Tani Hideki, Fukuma Aiko, Fukushi Shuetsu, Taniguchi Satoshi, Yoshikawa Tomoki, Iwata-Yoshikawa Naoko, Sato Yuko, Suzuki Tadaki, Nagata Noriyo, Hasegawa Hideki, Kawai Yasuhiro, Uda Akihiko, Morikawa Shigeru, Shimojima Masayuki, Watanabe Haruo, Saijo Masayuki
Department of Virology I, National Institute of Infectious Diseases, Tokyo, Japan.
Department of Pathology, National Institute of Infectious Diseases, Tokyo, Japan.
mSphere. 2016 Jan 6;1(1). doi: 10.1128/mSphere.00061-15. eCollection 2016 Jan-Feb.
Severe fever with thrombocytopenia syndrome virus (SFTSV) is the causative agent of SFTS, an emerging hemorrhagic fever. This disease has a high case fatality rate and is endemic to China, South Korea, and Japan. Because there are currently no effective therapeutics for SFTS, potent and safe antivirals are needed for the treatment of SFTS. The inhibitory effect of T-705 (favipiravir) on the replication of SFTSV in Vero cells was evaluated. Mice lacking the type I interferon receptor (IFNAR(-/-)) were used as an in vivo lethal model for SFTSV infection. T-705, which has been licensed as an anti-influenza drug in Japan, inhibits SFTSV replication both in vitro and in vivo. T-705 inhibited replication of SFTSV in Vero cells by 5 log units, with a 50% inhibitory concentration (IC50) and IC90 of 6.0 µM and 22 µM, respectively. Intraperitoneal or oral administration of T-705 for 5 days to IFNAR(-/-) mice infected with lethal SFTSV significantly improved survival rates (100% survival) without causing body weight loss and reduced the viral load in the serum. Ribavirin also inhibited SFTSV replication. However, it was less effective than T-705 both in vitro and in vivo. A time-of-drug-addition study revealed that therapeutic T-705 treatment of SFTSV infection in IFNAR(-/-) mice was effective. These results suggest that T-705 is a promising candidate for the treatment of SFTS. IMPORTANCE Severe fever with thrombocytopenia syndrome (SFTS), caused by SFTS virus (SFTSV), is a recently identified emerging viral infectious disease. Despite the medical importance of this disease, there are currently neither vaccines nor effective therapeutics for SFTS. T-705, which is a pyrazine derivative, has shown broad antiviral activity against various RNA viruses. The present study demonstrated, for the first time to our knowledge, the efficacy of T-705 in treating SFTSV infection in a mouse lethal model. T-705 showed a high efficacy in the treatment of SFTSV infection in the mouse model, even when treatments were initiated after onset of the disease.
严重发热伴血小板减少综合征病毒（SFTSV）是严重发热伴血小板减少综合征（SFTS）这种新发出血热的病原体。该病病死率高，在中国、韩国和日本呈地方性流行。由于目前尚无针对SFTS的有效治疗方法，因此需要强效且安全的抗病毒药物来治疗SFTS。评估了T-705（法匹拉韦）对SFTSV在Vero细胞中复制的抑制作用。缺乏I型干扰素受体的小鼠（IFNAR(-/-)）被用作SFTSV感染的体内致死模型。T-705在日本已被批准作为抗流感药物，它在体外和体内均能抑制SFTSV复制。T-705在Vero细胞中对SFTSV复制的抑制作用达5个对数单位，其50%抑制浓度（IC50）和IC90分别为6.0 μM和22 μM。对感染致死剂量SFTSV的IFNAR(-/-)小鼠腹腔注射或口服T-705 5天，可显著提高存活率（100%存活），且不导致体重减轻，并降低血清中的病毒载量。利巴韦林也能抑制SFTSV复制。然而，其在体外和体内的效果均不如T-705。药物添加时间研究表明，对IFNAR(-/-)小鼠感染的SFTSV进行治疗性T-705治疗是有效的。这些结果表明，T-705是治疗SFTS的一个有前景的候选药物。重要性 由SFTS病毒（SFTSV）引起的严重发热伴血小板减少综合征（SFTS）是一种最近发现的新发病毒性传染病。尽管该疾病具有医学重要性，但目前尚无针对SFTS的疫苗或有效治疗方法。T-705是一种吡嗪衍生物，已显示出对多种RNA病毒具有广泛的抗病毒活性。据我们所知，本研究首次证明了T-705在小鼠致死模型中治疗SFTSV感染的疗效。即使在疾病发作后开始治疗，T-705在小鼠模型中治疗SFTSV感染也显示出高效性。
