HBV Integration Induces Complex Interactions between Host and Viral Genomic Functions at the Insertion Site

Zhang, Dake; Zhang, Ke; Protzer, U.; Zeng, Changqing

doi:10.14218/jcth.2021.00062

Cited by 10 publications

(8 citation statements)

References 111 publications

(231 reference statements)

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“…One approach to address potential bias is digital droplet PCR (ddPCR) and it is reassuring to see consistent observations between our study and that of Prakash et al, who used this method [ 24 ]. Several studies have identified chimeric human-viral transcripts where HBV integrates in the proximity of promoters or inter/intra- genic region (reviewed in [ 45 ]). Our PCR approach cannot discriminate between chimeric 5’-human-HBV-3’ RNA transcripts and authentic viral RNAs.…”

Section: Discussionmentioning

confidence: 99%

Inflammatory Gene Expression Associates with Hepatitis B Virus cccDNA- but Not Integrant-Derived Transcripts in HBeAg Negative Disease

Magrì

Harris

D’Arienzo

et al. 2022

Viruses

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Chronic hepatitis B virus (HBV) infection is a global health problem that presents as a spectrum of liver disease, reflecting an interplay between the virus and the host immune system. HBV genomes exist as episomal covalently closed circular DNA (cccDNA) or chromosomal integrants. The relative contribution of these genomes to the viral transcriptome in chronic hepatitis B (CHB) is not well-understood. We developed a qPCR method to estimate the abundance of HBV cccDNA- and integrant-derived viral transcripts and applied this to a cohort of patients diagnosed with CHB in the HBe antigen negative phase of disease. We noted a variable pattern of HBV transcripts from both DNA templates, with preS1/S2 mRNAs predominating and a significant association between increasing age and the expression of integrant-derived mRNAs, but not with inflammatory status. In contrast, cccDNA-derived transcripts were associated with markers of liver inflammation. Analysis of the inflammatory hepatic transcriptome identified 24 genes significantly associated with cccDNA transcriptional activity. Our study uncovers an immune gene signature that associates with HBV cccDNA transcription and increases our understanding of viral persistence.

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Section: Discussionmentioning

confidence: 99%

Inflammatory Gene Expression Associates with Hepatitis B Virus cccDNA- but Not Integrant-Derived Transcripts in HBeAg Negative Disease

Magrì

Harris

D’Arienzo

et al. 2022

Viruses

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“…Theoretically, transcripts detected by RT-Alu-PCR targeting the X region would have a relatively higher level than those detected by targeting the S region. The inconsistent result observed by Erken et al (figure 2 of their study) could be explained by the instability and inward shortening of the integrated HBV fragments along with disease progression, [2,3] making it impossible to detect the 3′ truncated chimeric S and X transcripts. Indeed, levels of integrated HBV DNA containing open reading frame (ORF) X (but not S) in the chronic HBV-infected individuals (ChI) group were lower than those in the HBeAg-negative chronic hepatitis B (CH) group (figure 4A,D of their study).…”

mentioning

confidence: 73%

Letter to the editor: Low sensitivity of RT‐Alu‐PCR in detection of HBV integrated chimeric transcripts

Abulaiti

Jiang

et al. 2022

Hepatology

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To the editor, We read with great interest the study by Erken et al. in which they developed Alu-PCR and RT-Alu-PCR for quantitative detection of integrated HBV DNA and their chimeric transcripts, respectively. [1] Because their detection of chimeric transcripts relied on the presence of the Alu sequence, here we demonstrate that a huge amount of chimeric transcripts would not be detected by RT-Alu-PCR. Firstly, up to 468 unique HBV integration sites were identified from two RNA-sequencing (RNA-seq) data sets (GSE94660 and SRA447498) of liver samples derived from 47 HBV-related patients with HCC, through the Viral Integration Site Database. Among them, 344 unique long chimeric transcripts were reconstructed using transcriptome F I G U R E 1 Low proportion of chimeric transcripts containing Alu elements. (A) The unique HBV integration sites in two RNA-seq data sets of liver samples from 47 HBV-related patients with HCC were identified, and the integrated long chimeric transcripts were reconstructed by trinity v2.14.0. (B) Representative screenshots of the integrative genomics viewer (IGV) showing the reconstructed chimeric transcripts in one patient with HBV-related HCC with an Alu element. (C) Representative screenshots of the IGV showing the reconstructed chimeric transcripts in the same patient with HBV-related HCC (B) without an Alu element. (D) Schematic diagram of HBV transcripts sharing the overlapping 3′ end.

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“…Promising data have also emerged on the utility of circulating HBV-human chimeric DNA, resulting from HBV-DNA integration events, as a useful non-invasive biomarker for early identification of HCC development and its recurrence (Li et al, 2018;Liu et al, 2021;Zhang D. et al, 2021; Table 1). In 2019, a study demonstrated, for the first time, the presence of cell-free chimeric HBV-human DNA from blood samples of 20 patients with chronic HBV infection.…”

Section: Hepatitis B Virus Integration As a Diagnostic Biomarker Of H...mentioning

confidence: 99%

Hepatitis B virus DNA integration as a novel biomarker of hepatitis B virus-mediated pathogenetic properties and a barrier to the current strategies for hepatitis B virus cure

et al. 2022

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Chronic infection with Hepatitis B Virus (HBV) is a major cause of liver-related morbidity and mortality worldwide. HBV-DNA integration into the human genome is recognized as a frequent event occurring during the early phases of HBV infection and characterizing the entire course of HBV natural history. The development of refined molecular biology technologies sheds new light on the functional implications of HBV-DNA integration into the human genome, including its role in the progression of HBV-related pathogenesis and in triggering the establishment of pro-oncogenic mechanisms, promoting the development of hepatocellular carcinoma. The present review provides an updated and comprehensive overview of the current body of knowledge on HBV-DNA integration, focusing on the molecular mechanisms underlying HBV-DNA integration and its occurrence throughout the different phases characterizing the natural history of HBV infection. Furthermore, here we discuss the main clinical implications of HBV integration as a biomarker of HBV-related pathogenesis, particularly in reference to hepatocarcinogenesis, and how integration may act as a barrier to the achievement of HBV cure with current and novel antiviral therapies. Overall, a more refined insight into the mechanisms and functionality of HBV integration is paramount, since it can potentially inform the design of ad hoc diagnostic tools with the ability to reveal HBV integration events perturbating relevant intracellular pathways and for identifying novel therapeutic strategies targeting alterations directly related to HBV integration.

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HBV Integration Induces Complex Interactions between Host and Viral Genomic Functions at the Insertion Site

Cited by 10 publications

References 111 publications

Inflammatory Gene Expression Associates with Hepatitis B Virus cccDNA- but Not Integrant-Derived Transcripts in HBeAg Negative Disease

Inflammatory Gene Expression Associates with Hepatitis B Virus cccDNA- but Not Integrant-Derived Transcripts in HBeAg Negative Disease

Letter to the editor: Low sensitivity of RT‐Alu‐PCR in detection of HBV integrated chimeric transcripts

Hepatitis B virus DNA integration as a novel biomarker of hepatitis B virus-mediated pathogenetic properties and a barrier to the current strategies for hepatitis B virus cure

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