Department of Virology, University of the Saarland, Homburg, Germany.
PLoS One. 2011 Mar 31;6(3):e18375. doi: 10.1371/journal.pone.0018375.
Fitness interactions between mutations, referred to as epistasis, can strongly impact evolution. For RNA viruses and retroviruses with their high mutation rates, epistasis may be particularly important to overcome fitness losses due to the accumulation of deleterious mutations and thus could influence the frequency of mutants in a viral population. As human immunodeficiency virus type 1 (HIV-1) resistance to azidothymidine (AZT) requires selection of sequential mutations, it is a good system to study the impact of epistasis. Here we present a thorough analysis of a classical AZT-resistance pathway (the 41-215 cluster) of HIV-1 variants by fitness measurements in single round infection assays covering physiological drug concentrations ex vivo. The sign and value of epistasis varied and did not predict the epistatic effect on the mutant frequency. This complex behavior is explained by the fitness ranking of the variants that strongly depends on environmental factors, i.e., the presence and absence of drugs and the host cells used. Although some interactions compensate fitness losses, the observed small effect on the relative mutant frequencies suggests that epistasis might be inefficient as a buffering mechanism for fitness losses in vivo. While the use of epistasis-based hypotheses to make general assumptions on the evolutionary dynamics of viral populations is appealing, our data caution their interpretation without further knowledge on the characteristics of the viral mutant spectrum under different environmental conditions.
突变之间的适应相互作用（称为上位性）可以强烈影响进化。对于具有高突变率的 RNA 病毒和逆转录病毒，上位性可能对于克服由于有害突变的积累而导致的适应性损失特别重要，因此可能会影响病毒群体中突变体的频率。由于人类免疫缺陷病毒 1 型（HIV-1）对叠氮胸苷（AZT）的抗性需要选择连续的突变，因此它是研究上位性影响的一个很好的系统。在这里，我们通过涵盖生理药物浓度的单轮感染测定来对 HIV-1 变体的经典 AZT 抗性途径（41-215 簇）进行了全面分析。上位性的符号和值有所不同，并且不能预测对突变体频率的上位性效应。这种复杂的行为是由变体的适应性排序解释的，该排序强烈依赖于环境因素，即药物的存在与否以及所使用的宿主细胞。尽管一些相互作用可以补偿适应性损失，但观察到对相对突变体频率的微小影响表明，上位性作为体内适应性损失的缓冲机制可能效率不高。虽然基于上位性的假设用于对病毒群体的进化动态做出一般假设很有吸引力，但我们的数据警告说，在没有关于不同环境条件下病毒突变体谱特征的进一步知识的情况下，对其进行解释需要谨慎。
