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BACKGROUNDZika virus (ZIKV) is highly teratogenic, in contrast with dengue virus (DENV) or the yellow fever virus vaccine (YFV-17D). The mechanisms employed by ZIKV to cross the placenta need to be elucidated.METHODSParallel infections with ZIKV, DENV and YFV-17D were compared in terms of efficiency, activation of mTOR pathways and cytokine secretion profile in human cytotrophoblastic HTR8 cells (CTB), and monocytic U937 cells, differentiated to M2 macrophages (M2-MØ).RESULTSIn CTB, ZIKV replication was significantly more efficient than DENV or YFV-17D. In M2-MØ, ZIKV replication continued to be more efficient, although differences between strains were reduced. Significantly greater activation of Phospho-S6r and Phospho-AKT/Ser473 fractions in CTB infected with ZIKV than with DENV or YFV-17D, was observed. CTB treated with the mTOR inhibitors rapamycin or AZD8055, showed a 20-fold-reduction in ZIKV yield, versus 5 and 3.5-fold for DENV and YFV-17D, respectively. Finally, we detected that ZIKV infection, but not DENV or YFV-17D, efficiently inhibited the interferon response of CTB cells.CONCLUSIONSThese results suggest that CTB cells are permissive and act favoring ZIKV entry into the placental stroma, over DENV and YFV-17D and that the mTOR complex is a switch that enhances the replication of ZIKV in CTB cells.