Department of Internal Medicine, School of Medicine, Jeju National University, Korea.
J Med Virol. 2015 Apr;87(4):601-8. doi: 10.1002/jmv.24117. Epub 2015 Jan 21.
Mutations in the basal core promoter (BCP) and precore (PC) regions of the hepatitis B virus (HBV) are more common in genotypes B and C than in genotype A, suggesting that these mutations might affect replication competency depending on genotype. The purpose of the study was to investigate the influence of these mutations on the capacity of HBV for replication and antiviral drug susceptibility according to genotype. Genotypes A, B, and C of HBV strains with a BCP mutation, PC mutation, or BCP + PC mutation were made by site-directed mutagenesis. Replication competency of each construct and susceptibility to nucleos(t) ide analogues were tested in an Huh7 cell line. In genotype A, the BCP and BCP + PC mutations increased the viral replication around 6.5 times compared with the wild type, and the PC mutation alone similarly increased the viral replication around three times. In genotypes B and C, all three mutant types increased viral replication to a similar extent, regardless of mutation pattern. Interestingly, the BCP mutation appeared to have a greater effect on viral replication in genotype A than in genotypes B and C. This finding was unexpected because the BCP mutation is more common in HBV genotypes B and C. Moreover, the BCP, PC, and BCP + PC mutations decreased the sensitivity of HBV to antiviral agents to various degrees (2- to 10-fold) regardless of genotype. In conclusion, BCP and PC mutations increased viral replication regardless of HBV genotype and decreased in vitro antiviral susceptibility to the nucleos(t) ide analogues.
乙型肝炎病毒（HBV）的基本核心启动子（BCP）和前核心（PC）区域的突变在基因型 B 和 C 中比在基因型 A 中更为常见，这表明这些突变可能根据基因型影响复制能力。本研究的目的是根据基因型研究这些突变对 HBV 复制能力和抗病毒药物敏感性的影响。通过定点诱变生成了具有 BCP 突变、PC 突变或 BCP+PC 突变的 HBV 株的基因型 A、B 和 C。在 Huh7 细胞系中测试了每种构建体的复制能力和对核苷（酸）类似物的敏感性。在基因型 A 中，BCP 和 BCP+PC 突变使病毒复制增加了约 6.5 倍，而单独的 PC 突变使病毒复制增加了约 3 倍。在基因型 B 和 C 中，所有三种突变类型都使病毒复制增加到相似的程度，而与突变模式无关。有趣的是，BCP 突变似乎对基因型 A 中的病毒复制产生的影响大于基因型 B 和 C。这一发现出乎意料，因为 BCP 突变在 HBV 基因型 B 和 C 中更为常见。此外，BCP、PC 和 BCP+PC 突变不同程度地降低了 HBV 对抗病毒药物的敏感性（2-至 10 倍），而与基因型无关。总之，BCP 和 PC 突变增加了病毒复制，而与 HBV 基因型无关，并降低了体外对核苷（酸）类似物的抗病毒敏感性。
