Department of Virology, Swedish Institute for Infectious Disease Control, Solna, Sweden.
PLoS One. 2011;6(8):e21747. doi: 10.1371/journal.pone.0021747. Epub 2011 Aug 2.
The molecular evolution of HIV-1 is characterized by frequent substitutions, indels and recombination events. In addition, a HIV-1 population may adapt through frequency changes of its variants. To reveal such population dynamics we analyzed HIV-1 subpopulation frequencies in an untreated patient with stable, low plasma HIV-1 RNA levels and close to normal CD4+ T-cell levels. The patient was intensively sampled during a 32-day period as well as approximately 1.5 years before and after this period (days -664, 1, 2, 3, 11, 18, 25, 32 and 522). 77 sequences of HIV-1 env (approximately 3100 nucleotides) were obtained from plasma by limiting dilution with 7-11 sequences per time point, except day -664. Phylogenetic analysis using maximum likelihood methods showed that the sequences clustered in six distinct subpopulations. We devised a method that took into account the relatively coarse sampling of the population. Data from days 1 through 32 were consistent with constant within-patient subpopulation frequencies. However, over longer time periods, i.e. between days 1...32 and 522, there were significant changes in subpopulation frequencies, which were consistent with evolutionarily neutral fluctuations. We found no clear signal of natural selection within the subpopulations over the study period, but positive selection was evident on the long branches that connected the subpopulations, which corresponds to >3 years as the subpopulations already were established when we started the study. Thus, selective forces may have been involved when the subpopulations were established. Genetic drift within subpopulations caused by de novo substitutions could be resolved after approximately one month. Overall, we conclude that subpopulation frequencies within this patient changed significantly over a time period of 1.5 years, but that this does not imply directional or balancing selection. We show that the short-term evolution we study here is likely representative for many patients of slow and normal disease progression.
HIV-1 的分子进化以频繁的替换、插入和重组事件为特征。此外，HIV-1 群体可能通过其变体频率的变化来适应。为了揭示这种群体动态，我们分析了一位未经治疗的患者的 HIV-1 亚群频率，该患者的血浆 HIV-1 RNA 水平稳定且较低，CD4+T 细胞水平接近正常。在 32 天的时间内，以及在此期间之前和之后大约 1.5 年（时间点-664、1、2、3、11、18、25、32 和 522），对该患者进行了密集采样。通过 7-11 个序列的限制稀释从血浆中获得了 77 个 HIV-1 env 序列（约 3100 个核苷酸），除了时间点-664 之外。使用最大似然方法进行的系统发育分析表明，序列聚类成六个不同的亚群。我们设计了一种方法，该方法考虑了种群相对粗糙的采样。来自 1 至 32 天的数据与患者内亚群频率的恒定一致。然而，在较长的时间内，即 1...32 天和 522 天之间，亚群频率发生了显著变化，这与进化上的中性波动一致。在研究期间，我们在亚群内没有发现明显的自然选择信号，但在连接亚群的长分支上存在正选择，这对应于 >3 年，因为当我们开始研究时，亚群已经建立。因此，在建立亚群时可能涉及选择力。亚群内由从头替换引起的遗传漂移在大约一个月后就可以解决。总的来说，我们得出结论，在 1.5 年的时间内，该患者的亚群频率发生了显著变化，但这并不意味着定向或平衡选择。我们表明，我们在这里研究的短期进化可能代表了许多缓慢和正常疾病进展患者的情况。
