Fu L, Cheng Y C
Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA.
Biochem Pharmacol. 1998 May 15;55(10):1567-72. doi: 10.1016/s0006-2952(98)00050-1.
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.
L(-)拉米夫定（3TC）已被证明是用于治疗乙型肝炎病毒（HBV）感染的最有前景的核苷类似物。不幸的是，据报道，约12%的HBV感染患者在接受3TC治疗一段时间后会出现HBV复发。在来自3TC耐药患者的那些病毒的HBV聚合酶中检测到点突变。一种常见突变发生在YMDD基序的甲硫氨酸处。在本报告中，我们根据其他研究者的临床报告，通过定点诱变从HBV基因组（adr亚型）产生了突变体。利用瞬时转染系统发现，通过将YMDD基序中的甲硫氨酸变为缬氨酸或异亮氨酸，病毒DNA复制效率比野生型病毒低100倍以上。YMDD基序外的一些额外突变可增强含有YMDD突变的病毒的复制。在YMDD基序内外含有点突变的HBV突变体中观察到了对3TC的不同程度的耐药性。这些结果表明，YMDD基序外的突变在一定程度上补偿了YMDD突变对病毒复制的影响，也可能导致临床上对3TC的病毒耐药性。
