Limited Effects of Type I Interferons on Kyasanur Forest Disease Virus in Cell Culture

Citation: Cook BWM, Ranadheera C, Nikiforuk AM, Cutts TA, Kobasa D, Court DA, et al. (2016) Limited Effects of Type I Interferons on Kyasanur Forest Disease Virus in Cell Culture. PLoS Negl Trop Dis 10(8): e0004871. doi:10.1371/journal.pntd.0004871
Published: August 1, 2016

Abstract
interferonBackground: The tick-borne flavivirus, Kyasanur Forest disease virus (KFDV) causes seasonal infections and periodic outbreaks in south-west India. The current vaccine offers poor protection with reported issues of coverage and immunogenicity. Since there are no approved prophylactic therapeutics for KFDV, type I IFN-α/β subtypes were assessed for antiviral potency against KFDV in cell culture.
Methodology/Principal Findings: The continued passage of KFDV-infected cells with re-administered IFN-α2a treatment did not eliminate KFDV and had little effect on infectious particle production whereas the IFN-sensitive, green fluorescent protein-expressing vesicular stomatitis virus (VSV-GFP) infection was controlled. Further evaluation of the other IFN-α/β subtypes versus KFDV infection indicated that single treatments of either IFN-αWA and IFN-αΚ appeared to be more effective than IFN-α2a at reducing KFDV titres. Concentration-dependent analysis of these IFN-α/β subtypes revealed that regardless of subtype, low concentrations of IFN were able to limit cytopathic effects (CPE), while significantly higher concentrations were needed for inhibition of virion release. Furthermore, expression of the KFDV NS5 in cell culture before IFN addition enabled VSV-GFP to overcome the effects of IFN-α/β signalling, producing a robust infection.
Conclusions/Significance: Treatment of cell culture with IFN does not appear to be suitable for KFDV eradication and the assay used for such studies should be carefully considered. Further, it appears that the NS5 protein is sufficient to permit KFDV to bypass the antiviral properties of IFN. We suggest that other prophylactic therapeutics should be evaluated in place of IFN for treatment of individuals with KFDV disease.

Author Summary: Since 1957 Kyasanur Forest disease virus (KFDV) has caused seasonal infections and periodic outbreaks in south-west India. It is estimated that nearly 500 people acquire KFDV annually and 3–5% of those infected succumb to the disease. The vaccine strategy is complicated by the lack of coverage, compliance and efficacy, highlighted by the fact that less than half of the target population received the recommended three dose-regimen. Besides the prevention of tick bites and vaccination, there are no approved antivirals for KFDV infection. Based on these observations, the commonly-used-IFN-α2a was assessed and was not capable of limiting KFDV virus titres. Further characterization of the other IFN-α/β subtypes used at different concentrations revealed that KFDV replication was insensitive to all subtypes, even though signs of cellular damage were reduced. Thus, infectious titre, rather than monolayer staining or cytopathic effect (CPE) monitoring, is more reliable for IFN analyses. The capability of KFDV to overcome the antiviral properties of IFN was attributed to the NS5 protein. Thus, other treatment options need to be evaluated for patients suffering with Kyasanur Forest disease.

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