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介绍Worldwide,two billion people have been infected with the hepatitis B virus (HBV) at sometime, more than 370 million currently have chronic HBV infection, and about one milliondie each year from HBV-related liver disease. HBV is a non cytopathic virus,and the hostimmune response determines whether the virus is cleared or whether immunopathyand liverdamage are induced. Persistent inflammation during chronic HBV infectionresults in livercirrhosis or hepatocellular carcinoma in 25% of patients. HBV is currently thesecond leadingcarcinogen after tobacco, with up to 80% of hepatocellular carcinoma cases worldwideattributable to HBV [1]. Individuals with chronic HBV infection also serve asthe primaryreservoir for viral spread. Preventive vaccination is the most effective way toreduce theglobal incidence of hepatitis. Efficient vaccines against hepatitis B have beenavailable for over20 years, and their use should decrease the incidence of HBV infection [2]. Bycontrast, thetreatment of chronic HBV infection is based on the use of antiviral agents.These agents haveimproved considerably over the last 10 years, with the development of molecules targetingthe HBV polymerase and decreasing viral replication. The major goals ofanti-HBV treatmentare to prevent the development of progressive disease, specifically cirrhosis,liver failureand hepatocellular carcinoma. However, although currently available antiviraldrugs efficientlydecrease serum viral load to undetectable levels, they fail to eradicateinfection due tothe persistence of HBV covalently closed circular DNA (cccDNA) in hepatocytesand the emergenceof resistant viruses [3, 4]. In addition, such drugs rarely result in thelong-term immunologicalcontrol of HBV infection through the elimination of residual infected hepatocytes,hepatitis B “e” antigen (HBeAg) seroconversion and/or hepatitis B surface antigen(HBsAg) clearance. Moreover, long-term treatment is expensive and may result in problems of toxicity andintolerance. 全世界,有2亿人被乙型肝炎病毒感染,超过370百万目前受到慢性乙肝感染,每年有100万死于HBV相关的肝部疾病。 HBV是一个不引起细胞病变的病毒,体内的免疫反应来确定病毒是否清楚或者是免疫性疾病和导致肝脏损伤。
在慢性感染者中,由于持续的炎症导致25%的患者转向肝纤维化或者是肝细胞癌化。HBV病毒是仅次于烟草的 第二大致癌因素,全世界超过80%的肝癌是由于HBV引起【1】。慢性乙肝病毒感染者是乙肝病毒传播的主要来 源预防性的疫苗接种是最有效的降低全球乙肝发生率方式。针对乙肝的有效的疫苗已经出现了20年,疫苗的广泛使 用降低了HBV的感染【2】。另一方面,治疗慢性乙肝感染主要基于抗病毒的药物,过去的10年,这些药剂有了很大 的改进,针对DNA聚合酶的分子有效的降低了病毒的复制,抗-HBV的主要治疗是为了阻止病情的持续发展, 尤其是肝硬化,肝衰竭和肝癌。但是,尽管现有的药物可以将血清中的病毒含量下降到检测范围以下,他们却不能 完全清除HBV,因为在肝细胞中有cccDNA的存在和耐药病毒的出现【3,4】。此外,这些药物很少能够达到长期的 通过清楚残余的感染肝细胞来免疫控制HBV的感染,比如说HbeAg血清转换或者是HbsAg的清除。更多的是,长期的 服药是昂贵的并且可能导致药物毒性和耐受问题(intolerance)。 Boththe adaptive and innate immune responses are known to be involved in viral clearanceduring HBV infection [5]. There is a clear dichotomy in the profile of theimmune responsesobserved, depending on whether patients naturally resolve viral infection or developchronic infection. Patients with self-limited acute hepatitis B displaymulti-specific CD4and CD8 T-cell responses, with the secretion of antiviral cytokines and theproduction of anti-HBVantibodies. By contrast, patients suffering from chronic infection have veryweak or functionallyimpaired immune responses. Therapeutic vaccination has been proposed as a potentiallypromising strategy for controlling viral infection, based on these observations. Therapeuticvaccination aims to eliminate persistent viral infection, by stimulating the patient’simmune responses. 我们知道在HBV感染中,先天和后天适应性(adaptive)的免疫反应参与到了病毒的清除中【5】。
在免疫响应中可以发现两种清晰的不同的信息(profile),取决于病人是否自发的清除病毒感染或者是发展成慢性感染。 患者带有自限制(self-limited:指不通过药物治疗,体内自己治愈)自治愈的急性感染显示多重特异性的CD4和CD8 T细胞响应,有分泌抗病毒的细胞 因子和产生抗病毒的抗体。相反,慢性感染患者有非常弱的或者功能损坏的免疫响应。基于以上这些观察,治疗 性疫苗刚开始被认为是非常有潜力的用于控制病毒的感染的治疗方案。治疗性疫苗瞄准的是通过激发病人的免疫 反应来清除长期持续的病毒感染。(ps:self-limited:不经治疗自己可以治愈的) In this review, we firstoutline the characteristics of cell-mediated immune responses andthe immunosuppressive environment generated during chronic HBV infection. Wethen describecurrent and future approaches for manipulation of the immune system to achieve sustainedcontrol of this persistent infection. 在这篇综述中,我们首先描述由细胞调节的免疫响应的特点和由慢性乙肝感染导致的免疫耐受
or免疫抑制?(immunosuppressive)环境。我们然后将描述当前和将来有哪些途径可以用来通过 调节免疫系统来达到持续的控制这个顽固的感染。 |