Deforche K, Camacho R, Van Laethem K, Lemey P, Rambaut A, Moreau Y, Vandamme A-M
Rega Institute for Medical Research, Katholieke Universiteit Leuven, Leuven, Belgium.
Bioinformatics. 2008 Jan 1;24(1):34-41. doi: 10.1093/bioinformatics/btm540. Epub 2007 Nov 17.
HIV-1 antiviral resistance is a major cause of antiviral treatment failure. The in vivo fitness landscape experienced by the virus in presence of treatment could in principle be used to determine both the susceptibility of the virus to the treatment and the genetic barrier to resistance. We propose a method to estimate this fitness landscape from cross-sectional clinical genetic sequence data of different subtypes, by reverse engineering the required selective pressure for HIV-1 sequences obtained from treatment naive patients, to evolve towards sequences obtained from treated patients. The method was evaluated for recovering 10 random fictive selective pressures in simulation experiments, and for modeling the selective pressure under treatment with the protease inhibitor nelfinavir.
The estimated fitness function under nelfinavir treatment considered fitness contributions of 114 mutations at 48 sites. Estimated fitness correlated significantly with the in vitro resistance phenotype in 519 matched genotype-phenotype pairs (R(2) = 0.47 (0.41 - 0.54)) and variation in predicted evolution under nelfinavir selective pressure correlated significantly with observed in vivo evolution during nelfinavir treatment for 39 mutations (with FDR = 0.05).
The software is available on request from the authors, and data sets are available from http://jose.med.kuleuven.be/~kdforc0/nfv-fitness-data/.
HIV-1抗病毒耐药性是抗病毒治疗失败的主要原因。原则上，病毒在治疗过程中所经历的体内适应性景观可用于确定病毒对治疗的敏感性以及耐药性的遗传屏障。我们提出了一种方法，通过对从未经治疗的患者获得的HIV-1序列逆向工程所需的选择压力，使其向从接受治疗的患者获得的序列进化，从而从不同亚型的横断面临床基因序列数据中估计这种适应性景观。该方法在模拟实验中评估了恢复10种随机虚拟选择压力的能力，并用于模拟蛋白酶抑制剂奈非那韦治疗下的选择压力。
奈非那韦治疗下估计的适应性函数考虑了48个位点处114个突变的适应性贡献。在519对匹配的基因型-表型对中，估计的适应性与体外耐药表型显著相关（R(2)=0.47(0.41 - 0.54)），并且在奈非那韦选择压力下预测进化的变化与奈非那韦治疗期间39个突变的体内观察进化显著相关（FDR = 0.05）。
该软件可根据作者要求提供，数据集可从http://jose.med.kuleuven.be/~kdforc0/nfv-fitness-data/获取。
