In vitro susceptibilities of wild-type or drug-resistant hepatitis B virus to (-)-β-D-2,6-diaminopurine dioxolane and 2′-fluoro-5-methyl-β-L-arabinofuranosyluracil
In vitro susceptibilities of wild-type or drug-resistant hepatitis B virus to (-)-β-D-2,6-diaminopurine dioxolane and 2′-fluoro-5-methyl-β-L-arabinofuranosyluracil
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DOI：
10.1128/aac.45.9.2495-2501.2001
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发表时间：
2001-09-01
影响因子：
4.9
通讯作者：
Locarnini, S
中科院分区：
文献类型：
--
作者：
Chin, R;Shaw, T;Locarnini, S
长期使用拉米夫定（[-]- β - l -2 ',3 ‘ -二脱氧-3 ’硫代胞苷）或泛环洛韦治疗慢性乙型肝炎病毒（HBV）感染可能会选择由于聚合酶基因点突变而产生耐药的病毒突变体。因此，确定这些HBV突变体是否对新的抗病毒药物敏感是很重要的。我们使用瞬时转染系统比较了野生型HBV和四种拉米夫定和/或泛环洛韦耐药HBV突变体对阿德福韦的敏感性[9-（2-膦基-甲氧基乙基）腺嘌呤；PMEA]和核苷类似物(-)- β -d - 2,6 -二氨基嘌呤二恶烷（DAPD）和2 ' -氟-5-甲基- β - l-阿拉伯糖脲嘧啶（L-FMAU）。耐药突变体在聚合酶蛋白中含有氨基酸取代。我们发现M5501和M550V加L526M的替代，使拉米夫定耐药，但对阿德福韦或DAPD不产生交叉耐药，但对L-FMAU产生交叉耐药。分离的M550V替代具有与M5501相似的表型，除了它没有赋予对L-FMAU的显着抗性。L526M取代与famciclovir耐药相关，对L-FMAU产生交叉耐药，但对阿德福韦或DAPD没有交叉耐药。DAPD、L-FMAU和阿德福韦对HBV分泌的抑制并不总是与抑制细胞内HBV复制中间体的产生相关，这表明这些类似物可能优先抑制病毒复制周期的特定阶段。
Prolonged treatment of chronic hepatitis B virus (HBV) infection with lamivudine ([-]-beta -L-2 ' ,3 ' -dideoxy-3 ' thiacytidine) or famciclovir may select for viral mutants that are drug resistant due to point mutations in the polymerase gene. Determining whether such HBV mutants are sensitive to new antiviral agents is therefore important. We used a transient transfection system to compare the sensitivities of wild-type HBV and four lamivudine- and/or famciclovir-resistant HBV mutants to adefovir [9- (2-phosphonyl-methoxyethyl)-adenine; PMEA] and the nucleoside analogues (-)-beta -D-2, 6-diaminopurine dioxolane (DAPD) and 2 ' -fluoro-5-methyl-beta -L-arabinofuranosyluracil (L-FMAU). The drug-resistant mutants contained amino acid substitutions in the polymerase protein. We found that the M5501 and M550V plus L526M substitutions, which confer lamivudine resistance, did not confer cross-resistance to adefovir or DAPD, but conferred cross-resistance to L-FMAU. The M550V substitution in isolation conferred a similar phenotype to M5501, except that it did not confer significant resistance to L-FMAU. The L526M substitution, which is associated with famciclovir resistance, conferred cross-resistance to L-FMAU but not to adefovir or DAPD. Inhibition of HBV secretion by DAPD, L-FMAU, and adefovir did not always correlate with inhibition of the generation of intracellular HBV replicative intermediates, suggesting that these analogs may preferentially inhibit specific stages of the viral replication cycle.