Max Planck Institute for Informatics, Saarbrücken, Germany.
PLoS One. 2009 Oct 9;4(10):e7387. doi: 10.1371/journal.pone.0007387.
The V3 loop of human immunodeficiency virus type 1 (HIV-1) is critical for coreceptor binding and is the main determinant of which of the cellular coreceptors, CCR5 or CXCR4, the virus uses for cell entry. The aim of this study is to provide a large-scale data driven analysis of HIV-1 coreceptor usage with respect to the V3 loop evolution and to characterize CCR5- and CXCR4-tropic viral phenotypes previously studied in small- and medium-scale settings. We use different sequence similarity measures, phylogenetic and clustering methods in order to analyze the distribution in sequence space of roughly 1000 V3 loop sequences and their tropism phenotypes. This analysis affords a means of characterizing those sequences that are misclassified by several sequence-based coreceptor prediction methods, as well as predicting the coreceptor using the location of the sequence in sequence space and of relating this location to the CD4(+) T-cell count of the patient. We support previous findings that the usage of CCR5 is correlated with relatively high sequence conservation whereas CXCR4-tropic viruses spread over larger regions in sequence space. The incorrectly predicted sequences are mostly located in regions in which their phenotype represents the minority or in close vicinity of regions dominated by the opposite phenotype. Nevertheless, the location of the sequence in sequence space can be used to improve the accuracy of the prediction of the coreceptor usage. Sequences from patients with high CD4(+) T-cell counts are relatively highly conserved as compared to those of immunosuppressed patients. Our study thus supports hypotheses of an association of immune system depletion with an increase in V3 loop sequence variability and with the escape of the viral sequence to distant parts of the sequence space.
人类免疫缺陷病毒 1 型（HIV-1）的 V3 环对于核心受体结合至关重要，是决定病毒使用哪种细胞核心受体（CCR5 或 CXCR4）进入细胞的主要决定因素。本研究旨在对 HIV-1 核心受体的使用情况进行大规模数据驱动分析，探讨 V3 环进化与 CCR5 和 CXCR4 嗜性病毒表型之间的关系，并对以前在小规模和中等规模研究中研究过的 CCR5 和 CXCR4 嗜性病毒表型进行特征描述。我们使用不同的序列相似性度量、系统发育和聚类方法，对大约 1000 个 V3 环序列及其嗜性表型在序列空间中的分布进行分析。这种分析提供了一种方法，可以对几种基于序列的核心受体预测方法错误分类的序列进行特征描述，也可以根据序列在序列空间中的位置来预测核心受体，并将该位置与患者的 CD4+T 细胞计数联系起来。我们支持之前的研究结果，即 CCR5 的使用与相对较高的序列保守性相关，而 CXCR4 嗜性病毒在序列空间中扩散到更大的区域。错误预测的序列大多位于其表型代表少数的区域或与相反表型主导的区域附近。然而，序列在序列空间中的位置可以用来提高核心受体使用预测的准确性。与免疫抑制患者相比，CD4+T 细胞计数高的患者的序列相对高度保守。因此，我们的研究支持了免疫系统耗竭与 V3 环序列变异性增加以及病毒序列逃避到序列空间遥远部分之间存在关联的假说。
