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Open AccessArticle

Combination Regimens of Favipiravir Plus Interferon Alpha Inhibit Chikungunya Virus Replication in Clinically Relevant Human Cell Lines

1
Institute for Therapeutic Innovation, Department of Medicine, College of Medicine, University of Florida, Orlando, FL 32827, USA
2
Department of Pharmaceutics, College of Pharmacy, University of Florida, Orlando, FL 32827, USA
3
Department of Pharmacotherapy & Translational Research, College of Pharmacy, University of Florida, Orlando, FL 32827, USA
*
Author to whom correspondence should be addressed.
Contributed equally to this work.
Academic Editor: Keivan Zandi
Microorganisms 2021, 9(2), 307; https://doi.org/10.3390/microorganisms9020307
Received: 11 January 2021 / Accepted: 30 January 2021 / Published: 2 February 2021
(This article belongs to the Special Issue Recent Advances in Antivirals for Emerging Viruses)
Chikungunya virus (CHIKV) is an alphavirus associated with a broad tissue tropism for which no antivirals or vaccines are approved. This study evaluated the antiviral potential of favipiravir (FAV), interferon-alpha (IFN), and ribavirin (RBV) against CHIKV as mono- and combination-therapy in cell lines that are clinically relevant to human infection. Cells derived from human connective tissue (HT-1080), neurons (SK-N-MC), and skin (HFF-1) were infected with CHIKV and treated with different concentrations of FAV, IFN, or RBV. Viral supernatant was sampled daily and the burden was quantified by plaque assay on Vero cells. FAV and IFN were the most effective against CHIKV on various cell lines, suppressing the viral burden at clinically achievable concentrations; although the degree of antiviral activity was heavily influenced by cell type. RBV was not effective and demonstrated substantial toxicity, indicating that it is not a feasible candidate for CHIKV. The combination of FAV and IFN was then assessed on all cell lines. Combination therapy enhanced antiviral activity in HT-1080 and SK-N-MC cells, but not in HFF-1 cells. We developed a pharmacokinetic/pharmacodynamic model that described the viral burden and inhibitory antiviral effect. Simulations from this model predicted clinically relevant concentrations of FAV plus IFN completely suppressed CHIKV replication in HT-1080 cells, and considerably slowed down the rate of viral replication in SK-N-MC cells. The model predicted substantial inhibition of viral replication by clinical IFN regimens in HFF-1 cells. Our results highlight the antiviral potential of FAV and IFN combination regimens against CHIKV in clinically relevant cell types. View Full-Text
Keywords: chikungunya virus; favipiravir; interferon-alpha; combination therapy; mathematical modeling chikungunya virus; favipiravir; interferon-alpha; combination therapy; mathematical modeling
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MDPI and ACS Style

Franco, E.J.; Tao, X.; Hanrahan, K.C.; Zhou, J.; Bulitta, J.B.; Brown, A.N. Combination Regimens of Favipiravir Plus Interferon Alpha Inhibit Chikungunya Virus Replication in Clinically Relevant Human Cell Lines. Microorganisms 2021, 9, 307. https://doi.org/10.3390/microorganisms9020307

AMA Style

Franco EJ, Tao X, Hanrahan KC, Zhou J, Bulitta JB, Brown AN. Combination Regimens of Favipiravir Plus Interferon Alpha Inhibit Chikungunya Virus Replication in Clinically Relevant Human Cell Lines. Microorganisms. 2021; 9(2):307. https://doi.org/10.3390/microorganisms9020307

Chicago/Turabian Style

Franco, Evelyn J.; Tao, Xun; Hanrahan, Kaley C.; Zhou, Jieqiang; Bulitta, Jürgen B.; Brown, Ashley N. 2021. "Combination Regimens of Favipiravir Plus Interferon Alpha Inhibit Chikungunya Virus Replication in Clinically Relevant Human Cell Lines" Microorganisms 9, no. 2: 307. https://doi.org/10.3390/microorganisms9020307

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