Sofosbuvir protects Zika virus-infected mice from mortality, preventing short- and long-term sequelae

Abstract

Zika virus (ZIKV) causes significant public health concerns because of its association with congenital malformations, neurological disorders in adults, and, more recently, death. Considering the necessity to mitigate ZIKV-associated diseases, antiviral interventions are an urgent necessity. Sofosbuvir, a drug in clinical use against hepatitis C virus (HCV), is among the FDA-approved substances endowed with anti-ZIKV activity. In this work, we further investigated the in vivo activity of sofosbuvir against ZIKV. Neonatal Swiss mice were infected with ZIKV (2 × 107 PFU) and treated with sofosbuvir at 20 mg/kg/day, a concentration compatible with pre-clinical development of this drug. We found that sofosbuvir reduced acute levels of ZIKV from 60 to 90% in different anatomical compartments, such as the blood plasma, spleen, kidney, and brain. Early treatment with sofosbuvir doubled the percentage and time of survival of ZIKV-infected animals. Sofosbuvir also prevented the acute neuromotor impairment triggered by ZIKV. In the long-term behavioural analysis of ZIKV-associated sequelae, sofosbuvir prevented loss of hippocampal- and amygdala-dependent memory. Our results indicate that sofosbuvir inhibits ZIKV replication in vivo, which is consistent with the prospective necessity of antiviral drugs to treat ZIKV-infected individuals.

Neonatal Zika virus infection causes epileptic seizures, viral persistence and long-term behavioral impairment

“…http://dx.doi.org/10.1101/195172 doi: bioRxiv preprint first posted online Sep. 28, 2017; Previous studies have detected ZIKV in the brains of neonatal mice shortly (5-10 dpi) after systemic inoculation (22,54). In agreement, we found that ZIKV subcutaneously inoculated successfully reaches and replicates in the mouse brain, with a replication peak between 6 and 12 dpi.…”

“…Here, we report that male and female adult mice infected with ZIKV at post-natal day 3 show impaired performance in the novel object recognition (NOR) task (~90 dpi), a non-rewarded, ethologically relevant paradigm widely used to assess declarative memory in rodents (71). Similar results have recently been reported using two different tasks to evaluate spatial and aversive memories (54). These results strongly suggest that ZIKV-exposed infants might develop learning problems, which can seriously compromise patient's life quality.…”

Untold stories of the Zika virus epidemic in Brazil

“…Zika virus treatment and prevention strategies are currently under intense investigation. Antivirals used for treatment of hepatitis C virus such as sofosbuvir and broad‐spectrum antiviral agents such as favipiravir were explored in in vitro and animal models for potential use as treatment of ZIKV infection. Sofosbuvir increased survival and reduced neurological impairment in ZIKV‐infected mice, but studies in humans are still unavailable.…”

“…Antivirals used for treatment of hepatitis C virus such as sofosbuvir and broad‐spectrum antiviral agents such as favipiravir were explored in in vitro and animal models for potential use as treatment of ZIKV infection. Sofosbuvir increased survival and reduced neurological impairment in ZIKV‐infected mice, but studies in humans are still unavailable. The antimalarial drug cloroquine inhibits ZIKV infection in vitro and attenuates ZIKV‐associated morbidity, mortality, and fetal microcephaly in mice .…”

Repurposing an HIV Drug for Zika Virus Therapy

“…Nevertheless, the in vivo potency of rilpivirine seems better than sofosbuvir, a hepatitis C virus (HCV) nucleoside drug that was reported with anti-ZIKV activity. 9 Specifically, rilpivirine completely protected ZIKV-infected mice from death, whereas sofosbuvir and other nucleoside inhibitors only conferred partial protection. 10 The study by Sariyer et al 2 has provided a good example of repurposing clinical drugs for potential treatment of ZIKV infection.…”