Tilorone-Dihydrochloride Protects against Rift Valley Fever Virus Infection and Disease in the Mouse Model

Rift Valley fever (RVF) is a mosquito-borne zoonotic disease endemic to Africa and the Middle East that can affect humans and ruminant livestock. Currently, there are no approved vaccines or therapeutics for the treatment of severe RVF disease in humans. Tilorone-dihydrochloride (Tilorone) is a broad-spectrum antiviral candidate that has previously shown efficacy against a wide range of DNA and RNA viruses, and which is clinically utilized for the treatment of respiratory infections in Russia and other Eastern European countries. Here, we evaluated the antiviral activity of Tilorone against Rift Valley fever virus (RVFV). In vitro, Tilorone inhibited both vaccine (MP-12) and virulent (ZH501) strains of RVFV at low micromolar concentrations. In the mouse model, treatment with Tilorone significantly improved survival outcomes in BALB/c mice challenged with a lethal dose of RVFV ZH501. Treatment with 30 mg/kg/day resulted in 80% survival when administered immediately after infection. In post-exposure prophylaxis, Tilorone resulted in 30% survival at one day after infection when administered at 45 mg/kg/day. These findings demonstrate that Tilorone has potent antiviral efficacy against RVFV infection in vitro and in vivo and supports further development of Tilorone as a potential antiviral therapeutic for treatment of RVFV infection.

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MVA Vectored Vaccines Encoding Rift Valley Fever Virus Glycoproteins Protect Mice against Lethal Challenge in the Absence of Neutralizing Antibody Responses

Vaccines ◽

10.3390/vaccines8010082 ◽

2020 ◽

Vol 8 (1) ◽

pp. 82 ◽

Cited By ~ 2

Author(s):

Elena López-Gil ◽

Sandra Moreno ◽

Javier Ortego ◽

Belén Borrego ◽

Gema Lorenzo ◽

...

Keyword(s):

Immune Response ◽

Immune Responses ◽

Cellular Immunity ◽

Rift Valley ◽

Neutralizing Antibodies ◽

Rift Valley Fever ◽

Rift Valley Fever Virus ◽

Fever Virus ◽

Valley Fever

In vitro neutralizing antibodies have been often correlated with protection against Rift Valley fever virus (RVFV) infection. We have reported previously that a single inoculation of sucrose-purified modified vaccinia Ankara (MVA) encoding RVFV glycoproteins (rMVAGnGc) was sufficient to induce a protective immune response in mice after a lethal RVFV challenge. Protection was related to the presence of glycoprotein specific CD8+ cells, with a low-level detection of in vitro neutralizing antibodies. In this work we extended those observations aimed to explore the role of humoral responses after MVA vaccination and to study the contribution of each glycoprotein antigen to the protective efficacy. Thus, we tested the efficacy and immune responses in BALB/c mice of recombinant MVA viruses expressing either glycoprotein Gn (rMVAGn) or Gc (rMVAGc). In the absence of serum neutralizing antibodies, our data strongly suggest that protection of vaccinated mice upon the RVFV challenge can be achieved by the activation of cellular responses mainly directed against Gc epitopes. The involvement of cellular immunity was stressed by the fact that protection of mice was strain dependent. Furthermore, our data suggest that the rMVA based single dose vaccination elicits suboptimal humoral immune responses against Gn antigen since disease in mice was exacerbated upon virus challenge in the presence of rMVAGnGc or rMVAGn immune serum. Thus, Gc-specific cellular immunity could be an important component in the protection after the challenge observed in BALB/c mice, contributing to the elimination of infected cells reducing morbidity and mortality and counteracting the deleterious effect of a subneutralizing antibody immune response.

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The pathogenesis of Rift Valley fever virus in the mouse model

Virology ◽

10.1016/j.virol.2010.08.016 ◽

2010 ◽

Vol 407 (2) ◽

pp. 256-267 ◽

Cited By ~ 73

Author(s):

Darci R. Smith ◽

Keith E. Steele ◽

Joshua Shamblin ◽

Anna Honko ◽

Joshua Johnson ◽

...

Keyword(s):

Mouse Model ◽

Rift Valley ◽

Rift Valley Fever ◽

Rift Valley Fever Virus ◽

Fever Virus ◽

Valley Fever

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Preliminary Evaluation of a Bunyavirus Vector for Cancer Immunotherapy

Journal of Virology ◽

10.1128/jvi.01105-15 ◽

2015 ◽

Vol 89 (17) ◽

pp. 9124-9127 ◽

Cited By ~ 1

Author(s):

N. Oreshkova ◽

L. Spel ◽

R. P. M. Vloet ◽

P. J. Wichgers Schreur ◽

R. J. M. Moormann ◽

...

Keyword(s):

Cancer Immunotherapy ◽

Rift Valley ◽

Rift Valley Fever ◽

Rift Valley Fever Virus ◽

Fever Virus ◽

Preliminary Evaluation ◽

Valley Fever ◽

Human Dendritic Cells

Replicon particles of Rift Valley fever virus, referred to as nonspreading Rift Valley fever virus (NSR), are intrinsically safe and highly immunogenic. Here, we demonstrate that NSR-infected human dendritic cells can activate CD8+T cellsin vitroand that prophylactic and therapeutic vaccinations of mice with NSR encoding a tumor-associated CD8 peptide can control the outgrowth of lymphoma cellsin vivo. These results suggest that the NSR system holds promise for cancer immunotherapy.

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An alphavirus replicon-derived candidate vaccine against Rift Valley fever virus

Epidemiology and Infection ◽

10.1017/s0950268808001696 ◽

2009 ◽

Vol 137 (9) ◽

pp. 1309-1318 ◽

Cited By ~ 37

Author(s):

M. T. HEISE ◽

A. WHITMORE ◽

J. THOMPSON ◽

M. PARSONS ◽

A. A. GROBBELAAR ◽

...

Keyword(s):

Rift Valley ◽

Rift Valley Fever ◽

Rift Valley Fever Virus ◽

Fluorescent Antibody ◽

Severe Disease ◽

Neutralizing Antibody ◽

Fever Virus ◽

Antibody Responses ◽

Valley Fever

SUMMARYRift Valley fever virus (RVFV) is a mosquito-transmitted bunyavirus (genusPhlebovirus) associated with severe disease in livestock and fatal encephalitis or haemorrhagic fever in a proportion of infected humans. Although live attenuated and inactivated vaccines have been used in livestock, and on a limited scale in humans, there is a need for improved anti-RVFV vaccines. Towards this goal, Sindbis virus replicon vectors expressing the RVFV Gn and Gc glycoproteins, as well as the non-structural nsM protein, were constructed and evaluated for their ability to induce protective immune responses against RVFV. These replicon vectors were shown to produce the RVFV glycoproteins to high levelsin vitroand to induce systemic anti-RVFV antibody responses in immunized mice, as determined by RVFV-specific ELISA, fluorescent antibody tests, and demonstration of a neutralizing antibody response. Replicon vaccination also provided 100% protection against lethal RVFV challenge by either the intraperitoneal or intranasal route. Furthermore, preliminary results indicate that the replicon vectors elicit RVFV-specific neutralizing antibody responses in vaccinated sheep. These results suggest that alphavirus-based replicon vectors can induce protective immunity against RVFV, and that this approach merits further investigation into its potential utility as a RVFV vaccine.

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Biochemical and biophysical characterization of cell-free synthesized Rift Valley fever virus nucleoprotein capsids enables in vitro screening to identify novel antivirals

Biology Direct ◽

10.1186/s13062-016-0126-5 ◽

2016 ◽

Vol 11 (1) ◽

Cited By ~ 2

Author(s):

Sean Broce ◽

Lisa Hensley ◽

Tomoharu Sato ◽

Joshua Lehrer-Graiwer ◽

Christian Essrich ◽

...

Keyword(s):

Rift Valley ◽

Rift Valley Fever ◽

Rift Valley Fever Virus ◽

Fever Virus ◽

In Vitro Screening ◽

Valley Fever ◽

Biophysical Characterization

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Inhibition of Rift Valley Fever Virus Replication and Perturbation of Nucleocapsid-RNA Interactions by Suramin

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.03595-14 ◽

2014 ◽

Vol 58 (12) ◽

pp. 7405-7415 ◽

Cited By ~ 14

Author(s):

Mary Ellenbecker ◽

Jean-Marc Lanchy ◽

J. Stephen Lodmell

Keyword(s):

Rift Valley ◽

Rift Valley Fever ◽

Rna Binding ◽

Therapeutic Potential ◽

Rift Valley Fever Virus ◽

Severe Disease ◽

Fever Virus ◽

Valley Fever ◽

Ribonucleoprotein Complexes

ABSTRACTRift Valley fever virus (RVFV) is an emerging infectious pathogen that causes severe disease in humans and livestock and has the potential for global spread. There are currently no proven safe and effective treatment options for RVFV infection. Inhibition of RNA binding to RVFV nucleocapsid protein (N) represents an attractive antiviral therapeutic strategy because several essential steps in the RVFV replication cycle involve N binding to viral RNA. In this study, we demonstrate the therapeutic potential of the drug suramin by showing that it functions well as an inhibitor of RVFV replication at multiple stages in human cell culture. Suramin has been used previously to treat trypanosomiasis in Africa. We characterize the dynamic and cooperative nature of N-RNA binding interactions and the dissociation of high-molecular-mass ribonucleoprotein complexes using suramin, which we previously identified as an N-RNA binding inhibitor in a high-throughput screen. Finally, we elucidate the molecular mechanism used by suraminin vitroto disrupt both specific and nonspecific binding events important for ribonucleoprotein formation.

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