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首页> 外文期刊>BMC Medical Genomics >Host sequence motifs shared by HIV predict response to antiretroviral therapy
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Host sequence motifs shared by HIV predict response to antiretroviral therapy

机译：HIV共有的宿主序列基序可预测对抗逆转录病毒疗法的反应

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Background The HIV viral genome mutates at a high rate and poses a significant long term health risk even in the presence of combination antiretroviral therapy. Current methods for predicting a patient's response to therapy rely on site-directed mutagenesis experiments and in vitro resistance assays. In this bioinformatics study we treat response to antiretroviral therapy as a two-body problem: response to therapy is considered to be a function of both the host and pathogen proteomes. We set out to identify potential responders based on the presence or absence of host protein and DNA motifs on the HIV proteome. Results An alignment of thousands of HIV-1 sequences attested to extensive variation in nucleotide sequence but also showed conservation of eukaryotic short linear motifs on the protein coding regions. The reduction in viral load of patients in the Stanford HIV Drug Resistance Database exhibited a bimodal distribution after 24 weeks of antiretroviral therapy, with 2,000 copies/ml cutoff. Similarly, patients allocated into responderon-responder categories based on consistent viral load reduction during a 24 week period showed clear separation. In both cases of phenotype identification, a set of features composed of short linear motifs in the reverse transcriptase region of HIV sequence accurately predicted a patient's response to therapy. Motifs that overlap resistance sites were highly predictive of responder identification in single drug regimens but these features lost importance in defining responders in multi-drug therapies. Conclusion HIV sequence mutates in a way that preferentially preserves peptide sequence motifs that are also found in the human proteome. The presence and absence of such motifs at specific regions of the HIV sequence is highly predictive of response to therapy. Some of these predictive motifs overlap with known HIV-1 resistance sites. These motifs are well established in bioinformatics databases and hence do not require identification via in vitro mutation experiments.
机译：背景技术即使在存在联合抗逆转录病毒疗法的情况下，HIV病毒基因组的突变率很高，并构成重大的长期健康风险。当前预测患者对治疗反应的方法依赖于定点诱变实验和体外耐药性分析。在这项生物信息学研究中，我们将对抗逆转录病毒疗法的反应视为一个两体问题：对疗法的反应被认为是宿主和病原体蛋白质组的一种功能。我们着手根据HIV蛋白质组中宿主蛋白和DNA图案的存在与否来确定潜在的应答者。结果数千个HIV-1序列的比对证明核苷酸序列有广泛的变异，但在蛋白质编码区上也显示出真核短线性基序的保守性。斯坦福大学艾滋病毒抗药性数据库中患者病毒载量的减少在抗逆转录病毒治疗24周后表现出双峰分布，截止值为2,000拷贝/ ml。同样，根据在24周内持续减少的病毒载量划分为反应者/非反应者类别的患者表现出明显的分离。在两种表型鉴定情况下，HIV序列逆转录酶区域中由短线性基序组成的一组特征都能准确预测患者对治疗的反应。重叠耐药位点的基元在单一药物方案中高度预测了应答者的识别，但是这些特征在定义多种药物疗法中的应答者时失去了重要性。结论HIV序列突变的方式优先保留了在人类蛋白质组中也发现的肽序列基序。在HIV序列的特定区域存在和不存在此类基序可高度预测对治疗的反应。这些预测性基序中的一些与已知的HIV-1抗性位点重叠。这些基序已在生物信息学数据库中很好地建立，因此不需要通过体外突变实验进行鉴定。

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