Origin of human immunodeficiency virus type 1 quasispecies emerging after antiretroviral treatment interruption in patients with therapeutic failure
Origin of human immunodeficiency virus type 1 quasispecies emerging after antiretroviral treatment interruption in patients with therapeutic failure
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DOI：
10.1128/jvi.76.14.7000-7009.2002
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发表时间：
2002-07-01
影响因子：
5.4
通讯作者：
Salomon, H
中科院分区：
文献类型：
--
作者：
Kijak, GH;Simon, V;Salomon, H
抗逆转录病毒（ARV）耐药人类免疫缺陷病毒1型（HIV-1）准种的出现是治疗失败的主要原因。当药物的选择压力被移除时，这些变体通常被药物敏感的变体所取代，因为前者在无药物环境中降低了适应性。这是设计结构化抗逆转录病毒治疗中断（STI）研究管理治疗失败的HIV-1患者的基本原理。我们研究了由于抗逆转录病毒药物耐药性导致治疗失败的患者在STI后出现的药物敏感的HIV-1准种的起源。在给药中断当天（第0天）以及给药后30天和60天采集血浆和外周血单核细胞样本。对HIV-1 pol和env基因进行部分扩增、克隆和测序。在第60天，耐药变异体被完全或部分敏感的准种所取代。pol的系统发育分析显示，STI后出现的药物敏感变体与其直接的时间祖先无关，但形成了一个单独的簇，表明STI导致隔离病毒群体的复发和重新出现，而不是导致耐药形式的回复突变。根据env序列推断，未发现病毒嗜性伴随变化的证据。这项研究表明，准种的重新出现在HIV-1的人口动态中起着重要的作用，并指出了困难，可能会发现，当回收抗逆转录病毒治疗与治疗失败的患者。
The emergence of antiretroviral (ARV) drug-resistant human immunodeficiency virus type 1 (HIV-1) quasispecies is a major cause of treatment failure. These variants are usually replaced by drug-sensitive ones when the selective pressure of the drugs is removed, as the former have reduced fitness in a drug-free environment. This was the rationale for the design of structured ARV treatment interruption (STI) studies for the management of HIV-1 patients with treatment failure. We have studied the origin of drug-sensitive HIV-1 quasispecies emerging after STI in patients with treatment failure due to ARV drug resistance. Plasma and peripheral blood mononuclear cell samples were obtained the day of treatment interruption (day 0) and 30 and 60 days afterwards. HIV-1 pol and env were partially amplified, cloned, and sequenced. At day 60 drug-resistant variants were replaced by completely or partially sensitive quasispecies. Phylogenetic analyses of pol revealed that drug-sensitive variants emerging after STI were not related to their immediate temporal ancestors but formed a separate cluster, demonstrating that STI leads to the recrudescence and reemergence of a sequestrated viral population rather than leading to the back mutation of drug-resistant forms. No evidence for concomitant changes in viral tropism was seen, as deduced from env sequences. This study demonstrates the important role that the reemergence of quasispecies plays in HIV-1 population dynamics and points out the difficulties that may be found when recycling ARV therapies with patients with treatment failure.