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Viruses 2018, 10(6), 317; https://doi.org/10.3390/v10060317

Antiviral Effects of Clinically-Relevant Interferon-α and Ribavirin Regimens against Dengue Virus in the Hollow Fiber Infection Model (HFIM)

1
Institute for Therapeutic Innovation, Department of Medicine, College of Medicine, University of Florida, Orlando, FL 32827, USA
2
Center for Personalized Nanomedicine, Institute of Neuroimmune Pharmacology, Department of Immunology, Herbert Wertheim College of Medicine, Florida International University, Miami, FL 33199, USA
*
Author to whom correspondence should be addressed.
Received: 11 May 2018 / Revised: 1 June 2018 / Accepted: 7 June 2018 / Published: 9 June 2018
(This article belongs to the Section Antivirals & Vaccines)
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Abstract

Dengue virus (DENV) is the most prevalent mosquito-borne viral illness in humans. Currently, there are no therapeutic agents available to prevent or treat DENV infections. Our objective was to fill this unmet medical need by evaluating the antiviral activity of interferon-α (IFN) and ribavirin (RBV) as a combination therapy against DENV. DENV-infected Vero and Huh-7 cells were exposed to RBV and/or IFN, and the viral burden was quantified over time by plaque assay. Drug-drug interactions for antiviral effect were determined by fitting a mathematical model to the data. We then assessed clinically-relevant exposures of IFN plus RBV using the hollow fiber infection model (HFIM) system. RBV monotherapy was only effective against DENV at toxic concentrations in Vero and Huh-7 cells. IFN, as a single agent, did inhibit DENV replication at physiological concentrations and viral suppression was substantial in Huh-7 cells (Half maximal effective concentration (EC50) = 58.34 IU/mL). As a combination therapy, RBV plus IFN was additive for viral suppression in both cell lines; however, enhancement of antiviral activity at clinically-achievable concentrations was observed only in Huh-7 cells. Finally, clinical exposures of RBV plus IFN suppressed DENV replication by 99% even when treatment was initiated 24 h post-infection in the HFIM. Further evaluation revealed that the antiviral effectiveness of the combination regimen against DENV is mostly attributed to activity associated with IFN. These findings suggest that IFN is a potential therapeutic strategy for the treatment of DENV. View Full-Text
Keywords: Dengue virus; antiviral therapy; combination therapy; ribavirin; interferon-α; hollow fiber infection model; mathematical modeling Dengue virus; antiviral therapy; combination therapy; ribavirin; interferon-α; hollow fiber infection model; mathematical modeling
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).
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Pires de Mello, C.P.; Drusano, G.L.; Rodriquez, J.L.; Kaushik, A.; Brown, A.N. Antiviral Effects of Clinically-Relevant Interferon-α and Ribavirin Regimens against Dengue Virus in the Hollow Fiber Infection Model (HFIM). Viruses 2018, 10, 317.

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