Cross-Reactive Dengue Virus Antibodies Augment Zika Virus Infection of Human Placental Macrophages

Zika virus (ZIKV), which emerged in regions endemic to dengue virus (DENV), is vertically transmitted and results in adverse pregnancy outcomes. Antibodies to DENV can cross-react with ZIKV, but whether these antibodies influence ZIKV vertical transmission remains unclear. Here, we find that DENV antibodies increase ZIKV infection of placental macrophages (Hofbauer cells [HCs]) from 10% to over 80% and enhance infection of human placental explants. ZIKV-anti-DENV antibody complexes increase viral binding and entry into HCs but also result in blunted type I interferon, pro-inflammatory cytokine, and antiviral responses. Additionally, ZIKV infection of HCs and human placental explants is enhanced in an immunoglobulin G subclass-dependent manner, and targeting FcRn reduces ZIKV replication in human placental explants. Collectively, these findings support a role for pre-existing DENV antibodies in enhancement of ZIKV infection of select placental cell types and indicate that pre-existing immunity to DENV should be considered when addressing ZIKV vertical transmission. [Display omitted] •Cross-reactive DENV antibodies enhance ZIKV infection in human Hofbauer cells•Enhanced ZIKV infection in mid-gestation explants is IgG subclass dependent•ZIKV immune complexes target Hofbauer cells within the villous stroma Zimmerman et al. find that DENV cross-reactive antibodies enhance ZIKV infection of human placental macrophages and mid-gestation placental explants. ZIKV-anti-DENV antibody complexes increase viral entry but also result in blunted antiviral responses. These studies suggest that pre-existing immunity to DENV should be considered when addressing ZIKV vertical transmission.