scholarly journals Therapy for Argentine hemorrhagic fever in nonhuman primates with a humanized monoclonal antibody

2021 ◽  
Vol 118 (11) ◽  
pp. e2023332118
Author(s):  
Larry Zeitlin ◽  
Robert W. Cross ◽  
Joan B. Geisbert ◽  
Viktoriya Borisevich ◽  
Krystle N. Agans ◽  
...  
Keyword(s):  
Large Scale ◽  
Viral Infections ◽  
Hemorrhagic Fever ◽  
Viral Pathogens ◽  
Monkey Model ◽  
Argentine Hemorrhagic Fever ◽  
Safety Risks ◽  
Humanized Monoclonal Antibody ◽  
Approved Drugs ◽  
Guinea Pig Model

The COVID-19 pandemic has reemphasized the need to identify safe and scalable therapeutics to slow or reverse symptoms of disease caused by newly emerging and reemerging viral pathogens. Recent clinical successes of monoclonal antibodies (mAbs) in therapy for viral infections demonstrate that mAbs offer a solution for these emerging biothreats. We have explored this with respect to Junin virus (JUNV), an arenavirus classified as a category A high-priority agent and the causative agent of Argentine hemorrhagic fever (AHF). There are currently no Food and Drug Administration-approved drugs available for preventing or treating AHF, although immune plasma from convalescent patients is used routinely to treat active infections. However, immune plasma is severely limited in quantity, highly variable in quality, and poses significant safety risks including the transmission of transfusion-borne diseases. mAbs offer a highly specific and consistently potent alternative to immune plasma that can be manufactured at large scale. We previously described a chimeric mAb, cJ199, that provided protection in a guinea pig model of AHF. To adapt this mAb to a format more suitable for clinical use, we humanized the mAb (hu199) and evaluated it in a cynomolgus monkey model of AHF with two JUNV isolates, Romero and Espindola. While untreated control animals experienced 100% lethality, all animals treated with hu199 at 6 d postinoculation (dpi) survived, and 50% of animals treated at 8 dpi survived. mAbs like hu199 may offer a safer, scalable, and more reproducible alternative to immune plasma for rare viral diseases that have epidemic potential.

The Guinea Pig Model for Argentine Hemorrhagic Fever *

1984 ◽  
Vol 33 (6) ◽  
pp. 1251-1257 ◽  
Author(s):  
José R. Oubiña ◽  
Guadalupe Carballal ◽  
Cristina M. Videla ◽  
Patricio M. Cossio
Keyword(s):  
Guinea Pig ◽  
Hemorrhagic Fever ◽  
Pig Model ◽  
Argentine Hemorrhagic Fever ◽  
Guinea Pig Model

scholarly journals Development of Reverse Genetics for the Prototype New World Mammarenavirus Tacaribe Virus

2020 ◽  
Vol 94 (19) ◽  
Author(s):  
Chengjin Ye ◽  
Juan Carlos de la Torre ◽  
Luis Martínez-Sobrido
Keyword(s):  
New World ◽  
Reverse Genetics ◽  
Viral Infections ◽  
Hemorrhagic Fever ◽  
Vaccine Vector ◽  
Live Attenuated Vaccine ◽  
Attenuated Vaccine ◽  
Argentine Hemorrhagic Fever ◽  
Tacaribe Virus ◽  
First Time

ABSTRACT The New World mammarenavirus Tacaribe virus (TCRV) has been isolated from fruit bats, mosquitoes, and ticks, whereas all other known New World mammarenaviruses are maintained in rodents. TCRV has not been linked to human disease, but it has been shown to protect against Argentine hemorrhagic fever-like disease in marmosets infected with the New World mammarenavirus Junín virus (JUNV), indicating the potential of TCRV as a live-attenuated vaccine for the treatment of Argentine hemorrhagic fever. Implementation of TCRV as a live-attenuated vaccine or a vaccine vector would be facilitated by the establishment of reverse genetics systems for the genetic manipulation of the TCRV genome. In this study, we developed, for the first time, reverse genetics approaches for the generation of recombinant TCRV (rTCRV). We successfully rescued a wild-type (WT) rTCRV (a trisegmented form of TCRV expressing two reporter genes [r3TCRV]) and a bisegmented TCRV expressing a single reporter gene from a bicistronic viral mRNA (rTCRV/GFP). These reverse genetics approaches represent an excellent tool to investigate the biology of TCRV and to explore its potential use as a live-attenuated vaccine or a vaccine vector for the treatment of other viral infections. Notably, we identified a 39-nucleotide (nt) deletion (Δ39) in the noncoding intergenic region (IGR) of the viral large (L) segment that is required for optimal virus multiplication. Accordingly, an rTCRV containing this 39-nt deletion in the L-IGR (rTCRV/Δ39) exhibited decreased viral fitness in cultured cells, suggesting the feasibility of using this deletion in the L-IGR as an approach to attenuate TCRV, and potentially other mammarenaviruses, for their implementation as live-attenuated vaccines or vaccine vectors. IMPORTANCE To date, no Food and Drug Administration (FDA)-approved vaccines are available to combat hemorrhagic fever caused by mammarenavirus infections in humans. Treatment of mammarenavirus infections is limited to the off-label use of ribavirin, which is partially effective and associated with significant side effects. Tacaribe virus (TCRV), the prototype member of the New World mammarenaviruses, is nonpathogenic in humans but able to provide protection against Junín virus (JUNV), the causative agent of Argentine hemorrhagic fever, demonstrating the feasibility of using TCRV as a live-attenuated vaccine vector for the treatment of JUNV and potentially other viral infections. Here, we describe for the first time the feasibility of generating recombinant TCRV (rTCRV) using reverse genetics approaches, which paves the way to study the biology of TCRV and also its potential use as a live-attenuated vaccine or a vaccine vector for the treatment of mammarenavirus and/or other viral infections in humans.

scholarly journals Structural basis for recognition and regulation of arenavirus polymerase L by Z protein

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Huiling Kang ◽  
Jingyuan Cong ◽  
Chenlong Wang ◽  
Wenxin Ji ◽  
Yuhui Xin ◽  
...  
Keyword(s):  
Rational Design ◽  
Viral Infections ◽  
Hemorrhagic Fever ◽  
Structural Basis ◽  
Exit Site ◽  
L Protein ◽  
Argentine Hemorrhagic Fever ◽  
L Proteins ◽  
Z Protein

AbstractJunin virus (JUNV) causes Argentine hemorrhagic fever, a debilitating human disease of high mortality rates and a great risk to public health worldwide. Studying the L protein that replicates and transcribes the genome of JUNV, and its regulator Z protein should provide critical clues to identify therapeutic targets for disrupting the life cycle of JUNV. Here we report the 3.54 Å cryo-EM structure of the JUNV L protein complexed with regulator Z protein. JUNV L structure reveals a conserved architecture containing signature motifs found in other L proteins. Structural analysis shows that L protein is regulated by binding of Z protein at the RNA product exit site. Based on these findings, we propose a model for the role of Z protein as a switch to turn on/off the viral RNA synthesis via its interaction with L protein. Our work unveils the mechanism of JUNV transcription, replication and regulation, which provides a framework for the rational design of antivirals for combating viral infections.

scholarly journals Multiple roles of the coagulation protease cascade during virus infection

Blood ◽  
2014 ◽  
Vol 123 (17) ◽  
pp. 2605-2613 ◽  
Author(s):  
Silvio Antoniak ◽  
Nigel Mackman
Keyword(s):  
Immune Response ◽  
Tissue Factor ◽  
Viral Infections ◽  
Factor Viia ◽  
Hemorrhagic Fever ◽  
Multiple Roles ◽  
Coagulation Cascade ◽  
Factor X ◽  
Antiviral Protein ◽  
Monkey Model

Abstract The coagulation cascade is activated during viral infections. This response may be part of the host defense system to limit spread of the pathogen. However, excessive activation of the coagulation cascade can be deleterious. In fact, inhibition of the tissue factor/factor VIIa complex reduced mortality in a monkey model of Ebola hemorrhagic fever. Other studies showed that incorporation of tissue factor into the envelope of herpes simplex virus increases infection of endothelial cells and mice. Furthermore, binding of factor X to adenovirus serotype 5 enhances infection of hepatocytes but also increases the activation of the innate immune response to the virus. Coagulation proteases activate protease-activated receptors (PARs). Interestingly, we and others found that PAR1 and PAR2 modulate the immune response to viral infection. For instance, PAR1 positively regulates TLR3-dependent expression of the antiviral protein interferon β, whereas PAR2 negatively regulates expression during coxsackievirus group B infection. These studies indicate that the coagulation cascade plays multiple roles during viral infections.

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.

scholarly journals Favipiravir (T-705) Inhibits Junín Virus Infection and Reduces Mortality in a Guinea Pig Model of Argentine Hemorrhagic Fever

2013 ◽  
Vol 7 (12) ◽  
pp. e2614 ◽  
Author(s):  
Brian B. Gowen ◽  
Terry L. Juelich ◽  
Eric J. Sefing ◽  
Trevor Brasel ◽  
Jennifer K. Smith ◽  
...  
Keyword(s):  
Virus Infection ◽  
Guinea Pig ◽  
Hemorrhagic Fever ◽  
Pig Model ◽  
Junin Virus ◽  
Argentine Hemorrhagic Fever ◽  
Guinea Pig Model ◽  
Junín Virus

scholarly journals A proteomic survey of Junín virus interactions with human proteins reveals host factors required for arenavirus replication

2017 ◽  
pp. JVI.01565-17 ◽  
Author(s):  
Christopher M. Ziegler ◽  
Philip Eisenhauer ◽  
Jamie A. Kelly ◽  
Loan N. Dang ◽  
Vedran Beganovic ◽  
...  
Keyword(s):  
Ribosomal Proteins ◽  
Large Scale ◽  
Matrix Protein ◽  
Hemorrhagic Fever ◽  
Etiologic Agent ◽  
Human Pathogens ◽  
Host Proteins ◽  
Protein Z ◽  
Argentine Hemorrhagic Fever ◽  
Human Proteins

Arenaviruses are negative-strand, enveloped RNA viruses that cause significant human disease. In particular, Junín mammarenvirus (JUNV) is the etiologic agent of Argentine hemorrhagic fever. At present, little is known about the cellular proteins that the arenavirus matrix protein (Z) hijacks to accomplish its various functions, including driving the process of virus release. Further, there is a little knowledge regarding host proteins incorporated into arenavirus particles and their importance for virion function. To address these deficiencies, we used mass spectrometry to identify human proteins that (i) interact with the JUNV matrix protein inside of cells or within virus-like particles (VLPs) and/or (ii) are incorporated intobona fideJUNV strain Candid #1 particles. Bioinformatic analyses revealed that multiple classes of human proteins were overrepresented in the datasets, including ribosomal proteins, Ras superfamily proteins, and endosomal sorting complex required for transport (ESCRT) proteins. Several of these proteins were required for the propagation of JUNV (ARF1, ATP6V0D1 and PRDX3), lymphocytic choriomeningitis mammarenavirus (LCMV) (Rab5c), or both viruses (ATP5B, IMPDH2). Further, we show that release of infectious JUNV particles, but not LCMV particles, requires a functional ESCRT pathway and that ATP5B and IMPDH2 are required for JUNV budding. In summary, we have provided a large-scale map of host machinery that associates with JUNV and identified key human proteins required for its propagation. This dataset provides a resource for the field to guide antiviral target discovery and to better understand the biology of the arenavirus matrix protein and the importance of host proteins for virion function.IMPORTANCEArenaviruses are deadly human pathogens for which there are no United States Food and Drug Administration-approved vaccines and only limited treatment options. Little is known about the host proteins that are incorporated into arenavirus particles or that associate with its multifunctional matrix protein. Using Junín mammarenavirus (JUNV), the causative agent of Argentine hemorrhagic fever, as a model organism, we mapped the human proteins that are incorporated into JUNV particles or that associate with the JUNV matrix protein. Functional analysis revealed host machinery that is required for JUNV propagation, including the cellular ESCRT pathway. This study improves our understanding of critical arenavirus-host interactions and provides a dataset that will guide future studies to better understand arenavirus pathogenesis and identify novel host proteins that can be therapeutically targeted.

The Diagnosis of Viral Disease by Electron Microscopy

1982 ◽  
Vol 40 ◽  
pp. 270-273
Author(s):  
William B. McCombs ◽  
Cameron E. McCoy
Keyword(s):  
Electron Microscopy ◽  
Hospital Stay ◽  
Viral Infections ◽  
Medical Profession ◽  
Bacterial Pathogens ◽  
Viral Disease ◽  
Viral Pathogens ◽  
Academic Interest ◽  
The Past

Recent years have brought a reversal in the attitude of the medical profession toward the diagnosis of viral infections. Identification of bacterial pathogens was formerly thought to be faster than identification of viral pathogens. Viral identification was dismissed as being of academic interest or for confirming the presence of an epidemic, because the patient would recover or die before this could be accomplished. In the past 10 years, the goal of virologists has been to present the clinician with a viral identification in a matter of hours. This fast diagnosis has the potential for shortening the patient's hospital stay and preventing the administering of toxic and/or expensive antibiotics of no benefit to the patient.

Factor VIII : C and Factor VIII R: Ag in Argentine Hemorrhagic Fever

1981 ◽  
Vol 46 (02) ◽  
pp. 525-527 ◽  
Author(s):  
Felisa C Molinas ◽  
Julio I Maiztegui
Keyword(s):  
Factor Viii ◽  
Normal Values ◽  
Hemorrhagic Fever ◽  
Plasma Samples ◽  
Two Dimensional ◽  
Plasma Infusion ◽  
Factor Viii Related Antigen ◽  
Clinical Forms ◽  
Argentine Hemorrhagic Fever ◽  
Immune Precipitation

SummaryFactor VIII procoagulant activity (F VIII: C) and factor VIII related antigen (F VIII R: Ag) were investigated in 35 patients with Argentine hemorrhagic fever. Since the results obtained in the three clinical forms of the disease were not significantly different, they were tabulated altogether. F VIII: C was low in early stages of the disease but increased progressively in later days (days 5–6:0.54 ± 0.10 I.U./ml; days 13–14:0.95 ± 0.13 I.U./ml). In contrst, the levels of F VIII R: Ag were high all along the disease and they returned to normal values during the convalescence period (days 5–6; 2.58 ± 0.54 I.U./ml; day 30: 1.30 ± 0.14 I.U./ml). The levels of F VIII R: Ag were similar in samples drawn before (11 cases) or after (10 cases) the treatment with immune plasma infusion. Plasma samples from 12 patients were studied by two-dimensional immunelectrophoresis. The only abnormality found was increased height of the immune precipitation arc.

Safety and Immunogenicity of a Live-Attenuated Junin (Argentine Hemorrhagic Fever) Vaccine in Rhesus Macaques

1993 ◽  
Author(s):  
Kelly T. McKee ◽  
Oro Jr. ◽  
Kuehne Julio G. ◽  
Spisso Anna I. ◽  
Mahlandt Joan A. ◽  
...  
Keyword(s):  
Rhesus Macaques ◽  
Hemorrhagic Fever ◽  
Argentine Hemorrhagic Fever
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