Role of additional mutations outside the YMDD motif of hepatitis B virus polymerase in L(-)SddC (3TC) resistance
Role of additional mutations outside the YMDD motif of hepatitis B virus polymerase in L(-)SddC (3TC) resistance
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DOI：
10.1016/s0006-2952(98)00050-1
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发表时间：
1998-05-15
影响因子：
5.8
通讯作者：
Cheng, YC
中科院分区：
文献类型：
--
作者：
Fu, L;Cheng, YC
L(-)SddC (3TC) 已被证明是用于治疗乙型肝炎病毒 (HBV) 感染的最有前途的核苷类似物。不幸的是，据报道，约 12% 的 HBV 感染患者在接受 3TC 治疗一段时间后出现 HBV 复发。在 3TC 耐药患者的这些病毒的 HBV 聚合酶中检测到点突变。 YMDD 基序中的蛋氨酸发生常见突变。在本报告中，我们展示了根据其他研究人员的临床报告，通过定点诱变从 HBV 基因组（adr 亚型）产生的突变体。通过瞬时转染系统，发现通过将YMDD基序处的蛋氨酸改为缬氨酸或异亮氨酸，病毒DNA复制效率将比野生型病毒低100倍以上。 YMDD 基序之外的一些额外突变可以增强含有 YMDD 突变的病毒的复制。在 YMDD 基序内部和外部含有点突变的 HBV 突变体中观察到不同程度的 3TC 耐药性。这些结果表明。 YMDD基序之外的突变在一定程度上补偿了YMDD突变对病毒复制的影响，也可能有助于临床病毒对3TC的耐药性。 (C) 1998 爱思唯尔科学公司。
L(-)SddC (3TC) has been shown to be the most promising nucleoside analogue used for the treatment of hepatitis B virus (HBV) infection. Unfortunately, it has been reported that about 12% of HBV-infected patients experience a recurrence of HBV after a period of treatment with 3TC. Point mutations were detected in the HBV polymerase of those viruses from 3TC-resistant patients. A common mutation occurred at methionine in the YMDD motif. In this report, we present mutants that were generated from the HBV genome (adr subtype) by site-directed mutagenesis based on clinical reports from other investigators. With the transient transfection system, it was found that by changing methionine to valine or isoleucine at the YMDD motif, the viral DNA replication would be more than 100-fold less efficient than that of the wild-type virus. Some additional mutations outside the YMDD motif could enhance the replication of the virus containing a YMDD mutation. Various levels of resistance to 3TC were observed in HBV mutants containing point mutations both inside and outside the YMDD motif. These results suggest. that the mutations outside the YMDD motif compensate the YMDD mutation to some extent for the viral replication and may also contribute to clinical viral resistance to 3TC. (C) 1998 Elsevier Science Inc.