University of California San Diego, School of Medicine, Department of Pediatrics/Rady Children's Hospital San Diego, Department of Cellular & Molecular Medicine, Stem Cell Program, La Jolla, CA, 92037-0695, USA.
Sanford Burnham Prebys Medical Discovery Institute, 10901N. Torrey Pines Rd., La Jolla, CA, 92037, USA.
Sci Rep. 2018 Jan 19;8(1):1218. doi: 10.1038/s41598-018-19526-4.
The outbreak of the Zika virus (ZIKV) has been associated with increased incidence of congenital malformations. Although recent efforts have focused on vaccine development, treatments for infected individuals are needed urgently. Sofosbuvir (SOF), an FDA-approved nucleotide analog inhibitor of the Hepatitis C (HCV) RNA-dependent RNA polymerase (RdRp) was recently shown to be protective against ZIKV both in vitro and in vivo. Here, we show that SOF protected human neural progenitor cells (NPC) and 3D neurospheres from ZIKV infection-mediated cell death and importantly restored the antiviral immune response in NPCs. In vivo, SOF treatment post-infection (p.i.) decreased viral burden in an immunodeficient mouse model. Finally, we show for the first time that acute SOF treatment of pregnant dams p.i. was well-tolerated and prevented vertical transmission of the virus to the fetus. Taken together, our data confirmed SOF-mediated sparing of human neural cell types from ZIKV-mediated cell death in vitro and reduced viral burden in vivo in animal models of chronic infection and vertical transmission, strengthening the growing body of evidence for SOF anti-ZIKV activity.
寨卡病毒（ZIKV）的爆发与先天性畸形发病率的增加有关。尽管最近的努力集中在疫苗开发上，但迫切需要针对感染个体的治疗方法。索非布韦（SOF）是一种已获得 FDA 批准的核苷酸类似物，可抑制丙型肝炎（HCV）RNA 依赖性 RNA 聚合酶（RdRp），最近的研究表明，它在体外和体内均具有抗 ZIKV 的作用。在这里，我们表明 SOF 可保护人神经祖细胞（NPC）和 3D 神经球免受 ZIKV 感染介导的细胞死亡，并重要的是恢复 NPC 中的抗病毒免疫反应。在体内，感染后（p.i.）给予 SOF 治疗可降低免疫缺陷小鼠模型中的病毒载量。最后，我们首次表明，急性 SOF 治疗感染后（p.i.）的孕鼠可耐受，并且可防止病毒垂直传播到胎儿。综上所述，我们的数据证实 SOF 可在体外减轻人类神经细胞类型因 ZIKV 介导的细胞死亡，并在慢性感染和垂直传播的动物模型中降低体内病毒载量，这进一步证实了 SOF 抗 ZIKV 活性的证据越来越多。
