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抑制病毒复制可减少转录活性不同的乙型肝炎病毒整合,从

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发表于 2022-3-17 12:37 |显示全部帖子
抑制病毒复制可减少转录活性不同的乙型肝炎病毒整合,从而影响宿主基因失调

    徐耀春
    维提卡·苏瑞
    敏迪·H·阮
    大卫 Z. 潘
    阿努杰·加格
    翁德雷·波德拉哈
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发布时间:2022 年 1 月 4 日 DOI:https://doi.org/10.1053/j.gastro.2021.12.286
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背景与目标
乙型肝炎病毒 (HBV) 感染的肝细胞癌发生可能源于病毒 DNA 整合到宿主基因组中。我们旨在评估病毒抑制对转录活跃的HBV-宿主整合事件的影响,并探索病毒整合与宿主基因失调的相关性。
方法
我们利用了一项介入试验的数据和生物样本,其中 HBV 病毒血症高于 2000 IU/mL 且血清肝酶升高程度最低的患者被随机分配接受富马酸替诺福韦酯 (TDF) 或安慰剂治疗 3 年。对 119 名患者在 3 年干预前后进行的配对肝活检进行了总 RNA 测序。捕获病毒宿主嵌合读数以量化不同病毒整合的数量。被病毒整合破坏的宿主基因的失调定义为与没有病毒整合的样品相差 >2 个标准差的异常表达。
结果
TDF (n = 64) 和安慰剂组 (n = 55) 在基线时具有可比性。在所有治疗前和治疗后样品中检测到表达的病毒整合。不同病毒整合的数量与指示病毒活性的循环生物标志物显着相关,包括 HBV DNA、RNA 和病毒抗原(所有相关性 P < .0003)。此外,TDF 与安慰剂相比,显着降低了不同的病毒整合,每百万读数的表达整合分别减少了 3.28 倍和 1.81 倍(协方差分析,P = .037)。此外,病毒整合与宿主基因失调显着相关。
结论
病毒复制的抑制减少了具有大量病毒血症的患者中转录活性不同的HBV-宿主DNA整合的数量。鉴于病毒整合的诱变潜力,在患者管理中应考虑这种治疗效果。

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发表于 2022-3-17 12:37 |显示全部帖子
Inhibition of Viral Replication Reduces Transcriptionally Active Distinct Hepatitis B Virus Integrations With Implications on Host Gene Dysregulation

    Yao-Chun Hsu
    Vithika Suri
    Mindie H. Nguyen
    David Z. Pan
    Anuj Gaggar
    Ondrej Podlaha
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Published:January 04, 2022DOI:https://doi.org/10.1053/j.gastro.2021.12.286
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Background & aims
Hepatocellular carcinogenesis of hepatitis B virus (HBV) infection may arise from integration of viral DNA into the host genome. We aimed to gauge the effect of viral inhibition on transcriptionally active HBV-host integration events and explore the correlation of viral integrations with host gene dysregulation.
Methods
We leveraged data and biospecimens from an interventional trial, in which patients with HBV viremia above 2000 IU/mL and minimally raised serum liver enzyme were randomized to receive tenofovir disoproxil fumarate (TDF) or placebo for 3 years. Total RNA-sequencing was performed on paired liver biopsies taken before and after the 3-year intervention in 119 patients. Virus-host chimeric reads were captured to quantify the number of distinct viral integrations. Dysregulation of a host gene disrupted by viral integration was defined by aberrant expression >2 standard deviations away from samples without viral integration.
Results
The TDF (n = 64) and placebo groups (n = 55) were comparable at baseline. Expressed viral integrations were detected in all pre- and posttreatment samples. The number of distinct viral integrations significantly correlated with circulatory biomarkers indicative of viral activities including HBV DNA, RNA, and viral antigens (P < .0003 for all correlations). Moreover, TDF vs placebo achieved a significantly greater reduction in distinct viral integrations, with 3.28-fold and 1.81-fold decreases in the expressed integrations per million reads, respectively (analysis of covariance, P = .037). Besides, viral integrations significantly correlated with host gene dysregulation.
Conclusion
Inhibition of viral replication reduces the number of transcriptionally active distinct HBV-host DNA integrations in patients with substantial viremia. Given the mutagenic potentials of viral integrations, such treatment effects should be considered in patient management.
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