Brown Richard J P, Juttla Vicky S, Tarr Alexander W, Finnis Rebecca, Irving William L, Hemsley Shelley, Flower Darren R, Borrow Persephone, Ball Jonathan K
Microbiology and Infectious Diseases, Institute of Infection, Immunity and Inflammation, The University of Nottingham, Queen's Medical Centre, Nottingham NG7 2UH, UK.
The Edward Jenner Institute for Vaccine Research, Compton, Newbury, Berkshire RG20 7NN, UK.
J Gen Virol. 2005 Jul;86(Pt 7):1931-1942. doi: 10.1099/vir.0.80957-0.
Hepatitis C virus (HCV) envelope glycoproteins E1 and E2 are important targets for the host immune response. The genes encoding these proteins exhibit a high degree of variability that gives rise to differing phenotypic traits, including alterations in receptor-binding affinity and immune recognition and escape. In order to elucidate patterns of adaptive evolution during chronic infection, a panel of full-length E1E2 clones was generated from sequential serum samples obtained from four chronically infected individuals. By using likelihood-based methods for phylogenetic inference, the evolutionary dynamics of circulating HCV quasispecies populations were assessed and a site-by-site analysis of the d(N)/d(S) ratio was performed, to identify specific codons undergoing diversifying positive selection. HCV phylogenies, coupled with the number and distribution of selected sites, differed markedly between patients, highlighting that HCV evolution during chronic infection is a patient-specific phenomenon. This analysis shows that purifying selection is the major force acting on HCV populations in chronic infection. Whilst no significant evidence for positive selection was observed in E1, a number of sites under positive selection were identified within the ectodomain of the E2 protein. All of these sites were located in regions hypothesized to be exposed to the selective environment of the host, including a number of functionally defined domains that have been reported to be involved in immune evasion and receptor binding. Dated-tip methods for estimation of underlying HCV mutation rates were also applied to the data, enabling prediction of the most recent common ancestor for each patient's quasispecies.
丙型肝炎病毒（HCV）包膜糖蛋白E1和E2是宿主免疫反应的重要靶点。编码这些蛋白的基因表现出高度的变异性，从而产生不同的表型特征，包括受体结合亲和力、免疫识别和逃逸的改变。为了阐明慢性感染期间的适应性进化模式，从四名慢性感染个体的连续血清样本中生成了一组全长E1E2克隆。通过使用基于似然性的系统发育推断方法，评估了循环HCV准种群体的进化动态，并对d(N)/d(S)比率进行了逐位点分析，以识别经历多样化正选择的特定密码子。患者之间的HCV系统发育以及所选位点的数量和分布存在显著差异，突出表明慢性感染期间的HCV进化是一种患者特异性现象。该分析表明，净化选择是慢性感染中作用于HCV群体的主要力量。虽然在E1中未观察到正选择的显著证据，但在E2蛋白的胞外域内鉴定出了一些正选择位点。所有这些位点都位于假定暴露于宿主选择环境的区域，包括一些据报道参与免疫逃逸和受体结合的功能定义域。还将用于估计潜在HCV突变率的日期-末端方法应用于这些数据，从而能够预测每位患者准种的最近共同祖先。
