乙型肝治疗模式识别受体与agonists：现状和潜在的治疗方法

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http://www.sciencedirect.com/sci ... i/S0166354215001692

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6.1. TLR7 agonists

GS-9620, a potent and orally available TLR7 agonist, is the front runner of PRR agonists under development for treatment of chronic hepatitis B. Its great therapeutic potential has been demonstrated in preclinical studies in woodchucks infected with woodchuck hepatitis virus (WHV) and HBV-infected chimpanzees. Specifically, treatment of woodchucks chronically infected by WHV with varying dose frequencies of GS-9620 for 4–8 weeks resulted in a greater than 6 log reduction of viral load. Intriguingly, while 15 out of 19 animals had dramatic viral load reductions during treatment, the suppressive effect on viral load was sustained in 12 of these 15 animals, and 13 of the 15 sustained WHsAg loss after cessation of treatment. Moreover, for those with sustained WHsAg loss, 8 of 13 developed an antibody against the surface antigen (Menne et al., 2015). This result is in marked contrast to treatment with nucleoside analogs and IFN-α, which rarely resulted in WHsAg seroconversion (Fletcher et al., 2012 and Menne and Cote, 2007). Mechanism of action studies suggested that consistent with activation of TLR-7 signaling, the antiviral response induced by GS-9620 is likely mediated by both the cytolytic activity of CD8+ T cells and/or NK cells, and type I/II IFN-mediated non-cytolytic activity, as well as activation of B cells, in the liver microenvironment.

In a chimpanzee study, GS-9620 treatment of three HBV chronically infected animals for 8 weeks also reduced viral load by more than 2 logs and resulted in greater than a 50% reduction in HBsAg and HBeAg serum levels. While reduction of viral load by 1 log persisted, no HBsAg seroconversion occurred in any of the treated animals (Lanford et al., 2013). Although IFN-α was transiently induced, the suppression of HBV/HBsAg coincided with NK/T cell activation. Hence, it is most likely that the TLR-7 therapeutic effect relies on not only induction of IFNs, but also activation of other branches of intrahepatic innate immune responses.

Pharmacokinetic and pharmacodynamic studies in healthy volunteers suggested that at low oral doses, GS-9620 induces a type I interferon-dependent antiviral innate immune response without the induction of systemic IFN-α. This presystemic response is likely due to its high intestinal absorption and activation of TLR7 locally via oral administration ( Fosdick et al., 2014). In two phase 1b studies reported recently, one or two low doses of GS-9620 administered once a week were safe and well tolerated ( Gane et al., 2015). However, phase 1 studies did not show evidence of clinical efficacy of GS-9620 in terms of HBV DNA decline, HBsAg reduction ( Gane et al., 2015) or decrease in HCV RNA ( Lawitz et al., 2014). Further clinical investigations are certainly warranted to optimize the dosage and treatment schedules.

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6.1。TLR7受体激动剂
GS - 9620，一个强有力的和口服TLR7激动剂，是领跑者，PRR激动剂下发展为慢性乙型肝炎的治疗潜力的伟大的治疗已感染土拨鼠肝炎病毒（WHV旱獭在临床前研究表明，HBV感染的黑猩猩）。具体来说，土拨鼠慢性感染WHV的GS - 9620不同剂量频率为4–8周治疗后，一个大于6的数减少病毒载量。有趣的是，在15的19种动物有戏剧性的病毒负荷降低在治疗过程中，病毒载量的抑制作用在12和13这15个动物持续，持续亏损的15表面停止治疗后。此外，对于那些遭受损失的8表面，13开发了一个表面抗原抗体（Menne等人。，2015）。这一结果是与核苷类似物和干扰素-α处理形成了鲜明的对比，而很少导致WHsAg血清转换（弗莱彻等人。，2012、门内和科，2007）。作用机制研究表明，活化TLR-7信号一致，诱导的GS - 9620抗病毒反应可能是由双方的杀伤活性的CD8 + T细胞和NK细胞，和I / II型干扰素介导的细胞毒活性，以及活化的B细胞，在肝脏微环境
在黑猩猩的研究中，8周三例HBV慢性感染的动物的GS - 9620治疗也降低病毒载量超过2日志和导致在大于HBsAg和HBeAg的血清水平降低50%。而由1日志持续降低病毒载量，无HBsAg血清学转换发生在任何治疗的动物（兰福德等人。，2013）。虽然干扰素α瞬时诱导HBV或HBsAg的抑制，同时NK／T细胞活化。因此，最有可能的是，TLR-7治疗效果不仅依赖于诱导干扰素，同时激活肝内天然免疫反应的其他分支
在健康志愿者的药代动力学和药效学的研究表明，在低剂量口服，GS - 9620诱导I型干扰素的抗病毒天然免疫反应不依赖性IFN-γ诱导α。这首过效应的反应可能是由于其较高的肠吸收和激活TLR7在当地通过口服（福斯迪克等人。，2014）。在两阶段1b研究最近报道说，一个或两个低剂量的GS - 9620每周一次给药的安全性和耐受性进行（Gane等人。，2015）。然而，1阶段的研究并没有显示出对HBV DNA下降的GS - 9620临床疗效的证据，HBsAg下降（Gane等人。，2015）或降低HCV RNA（Lawitz等人。，2014）。进一步的临床调查肯定是必要的，以优化剂量和治疗计划    （吉利德继续临床）

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abus研发的

6.5. STING agonists

Stimulator of interferon genes (STING) is the adaptor protein of multiple cytoplasmic DNA receptors and a PRR recognizing the bacterial second messengers, cyclic di-adenosine monophosphate (c-di-AMP) and cyclic di-guanosine monophosphate (c-di-GMP) (Burdette and Vance, 2013). It was discovered recently that cytoplasmic DNA activates cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) to produce cGAMP, which subsequently binds to STING and induces IFNs and other cytokines (Gao et al., 2013 and Ishikawa and Barber, 2008). The fact that STING can be activated by cyclic di-nucleotides implies that like TLR7 and TLR8, STING might be activated by other small molecules and thus be a potential target for pharmacological activation of innate immune responses, as well as priming of an adaptive immune response.

Indeed, we recently showed that 5,6-dimethylxanthenone-4-acetic acid (DMXAA), a mouse STING agonist, induced a type I-IFN-dominant cytokine response in macrophages, which potently suppressed HBV replication in mouse hepatocytes by reducing the amount of cytoplasmic viral nucleocapsids. Moreover, intraperitoneal administration of DMXAA significantly induced the expression of IFN-stimulated genes and reduced HBV DNA replication intermediates in the livers of HBV-hydrodynamically injected mice. Our study thus provides proof of concept that activation of the STING pathway induces a potent innate antiviral response, and that the development of small-molecule human STING agonists as immunotherapeutic agents for the treatment of chronic hepatitis B is warranted (Guo et al., 2015).

Many PRR agonists have thus far been tested in animal models or in clinical studies for their effects on chronic viral infections of the liver, including hepatitis B. Although promising results have been obtained, the search for the proper agonists that fine-tune host immune responses and cure chronic HBV infection is still under way. In addition, there are many studies reporting HBV evasion and antagonization of innate immune pathways under certain experimental conditions (reviewed in (Chang et al., 2012)). Further investigation is required to re-examine such phenomena in the context of viral replication and in human hepatocytes during natural infection. If confirmed, pharmacological interruption of HBV antagonism of host innate immune responses should be an ideal therapeutic strategy to restore innate, and possibly also adaptive immunity to HBV infection

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该研发的6.5。刺agonistsstimulator干扰素基因（刺）是多胞质DNA受体和PRR识别细菌第二信使的接头蛋白，环状二磷酸腺苷（C-DI-AMP）和环状二磷酸鸟苷（c-di-GMP）（伯德特和万斯，2013）。最近发现，细胞质DNA激活环磷酸鸟苷一磷酸腺苷合成酶（注册会计师）产生cgamp，随后结合刺激和诱导干扰素和其他细胞因子（Gao等人。，2013石川和理发师，2008）。事实上，刺可以通过环状二核苷酸激活意味着像TLR7和TLR8，刺可能被其他的小分子，因此是先天免疫反应的药理活性的潜在目标，以及启动适应性免疫应答。事实上，我们最近发现，乙酸（DMXAA），鼠标刺激动剂，诱导型i-ifn-dominant细胞因子反应的巨噬细胞，它能有效抑制HBV复制的小鼠肝细胞的细胞质的核衣壳的量减少。此外，腹腔注射DMXAA显著诱导干扰素刺激基因的表达，降低HBV DNA复制中间体HBV肝液注入小鼠。我们的研究概念，刺痛通路激活诱导有效的先天抗病毒反应提供了证据，而小分子人刺激动剂发展为治疗慢性乙型肝炎的免疫治疗剂是必要的（郭等人。，2015）。许多PRR激动剂迄今已在动物模型试验或临床研究对肝脏慢性病毒感染的影响，包括乙型肝炎，虽然已取得了可喜的成果，为调整宿主的免疫反应和慢性HBV感染仍在搜索适当的激动剂。此外，有许多研究在一定的实验条件下，乙肝病毒逃避先天免疫途径的拮抗报告（审查（Chang等人。，2012））。需要进一步调查，重新审视这种现象在自然感染的背景下，病毒复制和人类肝细胞。如果证实，药物阻断宿主先天免疫反应的乙肝病毒拮抗剂，应是一种理想的治疗策略，以恢复先天的，也可能是适应性免疫的乙肝病毒感染