Role of minority populations of human immunodeficiency virus type 1 in the evolution of viral resistance to protease inhibitors
Role of minority populations of human immunodeficiency virus type 1 in the evolution of viral resistance to protease inhibitors
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DOI：
10.1128/jvi.78.8.4234-4247.2004
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发表时间：
2004-04-01
影响因子：
5.4
通讯作者：
Hance, AJ
中科院分区：
文献类型：
--
作者：
Charpentier, C;Dwyer, DE;Hance, AJ
人类免疫缺陷病毒1型（HIV-1）耐药性是由药物靶向的病毒基因突变积累引起的。然而，这些遗传变化通常通过仅考虑血浆病毒的优势群体的技术来检测和监测。由于HIV-1感染患者体内含有复杂多样的病毒群，因此耐药性出现和演变的机制尚未完全阐明。使用允许定量少数病毒种属中耐药突变的技术，我们监测了蛋白酶抑制剂治疗失败患者血浆病毒群体中耐药性的演变。在整个耐药演变过程中，在所有患者中检测到具有不同耐药基因型的少数人群。新的显性基因型的出现遵循两种可能的机制：（i）在当前显性基因型中出现新的突变，以及（ii）出现来自少数病毒物种的新基因型。在大多数情况下，这些群体变化与以复制能力降低为代价的抗性增加有关。我们的研究结果提供了一个初步的迹象，少数病毒物种，独立于大多数病毒种群的演变，最终可以成为占主导地位的人口，从而作为一个水库的多样性，并可能加速耐药性的发展。
Human immunodeficiency virus type 1 (HIV-1) drug resistance results from the accumulation of mutations in the viral genes targeted by the drugs. These genetic changes, however, are commonly detected and monitored by techniques that only take into account the dominant population of plasma virus. Because HIV-1-infected patients harbor a complex and diverse mixture of virus populations, the mechanisms underlying the emergence and the evolution of resistance are not fully elucidated. Using techniques that allow the quantification of resistance mutations in minority virus species, we have monitored the evolution of resistance in plasma virus populations from patients failing protease inhibitor treatment. Minority populations with distinct resistance genotypes were detected in all patients throughout the evolution of resistance. The emergence of new dominant genotypes followed two possible mechanisms: (i) emergence of a new mutation in a currently dominant genotype and (ii) emergence of a new genotype derived from a minority virus species. In most cases, these population changes were associated with an increase in resistance at the expense of a reduction in replication capacity. Our findings provide a preliminary indication that minority viral species, which evolve independently of the majority virus population, can eventually become dominant populations, thereby serving as a reservoir of diversity and possibly accelerating the development of drug resistance.