Impact of human immunodeficiency virus type 1 reverse transcriptase inhibitor drug resistance mutation interactions on phenotypic susceptibility.
Impact of human immunodeficiency virus type 1 reverse transcriptase inhibitor drug resistance mutation interactions on phenotypic susceptibility.
复制标题
人类免疫缺陷病毒1型逆转录酶抑制剂耐药突变相互作用对表型易感性的影响。
DOI：
10.1089/aid.2007.0244
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发表时间：
2008
影响因子：
1.5
通讯作者：
Ferguson,MoniqueR
中科院分区：
文献类型：
--
作者：
Trivedi,Vinod;VonLindern,Jana;Montes-Walters,Miguel;Rojo,DanielR;Shell,ElisabethJ;Parkin,Neil;O'Brien,WilliamA;Ferguson,MoniqueR
使用由来自两名治疗经验患者的血浆HIV-1 RNA的RT-PCR扩增片段组成的重组病毒，评估了特异性逆转录酶（RT）耐药突变在影响具有复杂耐药相互作用模式的病毒株对RT抑制剂表型敏感性方面的作用。通过定点诱变进行关键RT氨基酸的特异性修饰。评估了一组具有确定基因型耐药突变的病毒的表型耐药性。将M184 V导入表达各种RT抗性突变的几个不同克隆中，均降低了对阿巴卡韦、拉米夫定和去羟肌苷的敏感性，增加了对齐多夫定、司他夫定和替诺福韦的敏感性;复制能力降低。L74 V突变具有相似但略有不同的作用，导致对阿巴卡韦、拉米夫定和去羟肌苷的敏感性降低，对齐多夫定和替诺福韦的敏感性增加，但与M184 V相反，L74 V导致对司他夫定的敏感性降低。在非核苷类逆转录酶抑制剂（NNRTI）突变K101 E和G190 S的病毒株中，L74 V突变增加了复制能力，与已发表的观察结果一致，但在没有NNRTI耐药突变的病毒株中，复制能力降低。K101 E和G190 S共同降低对所有核苷类RT抑制剂的敏感性，但K103 N突变对核苷类RT抑制剂的敏感性影响不大。突变相互作用可对耐药表型和复制能力产生实质性影响，并且这已在临床实践中随着固定剂量组合药丸的开发而被利用。然而，我们是第一个报告这些突变的相互作用，使用分子克隆的重组株来自病毒，自然发生在艾滋病毒感染者。
The role specific reverse transcriptase (RT) drug resistance mutations play in influencing phenotypic susceptibility to RT inhibitors in virus strains with complex resistance interaction patterns was assessed using recombinant viruses that consisted of RT-PCR-amplifiedpolfragments derived from plasma HIV-1 RNA from two treatment-experienced patients. Specific modifications of key RT amino acids were performed by site-directed mutagenesis. A panel of viruses with defined genotypic resistance mutations was assessed for phenotypic drug resistance. Introduction of M184V into several different clones expressing various RT resistance mutations uniformly decreased susceptibility to abacavir, lamivudine, and didanosine, and increased susceptibility to zidovudine, stavudine, and tenofovir; replication capacity was decreased. The L74V mutation had similar but slightly different effects, contributing to decreased susceptibility to abacavir, lamivudine, and didanosine and increased susceptibility to zidovudine and tenofovir, but in contrast to M184V, L74V contributed to decreased susceptibility to stavudine. In virus strains with the nonnucleoside reverse transcriptase inhibitor (NNRTI) mutations K101E and G190S, the L74V mutation increased replication capacity, consistent with published observations, but replication capacity was decreased in strains without NNRTI resistance mutations. K101E and G190S together tend to decrease susceptibility to all nucleoside RT inhibitors, but the K103N mutation had little effect on nucleoside RT inhibitor susceptibility. Mutational interactions can have a substantial impact on drug resistance phenotype and replication capacity, and this has been exploited in clinical practice with the development of fixed-dose combination pills. However, we are the first to report these mutational interactions using molecularly cloned recombinant strains derived from viruses that occur naturally in HIV-infected individuals.