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

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Pires de Mello CP, Drusano GL, Rodriquez JL, Kaushik A, Brown AN

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

Viruses. 2018 Jun 9;10(6). pii: v10060317. doi: 10.3390/v10060317.

PubMed ID

29890736 [ View in PubMed

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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.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Ribavirin	Genome polyprotein	Protein	DENV-2	Yes	Inhibitor	Details