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标题: 通过细胞因子控制乙型肝炎病毒 [打印本页]

作者: StephenW    时间: 2017-2-22 21:48     标题: 通过细胞因子控制乙型肝炎病毒

          Viruses      2017,      9(1),      18;      doi:10.3390/v9010018   
  
      Review  
  Control of Hepatitis B Virus by Cytokines
       Yuchen Xia 1         and    Ulrike Protzer 2,3,*           
            1   
    Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA
  
            2   
    Institute of Virology, Technische Universität München/Helmholtz Zentrum München, Munich 81675, Germany
  
            3   
    German Center for Infection Research (DZIF), Munich Partner Site, Munich 81675, Germany
  

                    *      
      Correspondence: Tel: +49-89-41406821
   
  
        Academic Editor:      Eric O. Freed        
      Received: 17 November 2016 / Accepted: 13 January 2017 / Published: 20 January 2017  
        Abstract:      Hepatitis B virus (HBV) infection remains a major public health problem worldwide with more than 240 million individuals chronically infected. Current treatments can control HBV replication to a large extent, but cannot eliminate HBV infection. Cytokines have been shown to control HBV replication and contribute to HBV cure in different models. Cytokines play an important role in limiting acute HBV infection in patients and mediate a non-cytolytic clearance of the virus. In this review, we summarize the effects of cytokines and cytokine-induced cellular signaling pathways on different steps of the HBV life cycle, and discuss possible strategies that may contribute to the eradication of HBV through innate immune activation.
        Keywords:
    hepatitis B virus (HBV); cytokine; interferon; interferon-induced gene (ISG); cccDNA; therapy
  

作者: StephenW    时间: 2017-2-22 21:49

病毒2017,9(1),18; doi:10.3390 / v9010018
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通过细胞因子控制乙型肝炎病毒
Yuchen Xia 1和Ulrike Protzer 2,3,
1
Liver Diseases Branch,National Institute of Diabetes and Digestive and Kidney Diseases,National Institutes of Health,Bethesda,MD 20892,USA
2
Institute of Virology,TechnischeUniversitätMünchen/ Helmholtz ZentrumMünchen,Munich 81675,Germany
3
德国感染研究中心(DZIF),慕尼黑合作伙伴网站,慕尼黑81675,德国
*:
通讯:电话:+ 49-89-41406821
学术编辑:Eric O. Freed
收到:2016年11月17日/接受日期:2017年1月13日/发布时间:2017年1月20日
摘要:乙型肝炎病毒(HBV)感染仍然是全球主要的公共卫生问题,超过2.4亿人慢性感染。目前的治疗可以在很大程度上控制HBV复制,但不能消除HBV感染。已显示细胞因子控制HBV复制并在不同模型中促进HBV治愈。细胞因子在限制患者的急性HBV感染和介导病毒的非细胞溶解清除中起重要作用。在本综述中,我们总结细胞因子和细胞因子诱导的细胞信号通路对HBV生命周期的不同步骤的影响,并讨论可能有助于通过先天免疫激活根除HBV的可能策略。
关键词:
乙型肝炎病毒(HBV);细胞因子;干扰素干扰素诱导基因(ISG); cccDNA;治疗
作者: StephenW    时间: 2017-2-22 21:51

10. Summary and Prospective
A complete cure of hepatitis B can, in theory, be achieved by elimination of viral infection via inhibition of the viral replication intermediate, a complete decay of cccDNA, and a total blockade of reinfection. Current therapeutic goal of chronic hepatitis B is a functional cure of HBV infection comprising HBsAg loss, anti-HB seroconversion, and inactivation of cccDNA, but it is rarely achieved with treatments currently available [63]. Cytokines are believed to be involved in the non-cytolytic clearance of HBV during acute infection and during T-cell-mediated virus control, and their antiviral effects are approved in a variety of experimental models.
As summarized in Table 1, different IFNs and proinflammatory cytokines show antiviral effects on HBV. Although some of the mechanisms have not been tested in primary human liver tissue or HBV-infected primary human hepatocytes, the cytokine-mediated antiviral effects are multifunctional and target several key steps of viral replication. In this respect, cytokine-based therapies could provide interesting approaches to achieve a functional cure or even the eradication of virus infection if the side effects can be managed.
Table
Table 1. Control of hepatitis B virus (HBV) by cytokines.
One option is to improve IFN-α treatment. It is well accepted that, although binding to the same receptors, different IFN-α subtypes mediate different biological functions and display distinct antiviral activities [64]. Interferon-α2b has been used to treat hepatitis B for more than 25 years [65]. However, it may not be the most potent IFN-α subtype [66]. Antiviral and side effects of other IFN-α subtypes on HBV infection should be further studied. The low response rates and significant side effects of IFN-α treatment may be overcome by a higher local concentration in the liver. PEGylation has been developed to counter this problem via extending the half-life of IFN-α and has been widely used in several clinical applications [67]. However, the high cost of in vitro chemical coupling, accumulating evidence on the immunogenicity of PEG and lacking biodegradability of the unnatural PEG polymer, which can lead to renal tubular vacuolation hamper its application [68,69]. Recently, a novel, longer acting IFN-α was generated via PASylation technology [70]. PASylated IFN-α showed strong receptor binding affinity without inducing an observable immunogenic footprint [71]. More importantly, PASylated IFN-α demonstrated superior efficacy against HBV replication in HBV transgenetic mice than IFN-α [72].
Besides IFN-α, other IFNs may also consider as potential treatments for HBV infection. IFN-β, which is used to treat multiple sclerosis, has been considered as an alternative. The efficacy of IFN-β for HCV infection has been extensively investigated [73,74,75]. These studies not only proved the efficacy of IFN-β as an HCV therapy, but also showed promising results in patients who had poor responses to IFN-α2b/ribavirin treatment. The effect of IFN-β on chronic hepatitis B needs to be investigated.
Wu et al. showed that HBsAg-positive patients with stage 2–4 hepatic fibrosis achieved a significantly improved fibrotic score after nine months of IFN-γ treatment [76]. However, the majority of patients did not show a long-term benefit. Restricted expression of IFN-λ receptors is expected to positively impact on the toxicity profile of IFN-λ [77]. A Phase IIb clinical trial of PEG-IFN-λ on chronic hepatitis C patients showed good response rates and tolerability [78]. This result should encourage clinical trials in chronic hepatitis B patients.
Activation of cytokine in the liver is another option for hepatitis B treatment. Small molecule toll-like receptor (TLR) agonists have been developed for this purpose. Promising results were obtained with TLR-7 agonists, GS-9620, that is able to induce IFNs and ISGs, in woodchucks and chimpanzees. In woodchucks, an oral application of GS-9620 leads to sustained viral load reduction, induced anti-HBs seroconversion, and a reduced incidence of hepatocellular carcinoma [79]. In chimpanzees, short-term oral administration of GS-9620 provided long-term suppression of serum and liver HBV DNA, and low doses were well-tolerated in chronic hepatitis B patients [80,81]. Its therapeutic effect, however, cannot be hepatocyte- or liver-specific due to TLR-7 expression profiles, and further clinical trials are needed to judge the suitability of TLR-7 agonists as hepatitis B therapeutics.
The concept of immunomodulation through therapeutic innate immune activation has a substantial amount of experimental evidence. Translating the experimental results into effective novel therapies that minimize potential side effects could promote both the cytokine-mediated innate immune control of viral infection as well as restoration of adaptive immunity. In combination with other therapeutics, immune therapy may contribute to the eradication of HBV.
As elaborated above, T-cell-derived cytokines have distinct antiviral potential. They contribute to HBV control and elimination in a non-cytolytic fashion, which, in addition to the cytotoxic effect of T-cells, results in the deprivation of HBV infection [9]. Thus, the adoptive transfer of T-cells is a promising option for hepatitis B treatment [82,83,84]. Qasim et al. reported an adoptive transfer of engineered lymphocytes into a patient who had undergone liver transplantation for HBV-related HCC and carried tumor cells expressing HBsAg, which can be recognized by T-cells expressing an HBV-specific T-cell receptor [85]. They demonstrated that gene-modified T-cells survived in vivo, expanded, and mediated a reduction in HBsAg levels without exacerbation of liver inflammation or other toxicity [85]. This encourages the development of therapies restoring T-cell responses in chronic hepatitis B by therapeutic vaccination, adoptive T-cell transfer, redirection of T-cells, or the use of checkpoint inhibitors.
Acknowledgments
Work in the authors’ laboratory was funded by the German Research Foundation (DFG) via TRR 36 and TRR179, the EU via the HepCar consortium within Horizon 2020, the Helmholtz Association via the iMed Initiative, the Helmholtz Validation Fund, and the Helmholtz-Alberta Initiative, Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health. Yuchen Xia is partly sponsored by the ILCA-Bayer fellowship.
Conflicts of Interest
The authors declare no conflict of interest.
作者: StephenW    时间: 2017-2-22 21:53

10.总结和展望
理论上,乙型肝炎的完全治愈可以通过抑制病毒复制中间体来消除病毒感染,cccDNA完全衰减以及完全阻断再感染来实现。慢性乙型肝炎的目前治疗目标是包括HBsAg缺失,抗HB血清转化和cccDNA失活的HBV感染的功能性治愈,但是目前可用的治疗很少实现[63]。认为细胞因子涉及在急性感染期间和在T细胞介导的病毒控制期间的HBV的非细胞溶解清除,并且它们的抗病毒效果在各种实验模型中被批准。
如表1中总结的,不同的IFN和促炎细胞因子显示对HBV的抗病毒作用。虽然一些机制尚未在原发性人肝组织或HBV感染的原发性人类肝细胞中测试,但细胞因子介导的抗病毒效应是多功能的并且靶向病毒复制的几个关键步骤。在这方面,基于细胞因子的疗法可以提供有趣的方法来实现功能性治愈,甚至根除病毒感染,如果可以管理副作用。

表1.细胞因子对乙型肝炎病毒(HBV)的控制。
一个选择是改善IFN-α治疗。众所周知,尽管结合相同的受体,不同的IFN-α亚型介导不同的生物学功能并显示不同的抗病毒活性[64]。干扰素-α2b已被用于治疗乙型肝炎25年以上[65]。然而,它可能不是最强的IFN-α亚型[66]。应进一步研究其他IFN-α亚型对HBV感染的抗病毒和副作用。 IFN-α治疗的低反应率和显着副作用可以通过在肝脏中更高的局部浓度来克服。已经开发了PEG化以通过延长IFN-α的半衰期来解决这个问题,并且已经广泛用于几种临床应用中[67]。然而,体外化学偶联的高成本,聚集PEG的免疫原性的证据和缺乏非天然PEG聚合物的生物降解性,这可导致肾小管空泡形成妨碍其应用[68,69]。最近,通过PASylation技术产生了一种新的,更长时间作用的IFN-α[70]。 PAS化的IFN-α显示出强的受体结合亲和力,而不诱导可观察到的免疫原性足迹[71]。更重要的是,PAS化IFN-α在HBV转基因小鼠中表现出优于IFN-α的HBV复制的功效[72]。
除了IFN-α,其他IFN也可以考虑作为HBV感染的潜在治疗。用于治疗多发性硬化的IFN-β已被认为是一种选择。 IFN-β对HCV感染的功效已被广泛研究[73,74,75]。这些研究不仅证明了IFN-β作为HCV治疗的功效,而且在对IFN-α2b/利巴韦林治疗反应较差的患者中也显示出有希望的结果。需要研究IFN-β对慢性乙型肝炎的影响。
Wu et al。显示HBsAg阳性患者2-4期肝纤维化在9个月的IFN-γ治疗后达到明显改善的纤维化评分[76]。然而,大多数患者没有表现出长期的益处。预期IFN-λ受体的限制性表达对IFN-λ的毒性特征产生积极影响[77]。 PEG-IFN-λ对慢性丙型肝炎患者的IIb期临床试验显示出良好的反应率和耐受性[78]。该结果应鼓励慢性乙型肝炎患者的临床试验。
肝中细胞因子的激活是乙型肝炎治疗的另一个选择。为此目的已经开发了小分子toll样受体(TLR)激动剂。在土拨鼠和黑猩猩中使用能够诱导IFN和ISG的TLR-7激动剂GS-9620获得了令人满意的结果。在土拨鼠中,GS-9620的口服应用导致持续的病毒载量减少,诱导的抗HBs血清转化和减少肝细胞癌的发生率[79]。在黑猩猩中,GS-9620的短期口服给药提供了血清和肝脏HBV DNA的长期抑制,低剂量在慢性乙型肝炎患者中耐受性良好[80,81]。然而,由于TLR-7表达谱,其治疗效果不能是肝细胞或肝脏特异性的,并且需要进一步的临床试验来判断TLR-7激动剂作为乙型肝炎治疗剂的适合性。
通过治疗先天免疫激活的免疫调节的概念具有大量的实验证据。将实验结果转化为使潜在副作用最小化的有效的新疗法可以促进细胞因子介导的病毒感染的先天免疫控制以及适应性免疫的恢复。与其他治疗剂组合,免疫治疗可有助于根除HBV。
如上所述,T细胞来源的细胞因子具有不同的抗病毒潜力。它们以非细胞溶解的方式促进HBV的控制和消除,除了T细胞的细胞毒性作用外,还导致HBV感染的缺乏[9]。因此,T细胞的过继转移是乙型肝炎治疗的一个有希望的选择[82,83,84]。 Qasim等人报道了将工程淋巴细胞过继转移到已经接受HBV相关HCC的肝移植的患者中,并携带表达HBsAg的肿瘤细胞,其可以被表达HBV特异性T细胞受体的T细胞识别[85]。他们证明基因修饰的T细胞在体内存活,扩增和介导HBsAg水平的降低而没有肝脏炎症或其他毒性的加重[85]。这促进了通过治疗性疫苗接种,过继性T细胞转移,T细胞重定向或检查点抑制剂的使用来恢复慢性乙型肝炎中T细胞应答的疗法的开发。
致谢
作者实验室的工作由德国研究基金会(DFG)通过TRR 36和TRR179,欧盟通过地平线2020中的HepCar联盟,亥姆霍兹协会通过iMe​​d倡议,亥姆霍兹验证基金和亥姆霍兹 - 阿尔伯塔倡议,国立糖尿病和消化和肾脏疾病研究所,国立卫生研究院的校内研究计划。 Yuchen Xia部分由ILCA-Bayer奖学金赞助。
利益冲突
作者宣称没有利益冲突。
作者: StephenW    时间: 2017-2-22 21:53

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