A systems analysis of mutational effects in HIV-1 protease and reverse transcriptase
A systems analysis of mutational effects in HIV-1 protease and reverse transcriptase
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DOI：
10.1038/ng.795
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发表时间：
2011-05-01
期刊：
影响因子：
30.8
通讯作者：
Bonhoeffer, Sebastian
中科院分区：
文献类型：
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作者：
Hinkley, Trevor;Martins, Joao;Bonhoeffer, Sebastian
鉴于大量可用的药物和耐药突变，对病毒进化和HIV-1耐药性适应性景观的定量理解的发展是一个艰巨的挑战。我们分析了一个数据集，该数据集测量了从接受常规耐药检测的HIV-1 B亚型感染者中分离的70，081份病毒样本的体外适应性。我们测定了病毒样品在体外复制能力的药物存在下，以及在15个单独的药物。我们采用广义核岭回归估计主要的健身效果和上位相互作用的1,859个单一的氨基酸变异的HIV-1蛋白酶和逆转录酶序列内发现。包括上位性相互作用的模型预测的平均值为54.8%的变异在16个不同的环境中的复制能力，并大大优于模型的基础上的主要健身效果。我们发现，HIV-1蛋白酶和逆转录酶的适应度景观的特点是强烈的上位性。
The development of a quantitative understanding of viral evolution and the fitness landscape in HIV-1 drug resistance is a formidable challenge given the large number of available drugs and drug resistance mutations. We analyzed a dataset measuring the in vitro fitness of 70,081 virus samples isolated from HIV-1 subtype B infected individuals undergoing routine drug resistance testing. We assayed virus samples for in vitro replicative capacity in the absence of drugs as well as in the presence of 15 individual drugs. We employed a generalized kernel ridge regression to estimate main fitness effects and epistatic interactions of 1,859 single amino acid variants found within the HIV-1 protease and reverse transcriptase sequences. Models including epistatic interactions predict an average of 54.8% of the variance in replicative capacity across the 16 different environments and substantially outperform models based on main fitness effects only. We find that the fitness landscape of HIV-1 protease and reverse transcriptase is characterized by strong epistasis.