The M184V mutation in the reverse transcriptase of human immunodeficiency virus type 1 impairs rescue of chain-terminated DNA synthesis
The M184V mutation in the reverse transcriptase of human immunodeficiency virus type 1 impairs rescue of chain-terminated DNA synthesis
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DOI：
10.1128/jvi.74.8.3579-3585.2000
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发表时间：
2000-04-01
影响因子：
5.4
通讯作者：
Wainberg, MA
中科院分区：
文献类型：
--
作者：
Götte, M;Arion, D;Wainberg, MA
核苷类似物链终止子，如3‘-叠氮-3’-脱氧胸苷(AZT)和2‘，3’-二脱氧-3‘-硫代胞苷(3TC)是临床上用于抑制人类免疫缺陷病毒1型逆转录酶(RT)的一类重要药物，最近的数据表明，与AZT耐药相关的突变酶能够比野生型RT更有效地去除链终止残基，这反过来可能有助于DNA合成的挽救；这些实验分别使用生理浓度的焦磷酸或核苷三磷酸盐进行。目前的研究表明，M184V突变对3TC具有高水平的抗性，可以严重影响链终止核苷酸的去除。与野生型不同，含有RT的M184V不能检测到3TC末端引物链上的焦磷降解，而且末端AZT末端的DNA合成显著减少。因此，与AZT和3TC抗性相关的突变RT在这方面具有相反的表型，因此不相容。这些结果与组织培养和临床数据一致，表明在RT编码基因中含有M184V突变的病毒背景下，AZT具有持续的抗病毒作用。
Nucleoside analog chain terminators such as 3'-azido-3'-deoxythymidine (AZT) and 2',3'-dideoxy-3'-thiacytidine (3TC) represent an important class of drugs that are used in the clinic to inhibit the reverse transcriptase (RT) of human immunodeficiency virus type 1, Recent data have suggested that mutant enzymes associated with AZT resistance are capable of removing the chain-terminating residue with much greater efficiency than wild-type RT and this may, in turn, facilitate rescue of DNA synthesis; these experiments were performed using physiological concentrations of pyrophosphate or nucleoside triphosphates, respectively. The present study demonstrates that the M184V mutation, which confers high-level resistance to 3TC, can severely compromise the removal of chain-terminating nucleotides. Pyophosphorolysis on 3TC-terminated primer strands was not detectable with M184V containing, as opposed to wild-type, RT, and rescue of AZT-terminated DNA synthesis was significantly decreased with the former enzyme. Thus, mutated RTs associated with resistance to AZT and 3TC possess opposing, and therefore incompatible, phenotypes in this regard. These results are consistent with tissue culture and clinical data showing sustained antiviral effects of AZT in the context of viruses that contain the M184V mutation in the RT-encoding gene.