
...  
Keyword(s):  
Hemorrhagic Fever ◽  
Junin Virus ◽  
Argentine Hemorrhagic Fever ◽  
Epidemic Area ◽  
Rodent Populations ◽  
Junín Virus

Junin Virus Isolation from Lympho-Mononuclear Cells of Patients with Argentine Hemorrhagic Fever

Intervirology ◽  
1986 ◽  
Vol 25 (2) ◽  
pp. 97-102 ◽  
Author(s):  
Ana M. Ambrosio ◽  
Delia A. Enria ◽  
Julio I. Maiztegui
Keyword(s):  
Mononuclear Cells ◽  
Virus Isolation ◽  
Hemorrhagic Fever ◽  
Junin Virus ◽  
Argentine Hemorrhagic Fever ◽  
Junín Virus

scholarly journals Human Plasmacytoid Dendritic Cells Elicited Different Responses after Infection with Pathogenic and Nonpathogenic Junin Virus Strains

2015 ◽  
Vol 89 (14) ◽  
pp. 7409-7413 ◽  
Author(s):  
Soledad Negrotto ◽  
Hebe A. Mena ◽  
Agustin E. Ure ◽  
Carolina Jaquenod De Giusti ◽  
Mariela Bollati-Fogolín ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Peripheral Blood ◽  
Human Peripheral Blood ◽  
Hemorrhagic Fever ◽  
Plasmacytoid Dendritic Cells ◽  
Etiologic Agent ◽  
Junin Virus ◽  
Argentine Hemorrhagic Fever ◽  
Junín Virus ◽  
Virus Strains

The arenavirus Junin virus (JUNV) is the etiologic agent of Argentine hemorrhagic fever. We characterized the JUNV infection of human peripheral blood-derived plasmacytoid dendritic cells (hpDC), demonstrating that hpDC are susceptible to infection with the C#1 strain (attenuated) and even more susceptible to infection with the P (virulent) JUNV strain. However, hpDC elicited different responses in terms of viability, activation, maturation, and cytokine expression after infection with both JUNV strains.

Imidazo[2,1-b]thiazole carbohydrate derivatives: Synthesis and antiviral activity against Junin virus, agent of Argentine hemorrhagic fever

2011 ◽  
Vol 46 (1) ◽  
pp. 259-264 ◽  
Author(s):  
José Sebastián Barradas ◽  
María Inés Errea ◽  
Norma B. D'Accorso ◽  
Claudia Soledad Sepúlveda ◽  
Elsa Beatriz Damonte
Keyword(s):  
Antiviral Activity ◽  
Hemorrhagic Fever ◽  
Junin Virus ◽  
Argentine Hemorrhagic Fever ◽  
Junín Virus
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