抑制病毒复制可减少转录活性不同的乙型肝炎病毒整合与宿

StephenW

胃肠病学

. 2022 年 1 月 4 日；S0016-5085(22)00006-3。
doi: 10.1053/j.gastro.2021.12.286。在印刷之前在线。
抑制病毒复制可减少转录活性不同的乙型肝炎病毒整合与宿主基因失调的影响
Yao-Chun Hsu 1 , Vithika Suri 2 , Mindie H Nguyen 3 , Yen-Tsung Huang 4 , Chi-Yi Chen 5 , I-Wei Chang 6 , Cheng-Ha Teng 7 , Chun-Ying Wu 8 , Jaw-Town Lin 9 , David Z Pan 2 , Anuj Gaggar 2 , Ondrej Podlaha 10
隶属关系
隶属关系

    1
    台湾高雄义大医院肠胃肝病科；；台湾高雄义守大学医学院医学院；；国立阳明交通大学生物医学信息学研究所，台北，台湾；；台湾新北辅仁大学附属医院肠胃肝病科。
    2
    吉利德科学公司，美国加利福尼亚州福斯特城。
    3
    美国加利福尼亚州帕洛阿尔托斯坦福大学医学中心胃肠病学和肝病学部；；美国加利福尼亚州帕洛阿尔托市斯坦福大学医学中心流行病学和人口健康系。
    4
    台湾台北中央研究院统计科学研究所。
    5
    台湾嘉义迪特曼森医学基金会嘉义基督教医院肠胃肝病科。
    6
    病理学系，医学院，医学院，台北医科大学，台北，台湾；；台北医科大学万方医院临床病理科，台北，台湾。
    7
    台湾高雄义守大学医学院医学院；；台湾高雄义大肿瘤医院肠胃肝病科。
    8
    国立阳明交通大学生物医学信息学研究所，台北，台湾；；台湾台北荣民总医院转化研究部。
    9
    台湾高雄义大医院肠胃肝病科。
    10
    吉利德科学公司，美国加利福尼亚州福斯特城；。电子地址：[email protected]。

    PMID：34995536 DOI：10.1053/j.gastro.2021.12.286

抽象的

背景与目的：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：我们利用来自一项介入试验的数据和生物样本，其中 HBV 病毒血症高于 2,000 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脏活检进行了总 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<0.0003）。此外，TDF 与安慰剂相比，在不同的病毒整合方面实现了显着更大的减少，每百万读数的表达整合分别减少了 3.28 倍和 1.81 倍（ANCOVA，p = 0.037）。此外，病毒整合与宿主基因失调显着相关。

结论：抑制病毒复制可减少大量病毒血症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。

关键词：抗病毒治疗；慢性乙型肝炎；肝细胞癌变；转录组分析；病毒整合。

版权所有 © 2022 AGA 研究所。由 Elsevier Inc. 出版。保留所有权利。

StephenW

Gastroenterology

. 2022 Jan 4;S0016-5085(22)00006-3.
doi: 10.1053/j.gastro.2021.12.286. Online ahead of print.
Inhibition of Viral Replication Reduces Transcriptionally Active Distinct Hepatitis B Virus Integrations with Implications on Host Gene Dysregulation
Yao-Chun Hsu  1 , Vithika Suri  2 , Mindie H Nguyen  3 , Yen-Tsung Huang  4 , Chi-Yi Chen  5 , I-Wei Chang  6 , Cheng-Hao Tseng  7 , Chun-Ying Wu  8 , Jaw-Town Lin  9 , David Z Pan  2 , Anuj Gaggar  2 , Ondrej Podlaha  10
Affiliations
Affiliations

    1
    Division of Gastroenterology and Hepatology, E-Da Hospital, Kaohsiung, Taiwan;; School of Medicine, College of Medicine, I-Shou University, Kaohsiung, Taiwan;; Institute of Biomedical Informatics, National Yang Ming Chiao Tung University, Taipei, Taiwan;; Division of Gastroenterology and Hepatology, Fu-Jen Catholic University Hospital, New Taipei, Taiwan.
    2
    Gilead Sciences Inc., Foster City, CA, USA.
    3
    Division of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, CA, USA;; Department of Epidemiology and Population Health, Stanford University Medical Center, Palo Alto, CA, USA.
    4
    Institute of Statistical Science, Academia Sinica, Taipei, Taiwan.
    5
    Division of Gastroenterology and Hepatology, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chia-Yi, Taiwan.
    6
    Department of Pathology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan;; Department of Clinical Pathology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.
    7
    School of Medicine, College of Medicine, I-Shou University, Kaohsiung, Taiwan;; Division of Gastroenterology and Hepatology, E-Da Cancer Hospital, Kaohsiung, Taiwan.
    8
    Institute of Biomedical Informatics, National Yang Ming Chiao Tung University, Taipei, Taiwan;; Division of Translational Research, Taipei Veterans General Hospital, Taipei, Taiwan.
    9
    Division of Gastroenterology and Hepatology, E-Da Hospital, Kaohsiung, Taiwan.
    10
    Gilead Sciences Inc., Foster City, CA, USA;. Electronic address: [email protected].

    PMID: 34995536 DOI: 10.1053/j.gastro.2021.12.286

Abstract

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 2,000 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 post-treatment samples. The number of distinct viral integrations significantly correlated with circulatory biomarkers indicative of viral activities including HBV DNA, RNA, and viral antigens (p<0.0003 for all correlations). Moreover, TDF versus 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 (ANCOVA, p=0.037). 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.

Keywords: antiviral treatment; chronic hepatitis B; hepatocellular carcinogenesis; transcriptome analysis; viral integration.

Copyright © 2022 AGA Institute. Published by Elsevier Inc. All rights reserved.