Whole genome HBV deletion profiles and the accumulation of preS deletion mutant during antiviral treatment.
Whole genome HBV deletion profiles and the accumulation of preS deletion mutant during antiviral treatment.
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全基因组 HBV 缺失谱和抗病毒治疗期间 preS 缺失突变体的积累。
DOI：
10.1186/1471-2180-12-307
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发表时间：
2012-12-28
期刊：
影响因子：
4.2
通讯作者：
Zeng C
中科院分区：
文献类型：
--
作者：
Zhang D;Dong P;Zhang K;Deng L;Bach C;Chen W;Li F;Protzer U;Ding H;Zeng C
B型肝炎病毒（HBV）由于其易于出错的病毒聚合酶而具有高突变率，导致HBV基因组中广泛的替换、缺失和插入。缺失可能会显著改变病毒的生物学特征，使肝病进展复杂化。然而，与缺失突变体积累相关的临床状况仍不清楚。在这项研究中，我们通过对51例B型肝炎患者的样本进行全基因组测序，并通过监测治疗期间缺失变异体的变化，探索HBV缺失模式及其与疾病状态和抗病毒治疗的相关性。克隆测序用于分析另一组52例患者的preS区。在核心，前S，和基本核心启动子（BCP）缺失热点，我们确定前S具有最高的频率和最复杂的缺失模式，使用全基因组测序。对preS进一步克隆测序分析，鉴定出70个缺失，分为4种类型，最常见的是preS 2。此外，与核心和BCP区域相反，大多数preS缺失是框内的。大多数缺失都会中断病毒表面表位，并且可能参与逃避免疫监视。Logistic回归分析显示，抗病毒药物治疗影响缺失突变的累积（OR = 6.81，95% CI = 1.296 ~ 35.817，P = 0.023）。在慢性病毒携带者和慢性肝炎患者中，抗病毒治疗组的缺失率显著较高（Fisher精确检验，P = 0.007）。特别是，preS 2缺失与核苷（酸）类似物治疗的使用相关（Fisher精确检验，P = 0.023）。在ADV治疗前和治疗后3个月的患者样本准种中也观察到preS 1或preS 2缺失的动态增加。体外实验表明，单独的preS 2缺失不负责抗病毒耐药性，这意味着在病毒存活和疾病发展过程中野生型和突变株之间的协调。我们目前的HBV缺失分布模式和前S缺失的病毒基因组中的亚结构，是流行于北方中国。在核苷（酸）类似物治疗期间preS缺失突变体的积累可能是由于病毒逃避宿主免疫监视。
Hepatitis B virus (HBV), because of its error-prone viral polymerase, has a high mutation rate leading to widespread substitutions, deletions, and insertions in the HBV genome. Deletions may significantly change viral biological features complicating the progression of liver diseases. However, the clinical conditions correlating to the accumulation of deleted mutants remain unclear. In this study, we explored HBV deletion patterns and their association with disease status and antiviral treatment by performing whole genome sequencing on samples from 51 hepatitis B patients and by monitoring changes in deletion variants during treatment. Clone sequencing was used to analyze preS regions in another cohort of 52 patients. Among the core, preS, and basic core promoter (BCP) deletion hotspots, we identified preS to have the highest frequency and the most complex deletion pattern using whole genome sequencing. Further clone sequencing analysis on preS identified 70 deletions which were classified into 4 types, the most common being preS2. Also, in contrast to the core and BCP regions, most preS deletions were in-frame. Most deletions interrupted viral surface epitopes, and are possibly involved in evading immuno-surveillance. Among various clinical factors examined, logistic regression showed that antiviral medication affected the accumulation of deletion mutants (OR = 6.81, 95% CI = 1.296 ~ 35.817, P = 0.023). In chronic carriers of the virus, and individuals with chronic hepatitis, the deletion rate was significantly higher in the antiviral treatment group (Fisher exact test, P = 0.007). Particularly, preS2 deletions were associated with the usage of nucleos(t)ide analog therapy (Fisher exact test, P = 0.023). Dynamic increases in preS1 or preS2 deletions were also observed in quasispecies from samples taken from patients before and after three months of ADV therapy. In vitro experiments demonstrated that preS2 deletions alone were not responsible for antiviral resistance, implying the coordination between wild type and mutant strains during viral survival and disease development. We present the HBV deletion distribution patterns and preS deletion substructures in viral genomes that are prevalent in northern China. The accumulation of preS deletion mutants during nucleos(t)ide analog therapy may be due to viral escape from host immuno-surveillance.
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影响因子：
2.6
作者：
Fukuda, R;Ishimura, N;Fukumoto, S
通讯作者：
Fukumoto, S
影响因子：
13.5
作者：
Cho, SW;Hahm, KB;Kim, JH
通讯作者：
Kim, JH
影响因子：
4.7
作者：
Wang, Lily Hui-Ching;Huang, Wenya;Su, Ih-Jen
通讯作者：
Su, Ih-Jen
影响因子：
13.5
作者：
Preikschat, P;Günther, S;Meisel, H
通讯作者：
Meisel, H
DOI：
10.1099/vir.0.2008/002824-0
发表时间：
2008-11
期刊：
The Journal of general virology
影响因子：
--
作者：
Fang ZL;Sabin CA;Dong BQ;Wei SC;Chen QY;Fang KX;Yang JY;Huang J;Wang XY;Harrison TJ
通讯作者：
Harrison TJ