The antiviral action of resveratrol against Zika virus through the regulation of interferon responses by HMGB1

Zika virus (ZIKV) infection is a public health concern and currently there is no specific therapeutic or approved vaccine. Resveratrol (RESV), a natural antiviral compound, has been shown to possess antiviral properties, but the mechanisms of action against ZIKV remain unknown. This study aimed to investigate the role of the high mobility group box 1 protein (HMGB1) in the underlying anti-ZIKV mechanisms of RESV. HMGB1 protein expression and ZIKV replication in both RESV-treated wild-type (WT) and HMGB1-knockdown (shHMGB1) Huh7 cells were analyzed using ELISA, immunofluorescence assay, immunoblot assay, focus-forming assay and qRT-PCR. HMGB1’s role was explored by evaluating the changes in the type-1 interferon (IFN) response genes using qRT-PCR and immunoblot assays. The treatment of ZIKV-infected WT Huh7 cells with RESV significantly reduced ZIKV titers by >90% (P < 0.001) and inhibited ZIKV-induced HMGB1 translocation (P < 0.001), resulting in nuclear HMGB1 accumulation. Compared to WT Huh7 cells, shHMGB1 Huh7 cells without RESV treatment showed a significant increase in the infectious virus titers and RNA with a maximum rise of 74% (P < 0.001) and 65% (P < 0.01), respectively. RESV treatment of ZIKV-infected WT Huh7 cells significantly increased the MxA (one of the classical interferon-stimulated genes, ISGs) and IFN-β levels (p 0.05) and did not cause changes in the expressions of MxA and IFN-β. Findings presented here suggest that RESV possesses therapeutic activity against ZIKV infection and the mechanism of action is mainly attributed to HMGB1 nuclear retention, which could upregulate the type-1 IFN and ISGs.