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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\u2013virus 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.<\/jats:p>","DOI":"10.3390\/pathogens15050518","type":"journal-article","created":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T15:17:23Z","timestamp":1779203843000},"page":"518","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Vitamin A Modulates AHR Signaling and Restricts Zika Virus Replication in Human Retinal Pigment Epithelial Cells: Insights from Molecular Modeling and Antiviral Assays"],"prefix":"10.3390","volume":"15","author":[{"given":"Agostina B.","family":"Marquez","sequence":"first","affiliation":[{"name":"Laboratorio de Estrategias Antivirales, Departamento de Qu\u00edmica Biol\u00f3gica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires (UBA), Intendente G\u00fciraldes 2160, Ciudad Aut\u00f3noma de Buenos Aires 1428, Argentina"},{"name":"Instituto de Qu\u00edmica Biol\u00f3gica de la Facultad de Ciencias Exactas y Naturales (IQUIBICEN), Consejo Nacional de Investigaciones Cient\u00edficas y T\u00e9cnicas (CONICET)\u2013UBA, Intendente G\u00fciraldes 2160, Ciudad Aut\u00f3noma de Buenos Aires 1428, Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5872-5237","authenticated-orcid":false,"given":"Priscila A.","family":"Lanza Castronuovo","sequence":"additional","affiliation":[{"name":"QUIAMM-INBIOTEC, Departamento de Qu\u00edmica y Bioqu\u00edmica, Facultad de Ciencias Exactas y Naturales, Universidad Nacional de Mar del Plata, Funes 3350, Mar del Plata 7600, Argentina"},{"name":"Comisi\u00f3n de Investigaciones Cient\u00edficas (CIC), Calle 526 entre 10 y 11, La Plata 1900, Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cecilia L.","family":"Barbieri","sequence":"additional","affiliation":[{"name":"QUIAMM-INBIOTEC, Departamento de Qu\u00edmica y Bioqu\u00edmica, Facultad de Ciencias Exactas y Naturales, Universidad Nacional de Mar del Plata, Funes 3350, Mar del Plata 7600, Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mayra A.","family":"Casta\u00f1eda Cata\u00f1a","sequence":"additional","affiliation":[{"name":"Laboratorio de Estrategias Antivirales, Departamento de Qu\u00edmica Biol\u00f3gica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires (UBA), Intendente G\u00fciraldes 2160, Ciudad Aut\u00f3noma de Buenos Aires 1428, Argentina"},{"name":"Instituto de Qu\u00edmica Biol\u00f3gica de la Facultad de Ciencias Exactas y Naturales (IQUIBICEN), Consejo Nacional de Investigaciones Cient\u00edficas y T\u00e9cnicas (CONICET)\u2013UBA, Intendente G\u00fciraldes 2160, Ciudad Aut\u00f3noma de Buenos Aires 1428, Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2356-6624","authenticated-orcid":false,"given":"Claudia S.","family":"Sep\u00falveda","sequence":"additional","affiliation":[{"name":"Laboratorio de Estrategias Antivirales, Departamento de Qu\u00edmica Biol\u00f3gica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires (UBA), Intendente G\u00fciraldes 2160, Ciudad Aut\u00f3noma de Buenos Aires 1428, Argentina"},{"name":"Instituto de Qu\u00edmica Biol\u00f3gica de la Facultad de Ciencias Exactas y Naturales (IQUIBICEN), Consejo Nacional de Investigaciones Cient\u00edficas y T\u00e9cnicas (CONICET)\u2013UBA, Intendente G\u00fciraldes 2160, Ciudad Aut\u00f3noma de Buenos Aires 1428, Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8070-9620","authenticated-orcid":false,"given":"Agustina","family":"Alaimo","sequence":"additional","affiliation":[{"name":"Instituto de Qu\u00edmica Biol\u00f3gica de la Facultad de Ciencias Exactas y Naturales (IQUIBICEN), Consejo Nacional de Investigaciones Cient\u00edficas y T\u00e9cnicas (CONICET)\u2013UBA, Intendente G\u00fciraldes 2160, Ciudad Aut\u00f3noma de Buenos Aires 1428, Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D. 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