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Sariyer IK , Gordon J , Burdo TH , Wollebo HS , Gianti E , Donadoni M , Bellizzi A , Cicalese S , Loomis R , Robinson JA , Carnevale V , Steiner J , Ozdener MH , Miller AD , Amini S , Klein ML , Khalili K
Suppression of Zika Virus Infection in the Brain by the Antiretroviral Drug Rilpivirine
Mol Ther. 2019 Dec 4;27(12) :2067-2079
PMID: 31653397    PMCID: PMC6904669    URL: https://www.ncbi.nlm.nih.gov/pubmed/31653397
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Zika virus (ZIKV) infection is associated with microcephaly in neonates and Guillain-Barre syndrome in adults. ZIKV produces a class of nonstructural (NS) regulatory proteins that play a critical role in viral transcription and replication, including NS5, which possesses RNA-dependent RNA polymerase (RdRp) activity. Here we demonstrate that rilpivirine (RPV), a non-nucleoside reverse transcriptase inhibitor (NNRTI) used in the treatment of HIV-1 infection, inhibits the enzymatic activity of NS5 and suppresses ZIKV infection and replication in primary human astrocytes. Similarly, other members of the NNRTI family, including etravirine and efavirenz, showed inhibitory effects on viral infection of brain cells. Site-directed mutagenesis identified 14 amino acid residues within the NS5 RdRp domain (AA265-903), which are important for the RPV interaction and the inhibition of NS5 polymerase activity. Administration of RPV to ZIKV-infected interferon-alpha/beta receptor (IFN-A/R) knockout mice improved the clinical outcome and prevented ZIKV-induced mortality. Histopathological examination of the brains from infected animals revealed that RPV reduced ZIKV RNA levels in the hippocampus, frontal cortex, thalamus, and cerebellum. Repurposing of NNRTIs, such as RPV, for the inhibition of ZIKV replication offers a possible therapeutic strategy for the prevention and treatment of ZIKV-associated disease.
1525-0024 Sariyer, Ilker Kudret Gordon, Jennifer Burdo, Tricia H Wollebo, Hassen S Gianti, Eleonora Donadoni, Martina Bellizzi, Anna Cicalese, Stephanie Loomis, Regina Robinson, Jake A Carnevale, Vincenzo Steiner, Joseph Ozdener, Mehmet H Miller, Andrew D Amini, Shohreh Klein, Michael L Khalili, Kamel P30 MH092177/MH/NIMH NIH HHS/United States T32 MH079785/MH/NIMH NIH HHS/United States Journal Article Research Support, N.I.H., Extramural Research Support, U.S. Gov't, Non-P.H.S. United States Mol Ther. 2019 Dec 4;27(12):2067-2079. doi: 10.1016/j.ymthe.2019.10.006. Epub 2019 Oct 11.