肝损伤有助于消除慢性乙型肝炎中的HBV整合和克隆性肝细胞

StephenW

Liver damage favors the eliminations of HBV integration and clonal hepatocytes in chronic hepatitis B
Gang Hu #  1 , Ming X Huang #  1 , Wei Y Li #  2 , Chong J Gan  1 , Wen X Dong  1 , Xiao M Peng  3
Affiliations
Affiliations

    1
    Center of Infectious Diseases, the Fifth Affiliated Hospital, Sun Yat-Sen University, 52 Meihua East Road, Zhuhai, 519000, Guangdong, China.
    2
    Jining Medical University, Jining, 272057, Shandong, China.
    3
    Center of Infectious Diseases, the Fifth Affiliated Hospital, Sun Yat-Sen University, 52 Meihua East Road, Zhuhai, 519000, Guangdong, China. [email protected].

#
Contributed equally.

    PMID: 33534083 DOI: 10.1007/s12072-020-10125-y

Abstract

Background: HBV integration is suspected to be an obstinate risk factor for hepatocellular carcinoma (HCC) in the era of antiviral therapy. Integration events start to occur in the immunotolerance phase, but their fates in the immune clearance phase have not yet been clarified. Here, we report the influences of liver damage on HBV integration and clonal hepatocyte expansion in patients with chronic hepatitis B (CHB).

Methods: HBV integration breakpoints in liver biopsy samples from 54 CHB patients were detected using a modified next-generation sequencing assay.

Results: A total of 3729 (69 per sample) integration breakpoints were found in the human genome, including some hotspot genes and KEGG pathways, especially in patients with abnormal transaminases. The number of breakpoint types, an integration risk parameter, was negatively correlated with HBV DNA load and transaminase levels. The average, maximum and total frequencies of given breakpoint types, parameters of clonal hepatocyte expansion, were negatively correlated with HBV DNA load, transaminase levels and liver inflammation activity grade score. The HBV DNA load and inflammation activity grade score were further found to be positively correlated with transaminase levels. Moreover, nucleos(t)ide analog (NUC) treatment that normalized transaminases nonsignificantly reduced the types, but significantly increased the average frequency and negated the enrichments of integration breakpoints.

Conclusion: Liver damage mainly removed the inventories of viral integration and clonal hepatocytes in CHB. NUC treatment may have reduced HBV integration but clearly increased clonal hepatocyte expansion, which may explain why HCC risk cannot be ruled out by NUC treatment.

Keywords: Chronic hepatitis B; Clonal expansion; Hepatitis B virus; Hepatocarcinogenesis; Hepatocellular carcinoma; High-throughput viral integration detection; Immune clearance; Inflammation activity; Liver biopsy; Liver damage; Next-generation DNA sequencing; Viral DNA integration.

StephenW

肝损伤有助于消除慢性乙型肝炎中的HBV整合和克隆性肝细胞
Gang Hu＃1，Ming X Huang＃1，Wei Y Li＃2，Chong J Gan 1，Wen X Dong 1，Xiao M Peng 3
隶属关系
隶属关系

    1个
    中山大学附属第五医院传染病中心，广东省珠海市梅花东路52号，广东519000
    2
    济宁医科大学，山东济宁272057
    3
    中山大学附属第五医院传染病中心，广东省珠海市梅花东路52号，广东519000 [email protected]。

＃
贡献均等。

    PMID：33534083 DOI：10.1007 / s12072-020-10125-y

抽象

背景：在抗病毒治疗时代，HBV整合被怀疑是肝细胞癌（HCC）的顽固危险因素。整合事件开始在免疫耐受阶段发生，但它们在免疫清除阶段的命运尚未阐明。在这里，我们报道了慢性乙型肝炎（CHB）患者肝损伤对HBV整合和克隆性肝细胞扩增的影响。

方法：采用改良的下一代测序技术检测54例CHB患者肝活检样本中的HBV整合断裂点。

结果：在人类基因组中共发现3729个整合断点，包括一些热点基因和KEGG通路，特别是转氨酶异常的患者。断点类型的数量（整合风险参数）与HBV DNA负载和转氨酶水平呈负相关。给定断点类型的平均频率，最大频率和总频率，克隆性肝细胞扩增参数与HBV DNA负荷，转氨酶水平和肝脏炎症活性等级得分呈负相关。进一步发现，HBV DNA负荷和炎症活性等级评分与转氨酶水平呈正相关。此外，归一化转氨酶标准化的核苷类似物（NUC）处理无明显减少类型，但显着增加了平均频率，并消除了整合断点的富集。

结论：肝损伤主要清除了CHB中病毒整合和克隆肝细胞的清单。 NUC治疗可能减少了HBV整合，但明显增加了克隆肝细胞的扩增，这可以解释为什么NUC治疗不能排除HCC风险。

关键字：慢性乙型肝炎；克隆扩增；乙型肝炎病毒;肝癌发生；肝细胞癌；高通量病毒整合检测；免疫清除；炎症活动；肝活检；肝损害;下一代DNA测序病毒DNA整合。

StephenW

https://link.springer.com/conten ... 072-020-10125-y.pdf