核苷（酸）类似物对乙型肝炎病毒 DNA 整合的影响：炒作还是

StephenW

核苷（酸）类似物对乙型肝炎病毒 DNA 整合的影响：炒作还是现实？

    特蕾莎·波利奇诺

发布时间：2022 年 1 月 31 日 DOI：https://doi.org/10.1053/j.gastro.2022.01.039
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参见第 1160 页 Hsu Y-C、Suri V、Nguyen MH 等人的“抑制病毒复制减少转录活性不同的乙型肝炎病毒整合对宿主基因失调的影响”。
在其生命周期中，乙型肝炎病毒 (HBV) 会产生一个核共价闭合环状 DNA 微型染色体——负责持续感染的关键复制中间体——以及整合的 DNA 序列。 1
,2
这些整合序列被认为是 HBV 复制的副产品，因为它们不直接促进病毒后代的产生。 1
HBV DNA 整合发生在感染的早期阶段，以及慢性感染的所有阶段。 3
, 4
, 5
因此，病毒整合诱导的细胞基因组改变可能在急性或慢性病毒性肝炎过程中积累，并在乙型肝炎表面抗原（HBsAg）血清清除后持续存在。 4
, 5
, 6
, 7
大多数关于 HBV 整合的研究都集中在其促进肝细胞癌 (HCC) 发展的潜力上，5
而关于 HBV 整合在慢性乙型肝炎 (CHB) 过程中如何演变及其在调节慢性感染肝细胞的基因组和转录组谱中的作用知之甚少。此外，关于抗病毒治疗是否可能对 HBV 宿主整合事件产生影响的问题仍然几乎完全未探索。在本期胃肠病学中，Hsu 等人 8
通过利用随机临床试验的数据和生物样本来解决这些问题，在该试验中，初治轻度或中度 CHB 患者被随机分配接受富马酸替诺福韦二吡呋酯 (TDF) 或安慰剂治疗 3 年。 9
Hsu 等人的研究纳入了所有 CHB 患者8
在接受治疗前和完成 3 年试验后接受肝活检。因此，作者有难得的机会研究配对的新鲜冷冻肝活检和来自 119 名 CHB 患者的血液样本，其中 64 名接受 TDF 和 55 名安慰剂。因此，有可能评估对照组以对治疗效果进行有意义的估计。通过 RNA 测序和应用特定的计算流程，作者证明，与安慰剂治疗相比，使用 TDF 治疗 3 年显着减少了不同的转录活性病毒整合的数量（分别减少 3.28 倍和 1.81 倍； P = .037)（图 1）。作者进一步表明，不同病毒整合的数量与不同人类基因的失调表达密切相关，包括已知可能驱动肝细胞癌发生的基因，以及 HCC 相关途径的扰动（图 1）。这些发现支持病毒整合的诱变潜力，导致 Hsu 等人 8
推断对HBV整合的抗病毒治疗活性可能最终对预防HCC发展产生影响。

StephenW

The Impact of Nucleos(t)ide Analogs on Hepatitis B Virus DNA Integration: Hype or Reality?

    Teresa Pollicino

Published: January 31, 2022 DOI: https://doi.org/10.1053/j.gastro.2022.01.039
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See “Inhibition of viral replication reduces transcriptionally active distinct hepatitis B virus integrations with implications on host gene dysregulation,” by Hsu Y-C, Suri V, Nguyen MH, et al, on page 1160.
During its life cycle, hepatitis B virus (HBV) generates a nuclear covalently closed circular DNA minichromosome—the key replicative intermediate responsible for the persistence of infection—as well as integrated DNA sequences.1
,2
These integrated sequences are considered a byproduct of HBV replication, as they do not directly contribute to the production of virus progeny.1
HBV DNA integration occurs in the early stages of infection, as well as throughout all of the phases of a chronic infection.3
, 4
, 5
Thus, the cell genomic alterations induced by viral integration may accumulate in the course of acute or chronic viral hepatitis and persist after hepatitis B surface antigen (HBsAg) seroclearance.4
, 5
, 6
, 7
Most of the research on HBV integration has focused on its potential to promote hepatocellular carcinoma (HCC) development,5
whereas much less is known about how HBV integration evolves in the course of chronic hepatitis B (CHB) and its role in modulating the genomic and transcriptomic profiles of chronically infected hepatocytes. Furthermore, the question relating to whether antiviral treatment may have an impact on HBV –host integration events has remained almost completely unexplored. In the current issue of Gastroenterology, Hsu et al8
tackle these issues by exploiting data and biological samples from a randomized clinical trial in which treatment-naïve patients with mild or moderate CHB were randomly assigned to receive tenofovir disoproxil fumarate (TDF) or placebo for 3 years.9
All patients with CHB enrolled in the study by Hsu et al8
underwent liver biopsy before receiving treatments and after completing the 3-year trial. Therefore, the authors had the rare opportunity to study paired fresh-frozen liver biopsies and blood samples from 119 patients with CHB, 64 receiving TDF and 55 placebo. Thus, having the possibility to evaluate a control group for meaningful estimates of treatment effects. By means of RNA sequencing and applying a specific computational pipeline, the authors demonstrated that treatment with TDF for 3 years significantly decreased the number of distinct transcriptionally active viral integrations in comparison with placebo treatment (3.28-fold reduction vs 1.81-fold reduction, respectively; P = .037) (Figure 1). The authors further showed that the number of distinct viral integrations was strongly associated with both dysregulated expression of different human genes, including those known to potentially drive hepatocellular carcinogenesis, and perturbation of HCC-related pathways (Figure 1). These findings, supporting the mutagenic potentials of viral integrations, led Hsu et al8
to infer that antiviral treatment activity on HBV integration may eventually have an effect on preventing HCC development.

StephenW

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