Analysis of physicochemical and structural properties determining HIV-1 coreceptor usage.
Analysis of physicochemical and structural properties determining HIV-1 coreceptor usage.
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DOI：
10.1371/journal.pcbi.1002977
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发表时间：
2013
影响因子：
4.3
通讯作者：
Domingues FS
中科院分区：
文献类型：
--
作者：
Bozek K;Lengauer T;Sierra S;Kaiser R;Domingues FS
HIV嗜性与疾病进展的关系以及最近开发的CCR 5阻断药物强调了监测病毒辅助受体使用的重要性。作为昂贵的表型测定的替代方法，计算方法旨在基于病毒gp 120蛋白的V3环的序列和结构来预测病毒嗜性。在这里，我们提出了一个数字描述符的V3环编码其物理化学和结构特性。该描述符允许基于结构的预测HIV嗜性和鉴定V3环的性质，这对辅助受体的使用至关重要。与仅基于V3序列的预测相比，使用所提出的描述符进行预测导致统计学显著改善，AUC改善3个百分点，11/25规则特异性（95%）的灵敏度改善7个百分点。我们还评估了新方法对临床来源的“批量”序列数据的预测能力，并获得了比基于序列的预测3个百分点的AUC统计学显著改善。此外，我们通过将其应用于接受马拉韦罗治疗的患者的53个样本，证明了我们的方法预测治疗结果的能力。通过对向性信息环结构特征的分析，指出了两个环区的重要性及其理化性质。这些区域位于环茎的相对链上，并且各自的特征主要与电荷、疏水性和结构相关。这些区域在环的结合构象中非常接近，可能形成辅助受体结合的位点决定簇。该方法可通过http://structure.bioinf.mpi-inf.mpg.de/下的服务器获得。人类免疫缺陷病毒（HIV）需要趋化因子辅助受体CCR 5或CXCR 4之一来进入宿主细胞。病毒利用一种或两种辅助受体的能力称为嗜性。由于嗜CXCR 4病毒的出现与免疫缺陷进展的关系，以及最近开发的CCR 5拮抗剂对患者的治疗，因此监测HIV嗜性非常重要。预测HIV嗜性的计算方法是基于病毒gp 120蛋白的第三可变区（V3环）的序列和结构-HIV嗜性的主要决定因素。现有方法的局限性包括它们提供的对辅助受体使用的生化决定因素的有限见解、基于结构的方法的高计算负荷和对临床来源的患者样品的低预测准确性。在这里，我们提出了一个数字描述符的V3循环编码的物理化学和结构特性的循环。新的描述符允许基于服务器的病毒向性预测，其准确性与基于克隆和临床来源的患者数据的已建立的基于序列的方法的准确性相当，以及用于解释与向性相关的环的性质。该服务器可在http://structure.bioinf.mpi-inf.mpg.de/上找到。
The relationship of HIV tropism with disease progression and the recent development of CCR5-blocking drugs underscore the importance of monitoring virus coreceptor usage. As an alternative to costly phenotypic assays, computational methods aim at predicting virus tropism based on the sequence and structure of the V3 loop of the virus gp120 protein. Here we present a numerical descriptor of the V3 loop encoding its physicochemical and structural properties. The descriptor allows for structure-based prediction of HIV tropism and identification of properties of the V3 loop that are crucial for coreceptor usage. Use of the proposed descriptor for prediction results in a statistically significant improvement over the prediction based solely on V3 sequence with 3 percentage points improvement in AUC and 7 percentage points in sensitivity at the specificity of the 11/25 rule (95%). We additionally assessed the predictive power of the new method on clinically derived ‘bulk’ sequence data and obtained a statistically significant improvement in AUC of 3 percentage points over sequence-based prediction. Furthermore, we demonstrated the capacity of our method to predict therapy outcome by applying it to 53 samples from patients undergoing Maraviroc therapy. The analysis of structural features of the loop informative of tropism indicates the importance of two loop regions and their physicochemical properties. The regions are located on opposite strands of the loop stem and the respective features are predominantly charge-, hydrophobicity- and structure-related. These regions are in close proximity in the bound conformation of the loop potentially forming a site determinant for the coreceptor binding. The method is available via server under http://structure.bioinf.mpi-inf.mpg.de/. Human Immunodeficiency Virus (HIV) requires one of the chemokine coreceptors CCR5 or CXCR4 for entry into the host cell. The capacity of the virus to use one or both of these coreceptors is termed tropism. Monitoring HIV tropism is of high importance due to the relationship of the emergence of CXCR4-tropic virus with the progression of immunodeficiency and for patient treatment with the recently developed CCR5 antagonists. Computational methods for predicting HIV tropism are based on sequence and on structure of the third variable region (V3 loop) of the viral gp120 protein — the major determinant of the HIV tropism. Limitations of the existing methods include the limited insights they provide into the biochemical determinants of coreceptor usage, high computational load of the structure-based methods and low prediction accuracy on clinically derived patient samples. Here we propose a numerical descriptor of the V3 loop encoding the physicochemical and structural properties of the loop. The new descriptor allows for server-based prediction of viral tropism with accuracy comparable to that of established sequence-based methods both on clonal and clinically derived patient data as well as for the interpretation of the properties of the loop relevant for tropism. The server is available under http://structure.bioinf.mpi-inf.mpg.de/.
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DOI：
10.1093/bioinformatics/8.3.275
发表时间：
1992-06-01
期刊：
COMPUTER APPLICATIONS IN THE BIOSCIENCES
影响因子：
--
作者：
JONES, DT;TAYLOR, WR;THORNTON, JM
通讯作者：
THORNTON, JM
影响因子：
2.9
作者：
ISOGAI, Y;NEMETHY, G;SCHERAGA, HA
通讯作者：
SCHERAGA, HA
DOI：
10.1073/pnas.0408677102
发表时间：
2005-05-03
影响因子：
11.1
作者：
Atchley, WR;Zhao, JP;Drüke, T
通讯作者：
Drüke, T
影响因子：
56.9
作者：
Huang, Chih-chin;Lam, Son N.;Kwong, Peter D.
通讯作者：
Kwong, Peter D.
影响因子：
5.4
作者：
Jensen, MA;Li, FS;Mullins, JI
通讯作者：
Mullins, JI