Frequent Toggling between Alternative Amino Acids Is Driven by Selection in HIV-1
Frequent Toggling between Alternative Amino Acids Is Driven by Selection in HIV-1
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DOI：
10.1371/journal.ppat.1000242
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发表时间：
2008-12-01
期刊：
影响因子：
6.7
通讯作者：
Seoighe, Cathal
中科院分区：
文献类型：
--
作者：
Delport, Wayne;Scheffler, Konrad;Seoighe, Cathal
宿主对感染性病原体的免疫反应施加强大的选择压力，有利于防止免疫识别的逃逸突变的出现。在功能保守的表位内或侧翼发生逃逸突变可能会对病原体的有效复制能力造成重大损失。这样的突变在宿主的选择压力下恢复到野生型，而宿主对抗原表位没有免疫反应。表现出这种逃逸和逆转模式的氨基酸位置是令人感兴趣的，因为它们往往与有效控制病原体复制的免疫反应相吻合。我们使用蛋白质编码序列进化的概率模型来检测HIV-1中表现出快速逃逸和逆转模式的位点。我们的模型旨在检测易受特定免疫反应影响的野生型氨基酸和逃避免疫识别的复制适应性较低的氨基酸之间切换的位点。通过仿真，我们发现该模型在检测涉及免疫逃逸和逆转的选择方面比标准多样化选择模型有更大的能力，后者对非同义替代的总体增加率很敏感。应用于HIV-1蛋白编码序列比对，免疫逃逸和逆转模型检测到env和nef中大量的自适应进化位点。在所有被测试的基因中，该模型提供了比多样化选择的标准模型更好的适应性进化位点描述。检测到的几个位点证实了人类白细胞抗原（HLA）和病毒序列多态性之间的关联。总的来说，有证据表明HIV-1中的大量位点在强大的选择压力下进化，但表现出较低的序列多样性。一种用于检测野生型和逃逸型氨基酸之间快速切换的系统发育模型确定了HIV-1中大量的适应性进化位点，并且在某些情况下可以正确识别易受免疫反应影响的氨基酸。
Host immune responses against infectious pathogens exert strong selective pressures favouring the emergence of escape mutations that prevent immune recognition. Escape mutations within or flanking functionally conserved epitopes can occur at a significant cost to the pathogen in terms of its ability to replicate effectively. Such mutations come under selective pressure to revert to the wild type in hosts that do not mount an immune response against the epitope. Amino acid positions exhibiting this pattern of escape and reversion are of interest because they tend to coincide with immune responses that control pathogen replication effectively. We have used a probabilistic model of protein coding sequence evolution to detect sites in HIV-1 exhibiting a pattern of rapid escape and reversion. Our model is designed to detect sites that toggle between a wild type amino acid, which is susceptible to a specific immune response, and amino acids with lower replicative fitness that evade immune recognition. Through simulation, we show that this model has significantly greater power to detect selection involving immune escape and reversion than standard models of diversifying selection, which are sensitive to an overall increased rate of non-synonymous substitution. Applied to alignments of HIV-1 protein coding sequences, the model of immune escape and reversion detects a significantly greater number of adaptively evolving sites in env and nef. In all genes tested, the model provides a significantly better description of adaptively evolving sites than standard models of diversifying selection. Several of the sites detected are corroborated by association between Human Leukocyte Antigen (HLA) and viral sequence polymorphisms. Overall, there is evidence for a large number of sites in HIV-1 evolving under strong selective pressure, but exhibiting low sequence diversity. A phylogenetic model designed to detect rapid toggling between wild type and escape amino acids identifies a larger number of adaptively evolving sites in HIV-1, and can in some cases correctly identify the amino acid that is susceptible to the immune response.