Ribavirin inhibits Zika virus (ZIKV) replication in vitro and suppresses viremia in ZIKV-infected STAT1-deficient mice

Abstract

Zika fever, a mosquito-borne infectious disease caused by Zika virus (ZIKV), is an epidemic disease for which no effective therapy has been established. The recent outbreaks of ZIKV in Brazil and French Polynesia have been linked to a considerable increase in the incidence of fetal microcephaly and other diseases such as Guillain-Barre syndrome. Because there is currently no specific therapy or vaccine, the early exploitation of a method to prevent expansion of ZIKV is a high priority. To validate commonly used antiviral drugs, we evaluated the effect of ribavirin, a drug used to treat hepatitis C with interferon-β (IFN-β), on ZIKV replication. In mammalian cells, we observed an inhibitory effect of ribavirin on ZIKV replication and ZIKV-induced cell death without cytotoxic effect. Furthermore, we found that STAT1-deficient mice, which lack type I IFN signaling, were highly sensitive to ZIKV infection and exhibited lethal outcome. Ribavirin abrogated viremia in ZIKV-infected STAT-1-deficient mice. These data suggest that the inhibition of viral RNA-dependent RNA polymerases may be effective for treatment of ZIKV infection. Our data provide a new insight into the mechanisms for inhibition of ZIKV replication and prevention of Zika fever.

The celecoxib derivative kinase inhibitor AR-12 (OSU-03012) inhibits Zika virus via down-regulation of the PI3K/Akt pathway and protects Zika virus-infected A129 mice: A host-targeting treatment strategy

“…important for arboviruses such as ZIKV, DENV, and Chikungunya virus, which co-circulate in the same geographical regions and/or have similar clinical features. We and others have previously identified a number of clinically approved drugs, such as novobiocin, lopinavir-ritonavir, ribavirin, and sofosbuvir, to have anti-ZIKV activity in vitro and/or in vivo (Bullard-Feibelman et al, 2016;Kamiyama et al, 2017;Yuan et al, 2017). These repurposed drugs directly target the virus by inhibition of key viral enzymes, such as the viral protease and polymerase, and may not have antiviral activity against other co-circulating arboviruses with structurally different viral enzymes.…”

Genetic diversity of Collaborative Cross mice controls viral replication, clinical severity and brain pathology induced by Zika virus infection, independently of Oas1b

“…Effective systemic infection in mice occurs when this response is abrogated by genetic inactivation of the Ifnar1 gene (29) or by blocking the type I IFN receptor with the MAR1-5A3 monoclonal antibody (mAb) (30, 31). So far, host genetic factors involved in mouse susceptibility to ZIKV infection have been investigated mainly through reverse genetic approaches, by studying the consequences of genetic ablation of specific genes, such as innate or adaptive immunity genes (29, 32–35). While these models have contributed to our understanding of the mechanisms of ZIKV disease, they do not model the simultaneous contribution of variants in multiple pathways, as would most likely be observed in the natural population.…”

Drug Repurposing for Viral Infectious Diseases: How Far Are We?

“…Studies reporting the repurposing potential against ZIKV of drugs approved for the treatment HCV infections, that is, ribavirin and sofosbuvir, are worth mentioning, although conflicting results on the efficacy of the latter have been reported [15][16][17][18][19][20]. Discrepancies may be due to the different cell lines or animal models used and should be explained at a molecular level; moreover, deeper investigation on the safety of sofosbuvir during pregnancy is needed before considering this anti-HCV drug as a candidate for the treatment of ZIKV fetal infections.…”