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