Ribavirin potentiates interferon action by augmenting interferon-stimulated gene induction in hepatitis C virus cell culture models

Thomas, Emmanuel; Feld, Jordan J.; Li, Qisheng; Hu, Zongyi; Fried, Michael; Liang, T. Jake

doi:10.1002/hep.23985

Cited by 141 publications

(138 citation statements)

References 62 publications

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“…Therefore, NITD008 is a more potent inhibitor of EV71 than ribavirin is in vivo. A number of antiviral mechanisms have been reported for ribavirin, including depletion of the intracellular pool of nucleoside triphosphates (27), functioning as a mutagen to increase error catastrophe (28), and potentiating the action of interferon by augmenting the expression of interferon-stimulated genes (29). The exact mechanism of ribavirin inhibition of EV71 remains to be determined.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Enterovirus 71 by Adenosine Analog NITD008

Deng

Yeo

et al. 2014

J Virol

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Enterovirus 71 (EV71) is a major viral pathogen in China and Southeast Asia. There is no clinically approved vaccine or antiviral therapy for EV71 infection. NITD008, an adenosine analog, is an inhibitor of flavivirus that blocks viral RNA synthesis. Here we report that NITD008 has potent antiviral activity against EV71. In cell culture, the compound inhibits EV71 at a 50% effective concentration of 0.67 M and a 50% cytotoxic concentration of 119.97 M. When administered at 5 mg/kg in an EV71 mouse model, the compound reduced viral loads in various organs and completely prevented clinical symptoms and death. To study the antiviral mechanism and drug resistance, we selected escape mutant viruses by culturing EV71 with increasing concentrations of NITD008. Resistance mutations were reproducibly mapped to the viral 3A and 3D polymerase regions. Resistance analysis with recombinant viruses demonstrated that either a 3A or a 3D mutation alone could lead to resistance to NITD008. A combination of both 3A and 3D mutations conferred higher resistance, suggesting a collaborative interplay between the 3A and 3D proteins during viral replication. The resistance results underline the importance of combination therapy required for EV71 treatment.

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Section: Discussionmentioning

confidence: 99%

Inhibition of Enterovirus 71 by Adenosine Analog NITD008

Deng

Yeo

et al. 2014

J Virol

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“…Viral RNA was isolated using the QIAamp UltraSens Virus Kit (QIAGEN) and assessed for HCV RNA by RTqPCR as described previously (21,63,64). HCV core antigen was assessed using the QuickTiter HCV Core Antigen ELISA Kit (Cell Biolabs) according to the manufacturer's instructions.…”

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confidence: 99%

Engrafted human stem cell–derived hepatocytes establish an infectious HCV murine model

et al. 2014

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“…Depletion of the intracellular pool of nucleoside triphosphates was proposed to be a major antiviral mechanism for ribavirin to inhibit flaviviruses (24). In addition, ribavirin could function as a mutagen to increase error catastrophe (25) and potentiated the antiviral activity of IFN-␣/␤ by augmenting the expression of IFN-stimulated genes (ISGs) (26). Similar to ribavirin, brequinar also has a broad antiviral spectrum against both positive-and negative-strand RNA viruses (27,28).…”

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confidence: 99%

Synergistic Suppression of Dengue Virus Replication Using a Combination of Nucleoside Analogs and Nucleoside Synthesis Inhibitors

Yeo

Chen

et al. 2015

Antimicrob Agents Chemother

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Dengue virus (DENV) is the most prevalent mosquito-borne viral pathogen in humans. Currently, there is no clinically approved vaccine or antiviral for DENV. Combination therapy is a common practice in antiviral treatment and a potential approach to search for new treatments for infectious pathogens. In this study, we performed a combination treatment in cell culture by using three distinct classes of inhibitors, including ribavirin (a guanosine analog with several antiviral mechanisms), brequinar (a pyrimidine biosynthesis inhibitor), and INX-08189 (a guanosine analog). The compound pairs were evaluated for antiviral activity by use of a DENV-2 luciferase replicon assay. Our result indicated that the combination of ribavirin and INX-08189 exhibited strong antiviral synergy. This result suggests that synergy can be achieved with compound pairs in which one compound suppresses the synthesis of the nucleoside for which the other compound is a corresponding nucleoside analog. In addition, we found that treatment of cells with brequinar alone could activate interferon-stimulated response elements (ISREs); furthermore, brequinar and NITD-982 (another pyrimidine biosynthesis inhibitor) potentiated interferon-induced ISRE activation. Compared to treatment with brequinar, treatment of cells with ribavirin alone could also induce ISRE activation, but to a lesser extent; however, when cells were cotreated with ribavirin and beta interferon, ribavirin did not augment the interferoninduced ISRE activation. O ver 2.5 billion people worldwide are at risk of dengue virus (DENV) infection, with 390 million human infections and 96 million cases with disease manifestations each year (1). DENV is endemic throughout tropical and subtropical climates and is found mostly in urban and semiurban areas. This positive-sense single-stranded RNA virus is transmitted mainly by the Aedes aegypti mosquito and is classified under the genus Flavivirus in the family Flaviviridae. Other notable viruses in this group include yellow fever virus, Japanese encephalitis virus, West Nile virus, and tick-borne encephalitis virus. Currently, neither an antiviral nor a vaccine is approved for DENV. Care for hospitalized dengue patients is supportive, mainly through optimal replenishment of body fluids. Treatment is intensive for those who succumb to the severe forms of the disease, i.e., dengue shock syndrome (DSS) and dengue hemorrhagic fever (DHF).Multiples approaches have been taken to identify inhibitors of DENV (2, 3). Small-molecule inhibitors have been reported to target various DENV proteins, including capsid (4, 5), envelope (6), protease (7, 8), nonstructural protein (NS) 4B (9, 10), methyltransferase (2, 11), and RNA-dependent RNA polymerase (12-16). Inhibition of host factors important for viral replication and of compounds with immunomodulation activities, including imino sugars (17), cholesterol inhibitors (18), chloroquine (19), and prednisolone (20), has also been pursued for potential treatment of DENV infections.Ribavirin is a drug with a...

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Ribavirin potentiates interferon action by augmenting interferon-stimulated gene induction in hepatitis C virus cell culture models

Cited by 141 publications

References 62 publications

Inhibition of Enterovirus 71 by Adenosine Analog NITD008

Inhibition of Enterovirus 71 by Adenosine Analog NITD008

Engrafted human stem cell–derived hepatocytes establish an infectious HCV murine model

Synergistic Suppression of Dengue Virus Replication Using a Combination of Nucleoside Analogs and Nucleoside Synthesis Inhibitors

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