Multiple independent origins of a protease inhibitor resistance mutation in salvage therapy patients.
Multiple independent origins of a protease inhibitor resistance mutation in salvage therapy patients.
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DOI：
10.1186/1742-4690-5-7
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发表时间：
2008-01-25
期刊：
影响因子：
3.3
通讯作者：
Delwart EL
中科院分区：
文献类型：
--
作者：
Kapoor A;Shapiro B;Shafer RW;Shulman N;Rhee SY;Delwart EL
联合抗病毒疗法通过要求在同一病毒基因组上选择多个特定突变来传递高水平的耐药性，从而降低了治疗失败率。为了确定在抗病毒治疗失败的过程中，常见的蛋白酶抑制剂耐药突变L90M是只在不同的HIV基因骨架上选择一次还是重复选择，我们分析了病毒基因组在多药耐药进化过程中的一个连接区。利用L90M等位基因特异性聚合酶链式反应，我们扩增并测序了L90M早期含有HIV变异株的Gag-Pro区，并在15例抢救治疗失败的患者中检测到它们是优势病毒。然后将早期少数L90M连锁序列与后来主导血浆准种的L90M病毒的序列进行比较。使用贝叶斯进化分析抽样树，发现5名患者多次出现含有病毒的L90M，2名患者仅出现一次，其余8名患者的时间尚不确定。这些结果表明，早期的L90M突变经常可以被携带独立选择的L90M突变的病毒取代，而不是被早期突变的后代取代。
Combination anti-viral therapies have reduced treatment failure rates by requiring multiple specific mutations to be selected on the same viral genome to impart high-level drug resistance. To determine if the common protease inhibitor resistance mutation L90M is only selected once or repeatedly on different HIV genetic backbones during the course of failed anti-viral therapies we analyzed a linked region of the viral genome during the evolution of multi-drug resistance. Using L90M allele specific PCR we amplified and sequenced gag-pro regions linked to very early L90M containing HIV variants prior to their emergence and detection as dominant viruses in 15 failed salvage therapy patients. The early minority L90M linked sequences were then compared to those of the later L90M viruses that came to dominate the plasma quasispecies. Using Bayesian evolutionary analysis sampling trees the emergence of L90M containing viruses was seen to take place on multiple occasion in 5 patients, only once for 2 patients and an undetermined number of time for the remaining 8 patients. These results indicate that early L90M mutants can frequently be displaced by viruses carrying independently selected L90M mutations rather than by descendents of the earlier mutants.
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