Abstract
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.
Highlights
Chikungunya virus (CHIKV), a mosquito borne alphavirus endemic to Africa andAsia, first emerged in the Western Hemisphere in 2013 [1]
FAV was completely ineffective against CHIKV in HFF-1 cells, as viral burden in all treatment arms remained identical to the control group (Figure 1c)
Due to the pantropic nature of CHIKV infection, it is imperative to identify antiviral treatment strategies that effectively inhibit viral replication in numerous types of tissue targeted by the virus
Summary
First emerged in the Western Hemisphere in 2013 [1]. Since it swiftly spread throughout the Caribbean and Americas where it has caused an excess of 2 million infections [2,3,4,5]. CHIKV is associated with high morbidity rates as only 15% of patients are asymptomatic [6]. Acute CHIKV infection is characterized by debilitating joint and muscle pain, fever, headache, and maculopapular rash; a considerable percentage of patients experience chronic symptoms including recurrent and persistent arthralgia months to years following acute infection [7,8].
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