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ABSTRACT Zika virus (ZIKV) is a mosquito-borne Flavivirus that persistently infects patients; enters protected brain, placental, and testicular compartments; is sexually transmitted; and causes fetal microcephaly in utero. ZIKV persistently infects human brain microvascular endothelial cells (hBMECs) that form the blood-brain barrier and Sertoli cells that form testicular barriers, establishing reservoirs that enable viral dissemination. ZIKV persistence requires inhibiting interferon (IFN) responses that direct viral clearance. We found that ZIKV induces IFNβ and IFNλ in hBMECs but post-transcriptionally inhibits IFNβ/IFNλ expression. IFNβ/IFNλ mRNAs contain AU-rich elements (AREs) in their 3′ untranslated regions which regulate protein expression through interactions with ARE-binding proteins (ARE-BPs). We found that ZIKV infection of primary hBMECs induces the expression of the ARE-BP tristetraprolin (TTP) and that TTP is a novel regulator of endothelial IFN secretion. In hBMECs, TTP knockout (KO) increased IFNβ/IFNλ mRNA abundance and IFNβ/IFNλ secretion in response to ZIKV infection and inhibited viral persistence. In contrast, TTP expression dramatically reduced IFNβ/IFNλ secretion in hBMECs. IFNβ/IFNλ mRNA stability was not significantly altered by TTP and is consistent with TTP inhibition of IFNβ/IFNλ translation. TTP is similarly induced by ZIKV infection of Sertoli cells, and like hBMECs, TTP expression or KO inhibited or enhanced IFNβ/IFNλ mRNA levels, respectively. These findings reveal a mechanism for ZIKV-induced TTP to promote viral persistence in hBMECs and Sertoli cells by post-transcriptionally regulating IFNβ/IFNλ secretion. Our results demonstrate a novel role for virally induced TTP in regulating IFN secretion in barrier cells that normally restrict viral persistence and spread to protected compartments. IMPORTANCE Our findings define a novel role for ZIKV-induced TTP expression in regulating IFNβ/IFNλ production in primary hBMECs and Sertoli cells. These cells comprise key physiological barriers subverted by ZIKV to access brain and testicular compartments and serve as reservoirs for persistent replication and dissemination. We demonstrate for the first time that the ARE-binding protein TTP is virally induced and post-transcriptionally regulates IFNβ/IFNλ secretion. In ZIKV-infected hBMEC and Sertoli cells, TTP knockout increased IFNβ/IFNλ secretion, while TTP expression blocked IFNβ/IFNλ secretion. The TTP-directed blockade of IFN secretion permits ZIKV spread and persistence in hBMECs and Sertoli cells and may similarly augment ZIKV spread across IFNλ-protected placental barriers. Our work highlights the importance of post-transcriptional ZIKV regulation of IFN expression and secretion in cells that regulate viral access to protected compartments and defines a novel mechanism of ZIKV-regulated IFN responses which may facilitate neurovirulence and sexual transmission.