GS-9620, an oral agonist of Toll-like receptor-7, induces prolonged suppression of hepatitis B virus in chronically infected chimpanzees.
GS-9620, an oral agonist of Toll-like receptor-7, induces prolonged suppression of hepatitis B virus in chronically infected chimpanzees.
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GS-9620是Toll样受体-7的口服激动剂，可长期抑制慢性感染的黑猩猩的丙型肝炎病毒。
DOI：
10.1053/j.gastro.2013.02.003
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发表时间：
2013-06
期刊：
影响因子：
29.4
通讯作者：
Tumas DB
中科院分区：
文献类型：
--
作者：
Lanford RE;Guerra B;Chavez D;Giavedoni L;Hodara VL;Brasky KM;Fosdick A;Frey CR;Zheng J;Wolfgang G;Halcomb RL;Tumas DB
直接作用的抗病毒药物抑制乙型肝炎病毒（HBV）载量，但必须给予终身。刺激先天免疫系统可以增强其控制病毒的能力，并在有限的治疗后产生持久的效果。我们研究了gs -9620（一种有效的、选择性的口服活性toll样受体（TLR）7的小分子激动剂）对慢性HBV感染黑猩猩的免疫激活作用。GS-9620每隔一天（每周3次）给黑猩猩1 mg/kg剂量，连续4周，休息1周后，连续4周以2 mg/kg剂量给药。我们测量了血浆和肝脏样本中的病毒载量、GS-9620的药代动力学以及以下药效学参数：干扰素（IFN）刺激的基因表达、细胞因子和趋化因子水平、淋巴细胞和自然杀伤细胞活化以及病毒抗原表达。监测临床病理参数以确定GS-9620的安全性和耐受性。短期口服GS-9620可长期抑制血清和肝脏HBV DNA。GS-9620给药结束后1周内，病毒DNA的平均最大减少量为2.2 log；减少量大于1个log的情况持续数月。随着肝细胞凋亡的增加，血清HB表面抗原和HB e抗原水平以及HBV抗原阳性的肝细胞数量减少。GS-9620诱导IFN-α和其他细胞因子和趋化因子的产生，激活isg、自然杀伤细胞和淋巴细胞亚群。小分子GS-9620激活黑猩猩免疫细胞中的TLR-7信号，诱导hbv感染细胞的清除。该试剂可用于慢性HBV感染患者的治疗。
Direct-acting anti-viral agents suppress hepatitis B virus (HBV) load but must be given lifelong. Stimulation of the innate immune system could increase its ability to control the virus and have long lasting effects, after a finite regimen. We investigated the effects of immune activation with GS-9620—a potent and selective orally active small molecule agonist of Toll-Like Receptor (TLR)7—in chimpanzees with chronic HBV infection. GS-9620 was administered to chimpanzees every other day (3 times each week) for 4 weeks at 1 mg/kg and, after a 1 week rest, for 4 weeks at 2 mg/kg. We measured viral load in plasma and liver samples, the pharmacokinetics of GS-9620, and the following pharmacodynamics parameters: interferon (IFN)-stimulated gene expression, cytokine and chemokine levels, lymphocyte and natural killer cell activation, and viral antigen expression. Clinical pathology parameters were monitored to determine the safety and tolerability of GS-9620. Short-term oral administration of GS-9620 provided long-term suppression of serum and liver HBV DNA. The mean maximum reduction of viral DNA was 2.2 logs, which occurred within 1 week of the end of GS-9620 administration; reductions of greater than 1 log persisted for months. Serum levels of HB surface antigen and HB e antigen, and numbers of HBV antigen-positive hepatocytes, were reduced as hepatocyte apoptosis increased. GS-9620 administration induced production of IFN-α and other cytokines and chemokines, and activated ISGs, natural killer cells, and lymphocyte subsets. The small molecule GS-9620 activates TLR-7 signaling in immune cells of chimpanzees to induce clearance of HBV-infected cells. This reagent might be developed for treatment of patients with chronic HBV infection.
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