Hepatitis B virus mutations associated with antiviral therapy
Hepatitis B virus mutations associated with antiviral therapy
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DOI：
10.1002/jmv.20608
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发表时间：
2006-01-01
影响因子：
12.7
通讯作者：
Locarnini, S.
中科院分区：
文献类型：
--
作者：
Bartholomeusz, A.;Locarnini, S.
B型肝炎病毒（HBV）通过易于出错的病毒逆转录酶复制，导致大量准种，其突变遍布整个基因组。在抗病毒药物选择压力（例如，拉米夫定、阿德福韦或恩替卡韦）HBV突变体从预先存在的准种库中选择，并随着时间的推移成为优势种。并非所有的突变都会导致有复制能力的病毒，因为HBV具有重叠阅读框的额外复杂性。HBV聚合酶（Pol）基因以移码方式与肝炎B表面抗原（HBsAg）重叠，结果HBV Pol中的耐药突变可直接影响HBsAg的性质及其功能。HBV基因组数据库已经建立，以监测抗病毒选择性突变，并在确定保守残基，基因型差异，多态性，和突变谱选择在不同的抗病毒选择压力是有用的。这些HBV数据库可能有助于开发新的诊断试剂以及监测在不同抗病毒压力下选择的聚合酶和包膜突变。抗病毒药物耐药突变体的出现是至少六个因素的函数：病毒突变频率、抗病毒靶位点的内在突变性、药物施加的选择压力、病毒复制的幅度和速率、突变体的总体复制适应性和复制空间的可用性。在抗病毒治疗过程中，只有有限数量的HBsAg突变被鉴定，这些突变的诊断和公共卫生意义需要进一步研究。显然，迫切需要改进的治疗策略，以防止HBV耐药突变体的持续选择。
The hepatitis B virus (HBV) replicates via an error prone viral reverse transcriptase resulting in a large pool of quasispecies with mutations spread throughout the genome. During antiviral drug selection pressure (e.g., lamivudine, adefovir, or entecavir) HBV mutants are selected from the preexisting pool of quasispecies and over time become the dominant species. Not all mutations result in replication competent virus as HBV has the added complexity of overlapping reading frames. The HBV polymerase (Pol) gene overlaps the hepatitis B surface antigen (HBsAg) in a frame-shifted manner with the result that drug-resistant mutations in the HBV Pol can directly impact on the nature of HBsAg and its function. HBV genomic databases have been established to monitor antiviral selected mutations and are useful in determining conserved residues, genotypic differences, polymorphisms, and the mutation profiles selected under different antiviral selection pressures. These HBV databases may aid in the development of new diagnostic reagents as well as the monitoring of polymerase and envelope mutations selected under different antiviral pressures. Antiviral drug resistant mutants emerge as a function of at least six factors: the viral mutation frequency, the intrinsic mutability of the antiviral target site, the selective pressure exerted by the drug, the magnitude and rate of virus replication, the overall replication fitness of the mutant, and the availability of replication space. Only a limited number of HBsAg mutations selected during antiviral treatment have been characterized and the diagnostic and public health implications of these mutations need further investigation. Clearly, improved treatment strategies are required urgently to prevent the continued selection of HBV drug-resistant mutants.