Evolutionary dynamics of hepatitis C virus envelope genes during chronic infection
Evolutionary dynamics of hepatitis C virus envelope genes during chronic infection
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DOI：
10.1099/vir.0.80957-0
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发表时间：
2005-07-01
影响因子：
3.8
通讯作者：
Ball, JK
中科院分区：
文献类型：
--
作者：
Brown, RJP;Juttla, VS;Ball, JK
丙型肝炎病毒（HCV）包膜糖蛋白E1和E2是宿主免疫应答的重要靶点。编码这些蛋白质的基因表现出高度的变异性，导致不同的表型性状，包括受体结合亲和力和免疫识别和逃逸的改变。为了阐明慢性感染过程中的适应性进化模式，从4个慢性感染个体获得的连续血清样品中产生了一组全长E1 E2克隆。通过使用基于似然的方法进行系统发育推断，评估了循环HCV准种群体的进化动力学，并对d（N）/d（S）比率进行了逐位点分析，以鉴定经历多样化正选择的特定密码子。丙型肝炎病毒感染，再加上选定的网站的数量和分布，患者之间有显着差异，强调慢性感染期间的丙型肝炎病毒的演变是一个患者特异性的现象。这一分析表明，净化选择是慢性感染中HCV群体的主要力量。虽然在E1中没有观察到阳性选择的显著证据，但在E2蛋白的胞外域内鉴定了许多阳性选择位点。所有这些位点都位于假设暴露于宿主选择性环境的区域，包括许多已报道参与免疫逃避和受体结合的功能定义的结构域。用于估计潜在HCV突变率的过时提示方法也适用于数据，从而能够预测每个患者准种的最近共同祖先。
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.