编者按：Gyongyi Szabo博士，美国马萨诸塞大学医学院教授、AASLD2015主席。“第三届中国国际肝病论坛”召开期间，Szabo教授进行了题为“天然免疫和慢性丙型肝炎治疗启示”的主题演讲，并于会后就相关问题接受了《国际肝病》的采访。
《国际肝病》：天然免疫在慢性HCV感染中发挥什么样的作用？
Gyongyi Szabo教授：与其他病毒感染相似，免疫在HCV感染中的作用十分重要。作为宿主对抗感染的首要防线，如果天然免疫应答不够及时有效，其功能随后会被削弱从而导致慢性感染。在针对的HCV感染天然免疫中，关键步骤是产生包括Ⅰ型干扰素（IFN）在内的多种IFN，而且诱导产生IFN对于早期清除病毒是十分重要的。因此，天然免疫启动并诱导出强大多样的适应性免疫力是HCV感染清除的关键。
Prof. Szabo: The rule of the immunity in hep C infection is very important just like in any viral infection. In it that immunity is the first line of defense in the host immunity and if the innate immune response is not robust enough and does not start early enough then that itself can offset and lead to chronic infection. In case of innate immunity in hepatitis C infection, the induction of various interferons is a key step and that includes the type 1 interferons and also the induction of interferon that turns out is important in the early viral elimination and then of course the role of the innate immunities to trigger and induce a varied robust and adaptive immunity that is key in hep c viral elimination.
《国际肝病》：有什么血清学指标可以反映慢性HCV感染患者的先天免疫功能?
Gyongyi Szabo教授：现有多种反映天然免疫的血清学标志物，特别是多种循环性细胞因子及IFN。细胞因子方面，HCV感染患者血清中，多类促炎症因子（特别是TNF、IL-1）和一些趋化因子水平增高。但是这些因子与慢性感染并存，且参与诱导了肝脏的慢性轻度炎症。在部分患者中，低水平血清IFN-γ能够与慢性感染并存，但是其作为血清学指标反映天然免疫功能的可靠度较低。
Prof. Szabo: Yes, there are multiple serum markers for innate immunity particularly various circulating cytokines and interferons. In the case of cytokines it has been shown that in hep c virus infection some of the pro inflammatory cytokines, in particular TNF and IL-1, and some of the chemokines are actually increased in the serum but that goes along with the chronic infection and inducing a chronic low grade inflammation. In these patients the levels of serum interferons is less reliable although it is known that low levels of interferon gamma can go along with chronic infection.
《国际肝病》：对于以宿主为靶向的药物在丙型肝炎治疗中的作用，尤其是可以增强天然免疫功能的药物，您持什么样的观点？
Gyongyi Szabo教授：因为一些机制的干扰，HCV可逃避宿主免疫应答，所以直接抗病毒药物的出现是临床上非常重要且令人激动的发现。例如，血清蛋白酶抑制剂目前与病毒存在特异性干扰，并防止病毒血清蛋白酶抑制剂裂解某些宿主中诱导Ⅰ型IFN的适配分子。通过这种相互干扰的重要机制，HCV的NS3激活及一些直接抗病毒药物能够使宿主免疫应答十分有效运作。同样通过相互干扰机制，一些可降低病毒复制的NS5A、NS5B及NS3抑制剂能够启动宿主的天然抗病毒免疫应答。
Prof. Szabo: I think that the fascinating and the clinically important discovery was the direct acting antivirals because those interfere with some of the mechanism by which hepatitis c undermines the host immune response. For example, the serum protease inhibitors in particular interfere now with the virus and prevent the virus serum protease inhibitors to cleave off some of the adaptor molecules that are involved in type 1 interferon induction in the host. That is a very important mechanism and by interfering with this, NS3 activity of the hepatitis C virus and some of the direct acting antivirals can allow the host immune response to actually work very effectively and similarly too for some of the NS5A, NS5B, and NS3 inhibitors that reduce viral replication and therefore enable innate immune response to trigger the host antiviral immunity.
《国际肝病》：有哪些增强天然免疫功能的药物在进行临床试验？
Gyongyi Szabo教授：通过使宿主免疫应答有效激活的相同途径，所有的直接抗病毒药物都直接改善宿主免疫应答。另外，正在进行microRNA-122抑制剂的临床试验，尽管microRNA-122并不通过天然免疫应答途径影响宿主，但它是肝细胞中促进及保证HCV复制的重要宿主因素。
Prof. Szabo: So certainly all the direct acting antivirals could directly improve host immune responses the same way as I alluded to earlier today by permitting the host immune response to act effectively. Another component that is not necessarily innate immunity but affecting host factors is the clinical trial with the micron A1 22 inhibitor considering that micron a1 22 is a host factor in the hepatocytes that promotes and is required for hep c viral replication.
《国际肝病》：随着将来DAA和其他有效药物可及性的提高，我们可以期待有机会在全球范围内消灭HCV吗？
Gyongyi Szabo教授：所有临床肝病学者都希望新的DAAs及这些药物的联合应用能够治愈所有慢性HCV感染者，这也是最终目标。能够在世界范围内清除HCV感染是十分吸引人的目标！
Prof. Szabo: Well I think all of us in clinical hepatology hope that the new DAAs and combinations of these drugs will allow us to treat all patients who have chronic hep C v infection and I think it is a lofty goal but certainly it is a very enticing goal to eradicate hep C v around the world.