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1.
Antiviral Res ; : 105952, 2024 Jun 28.
Article in English | MEDLINE | ID: mdl-38945484

ABSTRACT

Argentine hemorrhagic fever, caused by Junín virus (JUNV), is the most common of the South American arenaviral hemorrhagic fevers. The disease has a case fatality rate of 15-30% in untreated patients. Although early intervention with immune plasma is effective, diminishing stocks and limited availability outside of Argentina underscores the need for new therapeutics. Ideally, these would be broadly active agents effective against all the pathogenic arenaviruses. The fusion inhibitor LHF-535 and the nucleoside analog favipiravir have shown promise in animal models of Lassa fever, a disease endemic in parts of Africa and the most prominent of the arenaviral hemorrhagic fevers. Against JUNV, a high dose of favipiravir is required to achieve protection in the gold-standard guinea pig infection model. Here, we demonstrate a synergistic effect by the coadministration of LHF-535 with a sub-optimal dose of favipiravir in guinea pigs challenged with JUNV. Administered individually, LHF-535 and sub-optimal favipiravir only delayed the onset of severe disease. However, combined dosing of the drugs afforded complete protection against lethal JUNV infection in guinea pigs. The benefits of the drug combination were also evident by the absence of viremia and infectious virus in tissues compared to guinea pigs treated with only the placebos. Thus, combined targeting of JUNV-endosomal membrane fusion and the viral polymerase with pan-arenaviral LHF-535 and favipiravir may expand their indication beyond Lassa fever, providing a significant barrier to drug resistance.

2.
J Virol ; 98(4): e0011224, 2024 Apr 16.
Article in English | MEDLINE | ID: mdl-38506509

ABSTRACT

Live-attenuated virus vaccines provide long-lived protection against viral disease but carry inherent risks of residual pathogenicity and genetic reversion. The live-attenuated Candid#1 vaccine was developed to protect Argentines against lethal infection by the Argentine hemorrhagic fever arenavirus, Junín virus. Despite its safety and efficacy in Phase III clinical study, the vaccine is not licensed in the US, in part due to concerns regarding the genetic stability of attenuation. Previous studies had identified a single F427I mutation in the transmembrane domain of the Candid#1 envelope glycoprotein GPC as the key determinant of attenuation, as well as the propensity of this mutation to revert upon passage in cell culture and neonatal mice. To ascertain the consequences of this reversion event, we introduced the I427F mutation into recombinant Candid#1 (I427F rCan) and investigated the effects in two validated small-animal models: in mice expressing the essential virus receptor (human transferrin receptor 1; huTfR1) and in the conventional guinea pig model. We report that I427F rCan displays only modest virulence in huTfR1 mice and appears attenuated in guinea pigs. Reversion at another attenuating locus in Candid#1 GPC (T168A) was also examined, and a similar pattern was observed. By contrast, virus bearing both revertant mutations (A168T+I427F rCan) approached the lethal virulence of the pathogenic Romero strain in huTfR1 mice. Virulence was less extreme in guinea pigs. Our findings suggest that genetic stabilization at both positions is required to minimize the likelihood of reversion to virulence in a second-generation Candid#1 vaccine.IMPORTANCELive-attenuated virus vaccines, such as measles/mumps/rubella and oral poliovirus, provide robust protection against disease but carry with them the risk of genetic reversion to the virulent form. Here, we analyze the genetics of reversion in the live-attenuated Candid#1 vaccine that is used to protect against Argentine hemorrhagic fever, an often-lethal disease caused by the Junín arenavirus. In two validated small-animal models, we find that restoration of virulence in recombinant Candid#1 viruses requires back-mutation at two positions specific to the Candid#1 envelope glycoprotein GPC, at positions 168 and 427. Viruses bearing only a single change showed only modest virulence. We discuss strategies to genetically harden Candid#1 GPC against these two reversion events in order to develop a safer second-generation Candid#1 vaccine virus.


Subject(s)
Hemorrhagic Fever, American , Junin virus , Viral Vaccines , Animals , Guinea Pigs , Humans , Mice , Glycoproteins/genetics , Hemorrhagic Fever, American/prevention & control , Junin virus/physiology , South American People , Vaccines, Attenuated/genetics , Viral Vaccines/genetics , Virulence
3.
J Virol ; 98(4): e0013224, 2024 Apr 16.
Article in English | MEDLINE | ID: mdl-38511932

ABSTRACT

Heartland virus (HRTV) is an emerging tick-borne bandavirus that causes a febrile illness of varying severity in humans, with cases reported in eastern and midwestern regions of the United States. No vaccines or approved therapies are available to prevent or treat HRTV disease. Here, we describe the genetic changes, natural history of disease, and pathogenesis of a mouse-adapted HRTV (MA-HRTV) that is uniformly lethal in 7- to 8-week-old AG129 mice at low challenge doses. We used this model to assess the efficacy of the ribonucleoside analog, 4'-fluorouridine (EIDD-2749), and showed that once-daily oral treatment with 3 mg/kg of drug, initiated after the onset of disease, protects mice against lethal MA-HRTV challenge and reduces viral loads in blood and tissues. Our findings provide insights into HRTV virulence and pathogenesis and support further development of EIDD-2749 as a therapeutic intervention for HRTV disease. IMPORTANCE: More than 60 cases of HRTV disease spanning 14 states have been reported to the United States Centers for Disease Control and Prevention. The expanding range of the Lone Star tick that transmits HRTV, the growing population of at-risk persons living in geographic areas where the tick is abundant, and the lack of antiviral treatments or vaccines raise significant public health concerns. Here, we report the development of a new small-animal model of lethal HRTV disease to gain insight into HRTV pathogenesis and the application of this model for the preclinical development of a promising new antiviral drug candidate, EIDD-2749. Our findings shed light on how the virus causes disease and support the continued development of EIDD-2749 as a therapeutic for severe cases of HRTV infection.


Subject(s)
Bunyaviridae Infections , Bunyaviridae , Uracil Nucleotides , Animals , Humans , Mice , Bunyaviridae Infections/drug therapy , Ticks , United States , Uracil Nucleotides/therapeutic use
4.
Nat Commun ; 14(1): 5650, 2023 09 13.
Article in English | MEDLINE | ID: mdl-37704627

ABSTRACT

The zoonotic Rift Valley fever virus (RVFV) can cause severe disease in humans and has pandemic potential, yet no approved vaccine or therapy exists. Here we describe a dual-mechanism human monoclonal antibody (mAb) combination against RVFV that is effective at minimal doses in a lethal mouse model of infection. We structurally analyze and characterize the binding mode of a prototypical potent Gn domain-A-binding antibody that blocks attachment and of an antibody that inhibits infection by abrogating the fusion process as previously determined. Surprisingly, the Gn domain-A antibody does not directly block RVFV Gn interaction with the host receptor low density lipoprotein receptor-related protein 1 (LRP1) as determined by a competitive assay. This study identifies a rationally designed combination of human mAbs deserving of future investigation for use in humans against RVFV infection. Using a two-pronged mechanistic approach, we demonstrate the potent efficacy of a rationally designed combination mAb therapeutic.


Subject(s)
Antibodies, Monoclonal , Rift Valley fever virus , Animals , Mice , Humans , Biological Assay , Disease Models, Animal , Low Density Lipoprotein Receptor-Related Protein-1
5.
Antiviral Res ; 217: 105678, 2023 09.
Article in English | MEDLINE | ID: mdl-37494979

ABSTRACT

The 36th International Conference on Antiviral Research (ICAR), sponsored by the International Society for Antiviral Research (ISAR), was held March 13-17, 2023, in Lyon, France, and concurrently through an interactive remote meeting platform. Here we provide a report summarizing the presentations at the 36th ICAR, including the ISAR speaker awards. We also detail special events, sessions, and additional awards conferred at the meeting. ICAR returned to in-person meetings in 2022, convening in Seattle, WA, USA. The 36th ICAR is the first in-person meeting of the society in Europe since the beginning of the COVID-19 pandemic, which restricted most events to virtual attendance to help mitigate the spread and subsequent public health impact of SARS-CoV-2. An exceptionally high number of registrants and record attendance at this year's ICAR, along with a vast array of demonstrable expertise in a variety of antiviral research-related fields, reflected a strong and growing antiviral research community committed to improving health outcomes from viral diseases, including SARS-CoV-2, and to future pandemic preparedness. This report highlights the breadth of expertise, quality of research, and notable advancements that were contributed by members of ISAR and other participants at the meeting. ICAR aims to continue to provide a platform for sharing information, fostering collaborations, and supporting trainees in the field of antiviral research. The 37th ICAR will be held in Gold Coast, Australia, May 20-24, 2024.


Subject(s)
Antiviral Agents , COVID-19 , Humans , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Iron-Dextran Complex , Pandemics , SARS-CoV-2
6.
ACS Med Chem Lett ; 14(4): 506-513, 2023 Apr 13.
Article in English | MEDLINE | ID: mdl-37077387

ABSTRACT

We report for the first time the antiviral activities of two iminovirs (antiviral imino-C-nucleosides) 1 and 2, structurally related to galidesivir (Immucillin A, BCX4430). An iminovir containing the 4-aminopyrrolo[2,1-f][1,2,4-triazine] nucleobase found in remdesivir exhibited submicromolar inhibition of multiple strains of influenza A and B viruses, as well as members of the Bunyavirales order. We also report the first syntheses of ProTide prodrugs of iminovir monophosphates, which unexpectedly displayed poorer viral inhibition than their parent nucleosides in vitro. An efficient synthesis of the 4-aminopyrrolo[2,1-f][1,2,4-triazine]-containing iminovir 2 was developed to enable preliminary in vivo studies, wherein it displayed significant toxicity in BALB/c mice and limited protection against influenza. Further modification of this anti-influenza iminovir will therefore be required to improve its therapeutic value.

7.
Antiviral Res ; 208: 105444, 2022 12.
Article in English | MEDLINE | ID: mdl-36243175

ABSTRACT

Infections by pathogenic New World mammarenaviruses (NWM)s, including Junín virus (JUNV), can result in a severe life-threatening viral hemorrhagic fever syndrome. In the absence of FDA-licensed vaccines or antivirals, these viruses are considered high priority pathogens. The mammarenavirus envelope glycoprotein complex (GPC) mediates pH-dependent fusion between viral and cellular membranes, which is essential to viral entry and may be vulnerable to small-molecule inhibitors that disrupt this process. ARN-75039 is a potent fusion inhibitor of a broad spectrum of pseudotyped and native mammarenaviruses in cell culture and Tacaribe virus infection in mice. In the present study, we evaluated ARN-75039 against pathogenic JUNV in the rigorous guinea pig infection model. The compound was well-tolerated and had favorable pharmacokinetics supporting once-per-day oral dosing in guinea pigs. Importantly, significant protection against JUNV challenge was observed even when ARN-75039 was withheld until 6 days after the viral challenge when clinical signs of disease are starting to develop. We also show that ARN-75039 combination treatment with favipiravir, a viral polymerase inhibitor, results in synergistic activity in vitro and improves survival outcomes in JUNV-challenged guinea pigs. Our findings support the continued development of ARN-75039 as an attractive therapeutic candidate for treating mammarenaviral hemorrhagic fevers, including those associated with NWM infection.


Subject(s)
Arenaviridae , Hemorrhagic Fever, American , Hemorrhagic Fevers, Viral , Junin virus , Guinea Pigs , Mice , Animals , Hemorrhagic Fever, American/drug therapy , Pyrazines/pharmacology , Pyrazines/therapeutic use , Amides/pharmacology , Amides/therapeutic use , Anti-Retroviral Agents/pharmacology
8.
Am J Trop Med Hyg ; 107(5): 1091-1098, 2022 11 14.
Article in English | MEDLINE | ID: mdl-36122681

ABSTRACT

The Rift Valley fever virus (RVFV) MP-12 vaccine is a promising human and veterinary vaccine. Although the vaccine elicited neutralizing antibody (nAb) in human volunteers, the minimal antibody titer that is needed to afford protection is unknown. Therefore, this study was conducted to determine the minimal nAb titer elicited by the RVFV MP-12 vaccine in human volunteers that protected mice against lethal RVFV challenge as a surrogate assessment of the protective efficacy of the vaccine. Among volunteers who were vaccinated with the MP-12 vaccine during a phase II trial, sera with antibody titers of 1:20 collected 5 years post-vaccination (PV), 1:40 titer collected 2 years PV, and 1:80 titer collected 1 year PV was passively transferred to groups of BALB/c mice. Blood samples were obtained 1 day after passive transfer to determine the RVFV neutralizing nAb titer before challenge with pathogenic RVFV (strain ZH501). Our results indicated that 1 day after passive transfer of the immune sera, an approximate 4-fold reduction in circulating nAb titers was detected in the mice. The presence of RVFV nAb titers in the range of 1:5 to 1:20 were generally protective (75-100% survival). These results suggested that circulating titers of 1:5 or higher offer a high degree of protection by MP-12-elicited antibody in human volunteers. Also, the findings highlighted the value of using the BALB/c mouse RVFV challenge model as a surrogate for evaluating the protective nAb responses elicited by MP-12 and possible use for evaluating the efficacy of other RVFV vaccine candidates.


Subject(s)
Rift Valley Fever , Rift Valley fever virus , Viral Vaccines , Mice , Humans , Animals , Healthy Volunteers , Vaccines, Attenuated , Antibodies, Viral , Antibodies, Neutralizing , Mice, Inbred BALB C , Disease Models, Animal
9.
Nat Commun ; 13(1): 558, 2022 01 28.
Article in English | MEDLINE | ID: mdl-35091550

ABSTRACT

Five New World mammarenaviruses (NWMs) cause life-threatening hemorrhagic fever (HF). Cellular entry by these viruses is mediated by human transferrin receptor 1 (hTfR1). Here, we demonstrate that an antibody (ch128.1/IgG1) which binds the apical domain of hTfR1, potently inhibits infection of attenuated and pathogenic NWMs in vitro. Computational docking of the antibody Fab crystal structure onto the known structure of hTfR1 shows an overlapping receptor-binding region shared by the Fab and the viral envelope glycoprotein GP1 subunit that binds hTfR1, and we demonstrate competitive inhibition of NWM GP1 binding by ch128.1/IgG1 as the principal mechanism of action. Importantly, ch128.1/IgG1 protects hTfR1-expressing transgenic mice against lethal NWM challenge. Additionally, the antibody is well-tolerated and only partially reduces ferritin uptake. Our findings provide the basis for the development of a novel, host receptor-targeted antibody therapeutic broadly applicable to the treatment of HF of NWM etiology.


Subject(s)
Antigens, CD/metabolism , Arenaviridae/metabolism , Hemorrhagic Fever, American/metabolism , Receptors, Transferrin/metabolism , Viral Envelope Proteins/metabolism , A549 Cells , Animals , Antibodies, Monoclonal/immunology , Antibodies, Monoclonal/metabolism , Antibodies, Monoclonal/pharmacology , Antigens, CD/immunology , Arenaviridae/drug effects , Arenaviridae/physiology , Chlorocebus aethiops , Hemorrhagic Fever, American/prevention & control , Hemorrhagic Fever, American/virology , Host-Pathogen Interactions/drug effects , Humans , Junin virus/drug effects , Junin virus/physiology , Mice, Inbred C57BL , Mice, Transgenic , Molecular Docking Simulation , Protein Binding/drug effects , Receptors, Transferrin/antagonists & inhibitors , Receptors, Transferrin/immunology , Vero Cells
10.
Antiviral Res ; 195: 105180, 2021 11.
Article in English | MEDLINE | ID: mdl-34551346

ABSTRACT

Galidesivir (BCX4430) is an adenosine nucleoside analog that is broadly active in cell culture against several RNA viruses of various families. This activity has also been shown in animal models of viral disease associated with Ebola, Marburg, yellow fever, Zika, and Rift Valley fever viruses. In many cases, the compound is more efficacious in animal models than cell culture activity would predict. Based on favorable data from in vivo animal studies, galidesivir has recently undergone evaluation in several phase I clinical trials, including against severe acute respiratory syndrome coronavirus 2, and as a medical countermeasure for the treatment of Marburg virus disease.


Subject(s)
Adenine/analogs & derivatives , Adenosine/analogs & derivatives , Antiviral Agents/pharmacology , Pyrrolidines/pharmacology , Adenine/pharmacology , Adenosine/pharmacology , Animals , Clinical Trials, Phase I as Topic , Drug Evaluation, Preclinical , Marburgvirus/drug effects , Nucleosides/analogs & derivatives , SARS-CoV-2/drug effects
11.
Antiviral Res ; 193: 105125, 2021 09.
Article in English | MEDLINE | ID: mdl-34197863

ABSTRACT

Several arenaviruses, including Lassa and Lujo viruses in Africa and five New World arenavirus (NWA) species in the Americas, cause life-threatening viral hemorrhagic fevers. In the absence of licensed antiviral therapies, these viruses pose a significant public health risk. The envelope glycoprotein complex (GPC) mediates arenavirus entry through a pH-dependent fusion of the viral and host endosomal membranes. It thus is recognized as a viable target for small-molecule fusion inhibitors. Here, we report on the antiviral activity and pre-clinical development of the novel broad-spectrum arenavirus fusion inhibitors, ARN-75039 and ARN-75041. In Tacaribe virus (TCRV) pseudotyped and native virus assays, the ARN compounds were active in the low to sub-nanomolar range with selectivity indices exceeding 1000. Pharmacokinetic analysis of the orally administered compounds revealed an extended half-life in mice supporting once-daily dosing, and the compounds were well tolerated at the highest tested dose of 100 mg/kg. In a proof-of-concept prophylactic efficacy study, doses of 10 and 35 mg/kg of either compound dramatically improved survival outcome and potently inhibited TCRV replication in serum and various tissues. Additionally, in contrast to surviving mice that received ribavirin or placebo, animals treated with ARN-75039 or ARN-75041 were cured of TCRV infection. In a follow-up study with ARN-75039, impressive therapeutic efficacy was demonstrated under conditions where treatment was withheld until after the onset of disease. Taken together, the data strongly support the continued development of ARN-75039 as a candidate therapeutic for the treatment of severe arenaviral diseases.


Subject(s)
Antiviral Agents/pharmacology , Arenaviridae Infections/drug therapy , Arenaviruses, New World/drug effects , Membrane Fusion/drug effects , Small Molecule Libraries/pharmacology , Administration, Oral , Animals , Antiviral Agents/pharmacokinetics , Chlorocebus aethiops , Male , Mice , Ribavirin/pharmacology , Small Molecule Libraries/pharmacokinetics , Vero Cells , Viral Envelope Proteins/chemistry , Viral Envelope Proteins/metabolism , Virus Internalization/drug effects
12.
J Virol ; 95(14): e0039721, 2021 06 24.
Article in English | MEDLINE | ID: mdl-33952638

ABSTRACT

Live-attenuated virus vaccines are highly effective in preventing viral disease but carry intrinsic risks of residual virulence and reversion to pathogenicity. The classically derived Candid#1 virus protects seasonal field workers in Argentina against zoonotic infection by Junín virus (JUNV) but is not approved in the United States, in part due to the potential for reversion at the attenuating locus, a phenylalanine-to-isoleucine substitution at position 427 in the GP2 subunit of the GPC envelope glycoprotein. Previously, we demonstrated facile reversion of recombinant Candid#1 (rCan) in cell culture and identified an epistatic interaction between the attenuating I427 and a secondary K33S mutation in the stable signal peptide (SSP) subunit of GPC that imposes an evolutionary barrier to reversion. The magnitude of this genetic barrier is manifest in our repeated failures to rescue the hypothetical revertant virus. In this study, we show that K33S rCan is safe and attenuated in guinea pigs and capable of eliciting potent virus-neutralizing antibodies. Immunized animals are fully protected against lethal challenge with virulent JUNV. In addition, we employed a more permissive model of infection in neonatal mice to investigate genetic reversion. RNA sequence analysis of the recovered virus identified revertant viruses in pups inoculated with the parental rCan virus and none in mice receiving K33S rCan (P < 0.0001). Taken together, our findings support the further development of K33S rCan as a safe second-generation JUNV vaccine. IMPORTANCE Our most successful vaccines comprise weakened strains of virus that initiate a limited and benign infection in immunized persons. The live-attenuated Candid#1 strain of Junín virus (JUNV) was developed to protect field workers in Argentina from rodent-borne hemorrhagic fever but is not licensed in the United States, in part due to the likelihood of genetic reversion to virulence. A single-amino-acid change in the GPC envelope glycoprotein of the virus is responsible for attenuation, and a single nucleotide change may regenerate the pathogenic virus. Here, we take advantage of a unique genetic interaction between GPC subunits to design a mutant Candid#1 virus that establishes an evolutionary barrier to reversion. The mutant virus (K33S rCan) is fully attenuated and protects immunized guinea pigs against lethal JUNV infection. We find no instances of reversion in mice inoculated with K33S rCan. This work supports the further development of K33S rCan as a second-generation JUNV vaccine.


Subject(s)
Hemorrhagic Fever, American/prevention & control , Junin virus/immunology , Viral Vaccines/immunology , Animals , Antibodies, Viral/biosynthesis , Antibodies, Viral/immunology , Chlorocebus aethiops , Guinea Pigs , Hemorrhagic Fever, American/immunology , Immunogenicity, Vaccine , Junin virus/genetics , Junin virus/pathogenicity , Male , Vaccines, Attenuated/genetics , Vaccines, Attenuated/immunology , Vaccines, Synthetic/genetics , Vaccines, Synthetic/immunology , Vero Cells , Viral Vaccines/genetics , Virulence
13.
Proc Natl Acad Sci U S A ; 118(14)2021 04 06.
Article in English | MEDLINE | ID: mdl-33782133

ABSTRACT

Rift Valley fever virus (RVFV), an emerging arboviral and zoonotic bunyavirus, causes severe disease in livestock and humans. Here, we report the isolation of a panel of monoclonal antibodies (mAbs) from the B cells of immune individuals following natural infection in Kenya or immunization with MP-12 vaccine. The B cell responses of individuals who were vaccinated or naturally infected recognized similar epitopes on both Gc and Gn proteins. The Gn-specific mAbs and two mAbs that do not recognize either monomeric Gc or Gn alone but recognized the hetero-oligomer glycoprotein complex (Gc+Gn) when Gc and Gn were coexpressed exhibited potent neutralizing activities in vitro, while Gc-specific mAbs exhibited relatively lower neutralizing capacity. The two Gc+Gn-specific mAbs and the Gn domain A-specific mAbs inhibited RVFV fusion to cells, suggesting that mAbs can inhibit the exposure of the fusion loop in Gc, a class II fusion protein, and thus prevent fusion by an indirect mechanism without direct fusion loop contact. Competition-binding analysis with coexpressed Gc/Gn and mutagenesis library screening indicated that these mAbs recognize four major antigenic sites, with two sites of vulnerability for neutralization on Gn. In experimental models of infection in mice, representative mAbs recognizing three of the antigenic sites reduced morbidity and mortality when used at a low dose in both prophylactic and therapeutic settings. This study identifies multiple candidate mAbs that may be suitable for use in humans against RVFV infection and highlights fusion inhibition against bunyaviruses as a potential contributor to potent antibody-mediated neutralization.


Subject(s)
Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , Rift Valley fever virus/immunology , Viral Fusion Proteins/immunology , Animals , Antibodies, Monoclonal/immunology , Cell Line, Tumor , Cells, Cultured , Chlorocebus aethiops , Epitopes/chemistry , Epitopes/immunology , HEK293 Cells , Humans , Mice , Mice, Inbred C57BL , Vero Cells , Viral Fusion Proteins/chemistry
14.
Antiviral Res ; 181: 104858, 2020 09.
Article in English | MEDLINE | ID: mdl-32645335

ABSTRACT

Crimean-Congo hemorrhagic fever virus (CCHFV) is a widely distributed hemorrhagic fever virus found throughout Eastern Europe, Africa, the Middle East and Asia. It is spread through bites from infected ticks, animal husbandry and can also be acquired in the healthcare setting during care of infected patients. In humans, CCHFV can cause a sudden onset of a non-specific febrile illness that can rapidly progress to severe hemorrhagic manifestations. Currently, there is no widely available vaccine and although ribavirin has been suggested for the treatment of CCHFV, clinical efficacy in both animal models and humans is inconsistent suggesting more potent antivirals are needed for CCHFV. Favipiravir is approved in Japan for the treatment of influenza virus infections and has shown promise against other highly pathogenic RNA viruses including CCHFV with demonstrated efficacy in the type I interferon deficient mouse model. In this report we utilized the cynomolgus macaque model to evaluate the efficacy of once- and twice-daily favipiravir treatment against CCHFV infection. We found that favipiravir treatment suppressed viremia and viral shedding when treatment was initiated 24 h post-infection and viral burdens in key tissues trended lower in favipiravir-treated animals. Our data indicate that favipiravir has efficacy against CCHFV in vivo in a non-human primate model of infection.


Subject(s)
Amides/therapeutic use , Antiviral Agents/therapeutic use , Hemorrhagic Fever, Crimean/drug therapy , Pyrazines/therapeutic use , Viremia/drug therapy , Virus Shedding/drug effects , Animals , Disease Models, Animal , Drug Administration Schedule , Female , Hemorrhagic Fever Virus, Crimean-Congo/drug effects , Macaca fascicularis/virology , Male , Viral Load
15.
Sci Rep ; 10(1): 12378, 2020 07 23.
Article in English | MEDLINE | ID: mdl-32704046

ABSTRACT

Crimean-Congo hemorrhagic fever virus (CCHFV) is a tick-borne pathogen causing a febrile illness in humans, which can progress to hemorrhagic manifestations, multi-organ failure, and death. Current mouse models of CCHFV infection reliably succumb to virus challenge but vary in their ability to reflect signs of disease similar to humans. In this study, we established a signal transducer and activator of transcription 2 (STAT2) knockout hamster model to expand the repertoire of animal models of CCHFV pathogenesis that can be used for therapeutic development. These hamsters demonstrated a systemic and lethal disease in response to infection. Hallmarks of human disease were observed including petechial rash, blood coagulation dysfunction, and various biochemistry and blood cell count abnormalities. Furthermore, we also demonstrated the utility of this model for anti-CCHFV therapeutic evaluation. The STAT2 knock-out hamster model of CCHFV infection may provide some further insights into clinical disease, viral pathogenesis, and pave the way for testing of potential drug and vaccine candidates.


Subject(s)
Animals, Genetically Modified , Disease Models, Animal , Hemorrhagic Fever Virus, Crimean-Congo/metabolism , Hemorrhagic Fever, Crimean , STAT2 Transcription Factor/deficiency , Animals , Animals, Genetically Modified/genetics , Animals, Genetically Modified/metabolism , Animals, Genetically Modified/virology , Cell Line , Cricetinae , Female , Gene Knockout Techniques , Hemorrhagic Fever Virus, Crimean-Congo/genetics , Hemorrhagic Fever, Crimean/genetics , Hemorrhagic Fever, Crimean/metabolism , Hemorrhagic Fever, Crimean/pathology , Male , STAT2 Transcription Factor/metabolism
16.
Elife ; 92020 05 26.
Article in English | MEDLINE | ID: mdl-32452770

ABSTRACT

Junín virus (JUNV) is one of five New World mammarenaviruses (NWMs) that causes fatal hemorrhagic disease in humans and is the etiological agent of Argentine hemorrhagic fever (AHF). The pathogenesis underlying AHF is poorly understood; however, a prolonged, elevated interferon-α (IFN-α) response is associated with a negative disease outcome. A feature of all NWMs that cause viral hemorrhagic fever is the use of human transferrin receptor 1 (hTfR1) for cellular entry. Here, we show that mice expressing hTfR1 develop a lethal disease course marked by an increase in serum IFN-α concentration when challenged with JUNV. Further, we provide evidence that the type I IFN response is central to the development of severe JUNV disease in hTfR1 mice. Our findings identify hTfR1-mediated entry and the type I IFN response as key factors in the pathogenesis of JUNV infection in mice.


Subject(s)
Antigens, CD/physiology , Hemorrhagic Fever, American/virology , Host-Pathogen Interactions , Interferon-alpha/physiology , Junin virus/physiology , Receptors, Transferrin/physiology , Animals , Mice
17.
Vaccine X ; 5: 100060, 2020 Aug 07.
Article in English | MEDLINE | ID: mdl-32337506

ABSTRACT

In November 2019, The World Health Organization (WHO) issued a draft set of Target Product Profiles (TPPs) describing optimal and minimally acceptable targets for vaccines against Rift Valley fever (RVF), a Phlebovirus with a three segmented genome, in both humans and ruminants. The TPPs contained rigid requirements to protect against genomic reassortment of live, attenuated vaccines (LAVs) with wild-type RVF virus (RVFV), which place undue constraints on development and regulatory approval of LAVs. We review the current LAVs in use and in development, and conclude that there is no evidence that reassortment between LAVs and wild-type RVFV has occurred during field use, that such a reassortment event if it occurred would have no untoward consequence, and that the TPPs should be revised to provide a more balanced assessment of the benefits versus the theoretical risks of reassortment.

18.
J Virol ; 94(4)2020 01 31.
Article in English | MEDLINE | ID: mdl-31748396

ABSTRACT

Several clade B New World arenaviruses (NWAs) can cause severe and often fatal hemorrhagic fever, for which preventive and therapeutic measures are severely limited. These NWAs use human transferrin receptor 1 (hTfR1) as a host cell receptor for virus entry. The most prevalent of the pathogenic NWAs is Junín virus (JUNV), the etiological agent of Argentine hemorrhagic fever. Small animal models of JUNV infection are limited because most laboratory rodent species are refractory to disease. Only guinea pigs are known to develop disease following JUNV infection, but the underlying mechanisms are not well characterized. In the present study, we demonstrate marked susceptibility of Hartley guinea pigs to uniformly lethal disease when challenged with as few as 4 PFU of the Romero strain of JUNV. In vitro, we show that infection of primary guinea pig macrophages results in greater JUNV replication compared to infection of hamster or mouse macrophages. We provide evidence that the guinea pig TfR1 (gpTfR1) is the principal receptor for JUNV, while hamster and mouse orthologs fail to support viral entry/infection of pseudotyped murine leukemia viruses expressing pathogenic NWA glycoproteins or JUNV. Together, our results indicate that gpTfR1 serves as the primary receptor for pathogenic NWAs, enhancing viral infection in guinea pigs.IMPORTANCE JUNV is one of five known NWAs that cause viral hemorrhagic fever in humans. Countermeasures against JUNV infection are limited to immunization with the Candid#1 vaccine and immune plasma, which are available only in Argentina. The gold standard small animal model for JUNV infection is the guinea pig. Here, we demonstrate high sensitivity of this species to severe JUNV infection and identify gpTfR1 as the primary receptor. Use of hTfR1 for host cell entry is a feature shared by pathogenic NWAs. Our results show that expression of gpTfR1 or hTfR1 comparably enhances JUNV virus entry/infectivity. Our findings shed light on JUNV infection in guinea pigs as a model for human disease and suggest that similar pathophysiological mechanisms related to iron sequestration during infection and regulation of TfR1 expression may be shared between humans and guinea pigs. A better understanding of the underlying disease process will guide development of new therapeutic interventions.


Subject(s)
Junin virus/immunology , Junin virus/pathogenicity , Receptors, Transferrin/metabolism , Animals , Arenavirus/immunology , Arenavirus/pathogenicity , CHO Cells , Chlorocebus aethiops , Cricetulus , Disease Models, Animal , Female , Glycoproteins/metabolism , Guinea Pigs/immunology , Guinea Pigs/metabolism , HEK293 Cells , Hemorrhagic Fever, American/immunology , Hemorrhagic Fever, American/virology , Hemorrhagic Fevers, Viral/immunology , Hemorrhagic Fevers, Viral/virology , Humans , Junin virus/metabolism , Macrophages/virology , Male , Receptors, Transferrin/immunology , Vero Cells , Virus Internalization , Virus Replication
19.
Pathogens ; 8(4)2019 Sep 21.
Article in English | MEDLINE | ID: mdl-31546590

ABSTRACT

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging viral hemorrhagic fever (VHF) endemic to China, South Korea, Japan, and Vietnam. Here we characterize the pathogenesis and natural history of disease in IFNAR-/- mice challenged with the HB29 strain of SFTS virus (SFTSV) and demonstrate hallmark features of VHF such as vascular leak and high concentrations of proinflammatory cytokines in blood and tissues. Treatment with FX06, a natural plasmin digest product of fibrin in clinical development as a treatment for vascular leak, reduced vascular permeability associated with SFTSV infection but did not significantly improve survival outcome. Further studies are needed to assess the role of vascular compromise in the SFTS disease process modeled in IFNAR-/- mice.

20.
Antiviral Res ; 169: 104550, 2019 09.
Article in English | MEDLINE | ID: mdl-31302149

ABSTRACT

The 32nd International Conference on Antiviral Research (ICAR), sponsored by the International Society for Antiviral Research (ISAR), was held in Baltimore, Maryland, USA, on May 12-15, 2019. This report gives an overview of the conference on behalf of the Society. It provides a general review of the meeting and awardees, summarizing the presentations, and their main conclusions from the perspective of researchers active in many different areas of antiviral research and development. As in past years, ICAR promoted and showcased the most recent progress in antiviral research, and continued to foster collaborations and interactions in drug discovery and development. The 33rd ICAR will be held in Seattle, Washington, USA, March 30th-April 3rd, 2020.


Subject(s)
Antiviral Agents , Research , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Chemistry, Pharmaceutical , Drug Discovery , Humans , Internationality , Technology, Pharmaceutical , Virus Diseases/drug therapy , Virus Diseases/physiopathology , Virus Diseases/virology
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