Locarnini Stephen, Zoulim Fabien
Victorian Infectious Diseases Reference Laboratory, North Melbourne, Victoria, Australia.
Antivir Ther. 2010;15 Suppl 3:3-14. doi: 10.3851/IMP1619.
HBV has evolved a unique life cycle that results in the production of enormous viral loads during active replication without actually killing the infected cells directly. Two of the key events in the viral life cycle of HBV involve firstly the generation of a covalently closed circular (ccc)DNA transcriptional template, either from input genomic DNA or newly replicated capsid-associated DNA, and secondly, reverse transcription of the viral pregenomic (pg)RNA to form progeny HBV DNA genomes. New data are emerging regarding the epigenetic control of cccDNA, which might represent another key factor involved in the pathogenesis and natural history of the disease. Because HBV uses reverse transcription to copy its genome, mutant viral genomes emerge frequently. Particular selection pressures, both endogenous (host immune clearance) and exogenous (vaccines and antiviral drugs), readily select out these escape mutants. The particular viral mutations or combination of mutations that directly affect the clinical outcome of infection are not known; however, four major 'pathways' of antiviral drug resistance-associated substitutions have now been identified. Further studies are clearly needed to identify the pathogenetic basis and clinical sequelae arising from the selection of these particular mutants. In the clinical context of antiviral drug resistance, treating physicians need to adopt therapeutic strategies that effectively control viral replication. Finally, the role of host genetics in influencing the outcome of HBV disease in the context of natural history and therapy is beginning to aid understanding in pathogenesis and, when this knowledge is linked to pathogen-specific databases, this should translate into more individualized patient care.
乙肝病毒（HBV）已经进化出一种独特的生命周期，在活跃复制过程中会产生大量病毒载量，但实际上并不会直接杀死被感染的细胞。HBV病毒生命周期中的两个关键事件，首先是从输入的基因组DNA或新复制的衣壳相关DNA中产生共价闭合环状（ccc）DNA转录模板，其次是病毒前基因组（pg）RNA的逆转录以形成子代HBV DNA基因组。关于cccDNA的表观遗传控制的新数据正在出现，这可能是该疾病发病机制和自然史中的另一个关键因素。由于HBV利用逆转录来复制其基因组，因此突变的病毒基因组经常出现。内源性（宿主免疫清除）和外源性（疫苗和抗病毒药物）的特定选择压力很容易筛选出这些逃逸突变体。直接影响感染临床结果的特定病毒突变或突变组合尚不清楚；然而，现已确定了与抗病毒药物耐药性相关替代的四个主要“途径”。显然需要进一步研究来确定这些特定突变体选择所产生的发病机制基础和临床后果。在抗病毒药物耐药性的临床背景下，治疗医生需要采取有效控制病毒复制的治疗策略。最后，宿主遗传学在自然史和治疗背景下影响HBV疾病结局的作用，开始有助于理解发病机制，当这些知识与病原体特异性数据库相关联时，这应该转化为更个性化的患者护理。
