Vitamin A Modulates AHR Signaling and Restricts Zika Virus Replication in Human Retinal Pigment Epithelial Cells:...

Zika virus (ZIKV) is an emerging flavivirus associated with congenital malformations and ocular complications, representing a significant public health concern. Retinal pigment epithelium (RPE) cells play a key role in maintaining retinal integrity and represent a primary target of ZIKV infection, making them a relevant model for studying host-virus interactions. In this study, we evaluated the antiviral activity of fat- and water-soluble vitamins against ZIKV in hTERT RPE-1 (hRPE1) cells. Particularly, vitamin A was identified as the compound that most effectively inhibited viral replication. Molecular dynamics simulations focusing on the PAS-B domain of the aryl hydrocarbon receptor (AHR) revealed a high affinity of vitamin A for the receptor. In hRPE1 cells, vitamin A treatment reduced viral RNA levels and decreased CYP1A1, TDO, and AHR mRNA expression. In parallel, IFNB1 expression increased, consistent with the involvement of type I interferon (IFN-I), as no antiviral effect was observed in IFN-I-deficient Vero cells. These findings suggest that vitamin A restricts ZIKV replication through host antiviral responses, potentially involving modulation of AHR-associated signaling. The combination of vitamin A and the well-known polyphenol resveratrol further enhanced antiviral activity, showing predominantly additive effects. Together, these results support the potential use of both bioactive compounds as a combined therapeutic strategy.