Immunosuppression-induced Zika virus reactivation causes brain inflammation and behavioral deficits in mice

Zika virus (ZIKV) is a neurotropic flavivirus that can persist for long periods in several tissues. The late consequences of ZIKV persistence and whether new rounds of active replication can occur, have never been explored. Here, we investigated whether neonatally ZIKV-infected mice are susceptible to viral reactivation in adulthood. We found that when ZIKV-infected mice are treated with immunosuppressant drugs, they present increased susceptibility to chemically-induced seizures.  Levels of subgenomic flavivirus RNAs (sfRNAs) were increased, relative to the amounts of genomic RNAs, in the brains of mice following immunosuppression and were associated with changes in cytokine expression. We investigated the impact of immunosuppression on the testicles and found that ZIKV genomic RNA levels are increased in mice following immunosuppression, which also caused significant testicular damage. These findings suggest that ZIKV can establish new rounds of active replication long after acute stages of disease, so exposed patients should be monitored to ensure complete viral eradication.