Chisari F V, Ferrari C
Department of Molecular and Experimental Medicine, Scripps Research Institute, La Jolla, California 92037, USA.
Annu Rev Immunol. 1995;13:29-60. doi: 10.1146/annurev.iy.13.040195.000333.
Approximately 5% of the world population is infected by the hepatitis B virus (HBV) that causes a necroinflammatory liver disease of variable duration and severity. Chronically infected patients with active liver disease carry a high risk of developing cirrhosis and hepatocellular carcinoma. The immune response to HBV-encoded antigens is responsible both for viral clearance and for disease pathogenesis during this infection. While the humoral antibody response to viral envelope antigens contributes to the clearance of circulating virus particles, the cellular immune response to the envelope, nucleocapsid, and polymerase antigens eliminates infected cells. The class I- and class II-restricted T cell responses to the virus are vigorous, polyclonal, and multispecific in acutely infected patients who successfully clear the virus, and the responses are relatively weak and more narrowly focused in chronically infected patients who do not. The pathogenetic and antiviral potential of the cytotoxic T lymphocyte (CTL) response to HBV has been demonstrated by the induction of a severe necroinflammatory liver disease following the adoptive transfer of HBsAg-specific CTL into HBV transgenic mice, and by the noncytolytic suppression of viral gene expression and replication in the same animals by a posttranscriptional mechanism mediated by interferon gamma, tumor necrosis factor alpha, and interleukin 2. The dominant cause of viral persistence during HBV infection is the development of a weak antiviral immune response to the viral antigens. While neonatal tolerance probably plays an important role in viral persistence in patients infected at birth, the basis for poor responsiveness in adult-onset infection is not well understood and requires further analysis. Viral evasion by epitope inactivation and T cell receptor antagonism may contribute to the worsening of viral persistence in the setting of an ineffective immune response, as can the incomplete downregulation of viral gene expression and the infection of immunologically privileged tissues. Chronic liver cell injury and the attendant inflammatory and regenerative responses create the mutagenic and mitogenic stimuli for the development of DNA damage that can cause hepatocellular carcinoma. Elucidation of the immunological and virological basis for HBV persistence may yield immunotherapeutic and antiviral strategies to terminate chronic HBV infection and reduce the risk of its life-threatening sequellae.
全球约5%的人口感染了乙型肝炎病毒（HBV），该病毒可引发持续时间和严重程度各异的坏死性炎症性肝病。患有活动性肝病的慢性感染患者发生肝硬化和肝细胞癌的风险很高。在这种感染过程中，对HBV编码抗原的免疫反应既负责病毒清除，也参与疾病发病机制。虽然对病毒包膜抗原的体液抗体反应有助于清除循环中的病毒颗粒，但对包膜、核衣壳和聚合酶抗原的细胞免疫反应可清除被感染的细胞。在成功清除病毒的急性感染患者中，对该病毒的I类和II类限制性T细胞反应强烈、多克隆且具有多特异性，而在未成功清除病毒的慢性感染患者中，这些反应相对较弱且更为局限。将HBsAg特异性细胞毒性T淋巴细胞（CTL）过继转移到HBV转基因小鼠后，可诱发严重的坏死性炎症性肝病，以及通过干扰素γ、肿瘤坏死因子α和白细胞介素2介导的转录后机制对同一动物中的病毒基因表达和复制进行非细胞溶解性抑制，这都证明了CTL对HBV反应的致病和抗病毒潜力。HBV感染期间病毒持续存在的主要原因是对病毒抗原产生了较弱的抗病毒免疫反应。虽然新生儿免疫耐受可能在出生时感染的患者病毒持续存在中起重要作用，但成人期感染中反应不佳的原因尚不完全清楚，需要进一步分析。在免疫反应无效的情况下，表位失活和T细胞受体拮抗导致的病毒逃避可能会使病毒持续存在的情况恶化，病毒基因表达的不完全下调以及免疫特惠组织的感染也会如此。慢性肝细胞损伤以及随之而来的炎症和再生反应会产生诱变和促有丝分裂刺激，从而导致DNA损伤，进而引发肝细胞癌。阐明HBV持续存在的免疫学和病毒学基础可能会产生免疫治疗和抗病毒策略，以终止慢性HBV感染并降低其危及生命的后遗症风险。
