In vitro and in vivo Phlebovirus inhibition by ribavirin

Sidwell, Robert W.; Huffman, John H.; Barnett, Bill B.; Pifat, Dominique Y.

doi:10.1128/aac.32.3.331

Cited by 62 publications

(48 citation statements)

References 14 publications

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“…As a reference method, the titration of infectious virus is currently used to evaluate antiviral activity. It requires a time-consuming cell culture as support for the quantification of the virus either by evaluating PFU per milliliter or TCID 50 milliliter (5,38). In this study, we obtained a good correlation when viral genomes were quantified by RTD-PCR.…”

Section: Discussionsupporting

confidence: 53%

Quantitative Real-Time PCR Detection of Rift Valley Fever Virus and Its Application to Evaluation of Antiviral Compounds

et al. 2001

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The Rift Valley fever virus (RVFV), a member of the genus Phlebovirus (family Bunyaviridae) is an enveloped negative-strand RNA virus with a tripartite genome. Until 2000, RVFV circulation was limited to the African continent, but the recent deadly outbreak in the Arabian Peninsula dramatically illustrated the need for rapid diagnostic methods, effective treatments, and prophylaxis. A method for quantifying the small RNA segment by a real-time detection reverse transcription (RT)-PCR using TaqMan technology and targeting the nonstructural protein-coding region was developed, and primers and a probe were designed. After optimization of the amplification reaction and establishment of a calibration curve with synthetic RNA transcribed in vitro from a plasmid containing the gene of interest, real-time RT-PCR was assessed with samples consisting of RVFV from infected Vero cells. The method was found to be specific for RVFV, and it was successfully applied to the detection of the RVFV genome in animal sera infected with RVFV as well as to the assessment of the efficiency of various drugs (ribavirin, alpha interferon, 6-azauridine, and glycyrrhizin) for antiviral activity. Altogether, the results indicated a strong correlation between the infectious virus titer and the amount of viral genome assayed by real time RT-PCR. This novel method could be of great interest for the rapid diagnosis and screening of new antiviral compounds, as it is sensitive and time saving and does not require manipulation of infectious material.The Rift Valley fever (RVF) virus (RVFV), a member of the genus Phlebovirus, belongs to the Bunyaviridae family and possesses a negative-stranded, tripartite RNA genome composed of a large, a medium, and a small (S) segment (for reviews, see references 9 and 37). Like other phleboviruses, the S segment utilizes an ambisense strategy to code for two proteins, the nucleocapsid protein and the nonstructural protein (NS s ), which are synthesized from subgenomic viral complementary and viral sense mRNA, respectively.RVF is a mosquito-borne zoonosis predominantly provoking the death of young animals and abortion (e.g., sheep and goats) (for reviews, see references 24, 39 and 41). The disease was first identified in sheep by Daubney et al. in Kenya in 1931, and it is endemic almost everywhere in subtropical Africa (6). Transmission to humans occurs primarily by contact with infected animal body fluids and by mosquito bites. Infection is usually asymptomatic or associated with a brief self-limited febrile illness. However, complications such as retinitis, encephalitis, or hemorrhagic fever occur in some patients with mortality rates of up to 10 to 12% (21, 28).The potential of RVF as a disease emerging in new areas was first documented in Egypt in 1977 (16), and since then, epidemics have occurred in Mauritania (1987Mauritania ( to 1988Mauritania ( and 1998, Madagascar (1990to 1991), Egypt (1993, and eastern Africa (in Kenya, Somalia, and Tanzania) (references 33 and 34 and references therein). Recently, the...

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Section: Discussionsupporting

confidence: 53%

Quantitative Real-Time PCR Detection of Rift Valley Fever Virus and Its Application to Evaluation of Antiviral Compounds

et al. 2001

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“…Ribavirin (1-(-D-ribofuranosyl-1,2,4-triazole-3-carboxamide) (Figure 1), which was first synthesized in 1970, is a purine nucleoside analogue, with demonstrated efficacy against a variety of DNA and RNA viral infections (reviewed in Sidwell et al, 1972, Sidwell 1980, 1984Crumpacker, 1984). Ribavirin may be more than a direct antiviral agent as it can be beneficial in the treatment of viral disease with [respiratory syncytial virus (Hall et al, 1983)] or without [hepatitis C virus (HCV) (Dusheiko et al, 1996)] directly inhibiting viral replication.…”

mentioning

confidence: 99%

Mechanisms of Action of Ribavirin in Antiviral Therapies

Tam¹,

Lau²,

Hong³

2001

Antivir Chem Chemother

113

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Although ribavirin was originally synthesized over 30 years ago and has been used to treat viral infections as monotherapy (respiratory syncytial virus and Lassa fever virus) or with interferon-α (IFN-α) as combination therapy (hepatitis C virus), the precise mechanism of its therapeutic activities remains controversial. In this review we focus on two main biological properties of ribavirin: its indirect and direct antiviral activities (with particular emphasis on its efficacy against chronic hepatitis C infection). Each property could individually or collectively account for its clinical efficacy against viral infections. First, with emphasis on the evidence for indirect activities of ribavirin, we will review the clinical observations that suggest that the immunomodulatory properties of ribavirin can in part account for its antiviral activities in vivo. We will then describe the mode of ribavirin's direct antiviral activities. These direct activities can be ascribed to several possible mechanisms, including the recently described activity as an RNA mutagen, a property that may be important in driving a rapidly mutating RNA virus over the threshold to 'error catastrophe'.

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“…The availability of these rodent models makes PTV a viable alternative to the use of Rift Valley fever virus for antiviral studies because the latter is highly restricted and requires high-level containment facilities. To that end, numerous evaluations of promising antivirals have been conducted using the PTV models of acute phlebovirus-induced disease (5)(6)(7)(8)(9)(10)(11)(12). Moreover, several large studies have involved the evaluation of immune modulators and have demonstrated that the PTV is acutely sensitive to IFN inducers (5,10).…”

Section: P Unta Toro Virus (Ptv)mentioning

confidence: 99%

“…Day 1 samples were also collected from untreated animals to provide a comparison point early during the course of infection. Virus titers were assayed using an infectious cell culture assay as described previously (7). Briefly, a specific volume of liver homogenate or serum was serially diluted and added to triplicate wells of LLC-MK 2 cell monolayers in 96-well microplates.…”

Section: Evaluation Of Dsrnas In Tlr3mentioning

confidence: 99%

TLR3 Is Essential for the Induction of Protective Immunity against Punta Toro Virus Infection by the Double-Stranded RNA (dsRNA), Poly(I:C12U), but not Poly(I:C): Differential Recognition of Synthetic dsRNA Molecules

Gowen

Wong

Jung

et al. 2007

The Journal of Immunology

104

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In the wake of RNA virus infections, dsRNA intermediates are often generated. These viral pathogen-associated molecular patterns can be sensed by a growing number of host cell cytosolic proteins and TLR3, which contribute to the induction of antiviral defenses. Recent evidence indicates that melanoma differentiation-associated gene-5 is the prominent host component mediating IFN production after exposure to the dsRNA analog, poly(I:C). We have previously reported that Punta Toro virus (PTV) infection in mice is exquisitely sensitive to treatment with poly(I:C12U), a dsRNA analog that has a superior safety profile while maintaining the beneficial activity of the parental poly(I:C) in the induction of innate immune responses. The precise host factor(s) mediating protective immunity following its administration remain to be elucidated. To assess the role of TLR3 in this process, mice lacking the receptor were used to investigate the induction of protective immunity, type I IFNs, and IL-6 following treatment. Unlike wild-type mice, those lacking TLR3 were not protected against PTV infection following poly(I:C12U) therapy and failed to produce IFN-α, IFN-β, and IL-6. In contrast, poly(I:C) treatment significantly protected TLR3−/− mice from lethal challenge despite some deficiencies in cytokine induction. There was no indication that the lack of protection was due to the fact that TLR3-deficient mice had a reduced capacity to fight infection because they were not found to be more susceptible to PTV. We conclude that TLR3 is essential to the induction of antiviral activity elicited by poly(I:C12U), which does not appear to be recognized by the cytosolic sensor of poly(I:C), melanoma differentiation-associated gene-5.

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In vitro and in vivo Phlebovirus inhibition by ribavirin

Cited by 62 publications

References 14 publications

Quantitative Real-Time PCR Detection of Rift Valley Fever Virus and Its Application to Evaluation of Antiviral Compounds

Quantitative Real-Time PCR Detection of Rift Valley Fever Virus and Its Application to Evaluation of Antiviral Compounds

Mechanisms of Action of Ribavirin in Antiviral Therapies

TLR3 Is Essential for the Induction of Protective Immunity against Punta Toro Virus Infection by the Double-Stranded RNA (dsRNA), Poly(I:C12U), but not Poly(I:C): Differential Recognition of Synthetic dsRNA Molecules

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