Hepatitis B virus genetic diversity and its impact on diagnostic assays
Hepatitis B virus genetic diversity and its impact on diagnostic assays
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DOI：
10.1111/j.1365-2893.2007.00910.x
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发表时间：
2007-11-01
影响因子：
2.5
通讯作者：
Hollinger, F. B.
中科院分区：
文献类型：
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作者：
Hollinger, F. B.
B型肝炎病毒（HBV）在血液中循环，作为密切相关，但遗传多样性分子称为准种。在复制过程中，HBV的产生可能接近1011分子/天，尽管在高峰活动期间，该速率可能增加100-1000倍。通常，DNA聚合酶在阅读DNA模板中具有优异的保真度，因为它们与去除不正确添加的核苷酸的核酸外切酶相关联。然而，HBV-DNA聚合酶缺乏保真度和校对功能，部分原因是核酸外切酶活性缺失或缺乏。因此，HBV基因组，特别是包膜基因，以异常高的频率突变。由于重叠的基因，这些突变可以影响一个以上的开放阅读框。S基因含有暴露的主要亲水区域（残基11.0-155），其包含对于诱导免疫重要的“a”决定簇。该区域的核苷酸替换是常见的，并导致结合减少或在诊断测定中检测不到B型肝炎表面抗原（HBsAg）。适应性免疫也依赖于特异性抗体对HBsAg的识别，如果变异体干扰与抗体的结合，就会构成威胁。最后，基因组高变允许HBV逃避抗病毒疗法、疫苗和宿主免疫系统施加的选择压力，并负责产生基因型、亚基因型和亚型。
Hepatitis B virus (HBV) circulates in blood as closely related, but genetically diverse molecules called quasispecies. During replication, HBV production may approach 1011 molecules/day, although during peak activity this rate may increase 100-1000 times. Generally, DNA polymerases have excellent fidelity in reading DNA templates because they are associated with an exonuclease which removes incorrectly added nucleotides. However, the HBV-DNA polymerase lacks fidelity and proofreading function partly because exonuclease activity is either absent or deffcient. Thus, the HBV genome and especially the envelope gene, is mutated with unusually high frequency. These mutations can affect more than one open reading frame because of overlapping genes. The S gene contains an exposed major hydrophilic region (residues 11.0-155), which encompasses the 'a' determinant that is important for inducing immunity. Nucleotide substitutions in this region are common and result in reduced binding or failure to detect hepatitis B surface antigen (HBsAg) in diagnostic assays. Adaptive immunity also depends on the recognition of HBsAg by specific antibody and variants pose a threat if they interfere with binding to antibody. Finally, genomic hypervariability allows HBV to escape selection pressures imposed by antiviral therapies, vaccines and the host immune system, and is responsible for creating genotypes, subgenotypes and subtypes.