Genomic modeling of hepatitis B virus integration frequency in the human genome

Podlaha, Ondřej; Wu, George Y.; Downie, Bryan; Ramamurthy, Raghuraman; Gaggar, Anuj; Subramanian, Mani; Ye, Zhishen; Jiang, Zhaoshi

doi:10.1371/journal.pone.0220376

Cited by 36 publications

(32 citation statements)

References 27 publications

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“…Epitopes from Env represent an attractive therapeutic target given that HBsAg elimination is essential to achieve resolution of HBV, with high levels associated with cirrhosis and HCC ( 18 ) and it can be expressed from both cccDNA and integrated DNA. ( 19,20 ) Furthermore, the Env target represented a conserved region, which is shared across all three envelope proteins (short, medium, and long) and CD8 + T Cell responses observed from chronically infected persons supports natural presentation of the epitope. ( 21 ) Therefore, ImmTAV‐Env‐S molecules (hereafter referred to as ImmTAV‐Env) were prioritized for further investigation.…”

Section: Resultsmentioning

confidence: 87%

Immune‐Mobilizing Monoclonal T Cell Receptors Mediate Specific and Rapid Elimination of Hepatitis B–Infected Cells

et al. 2020

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Background and Aims Therapies for chronic hepatitis B virus (HBV) infection are urgently needed because of viral integration, persistence of viral antigen expression, inadequate HBV‐specific immune responses, and treatment regimens that require lifelong adherence to suppress the virus. Immune mobilizing monoclonal T Cell receptors against virus (ImmTAV) molecules represent a therapeutic strategy combining an affinity‐enhanced T Cell receptor with an anti‐CD3 T Cell‐activating moiety. This bispecific fusion protein redirects T cells to specifically lyse infected cells expressing the target virus‐derived peptides presented by human leukocyte antigen (HLA). Approach and Results ImmTAV molecules specific for HLA‐A*02:01‐restricted epitopes from HBV envelope, polymerase, and core antigens were engineered. The ability of ImmTAV‐Env to activate and redirect polyclonal T cells toward cells containing integrated HBV and cells infected with HBV was assessed using cytokine secretion assays and imaging‐based killing assays. Elimination of infected cells was further quantified using a modified fluorescent hybridization of viral RNA assay. Here, we demonstrate that picomolar concentrations of ImmTAV‐Env can redirect T cells from healthy and HBV‐infected donors toward hepatocellular carcinoma (HCC) cells containing integrated HBV DNA resulting in cytokine release, which could be suppressed by the addition of a corticosteroid in vitro. Importantly, ImmTAV‐Env redirection of T cells induced cytolysis of antigen‐positive HCC cells and cells infected with HBV in vitro, causing a reduction of hepatitis B e antigen and specific loss of cells expressing viral RNA. Conclusions The ImmTAV platform has the potential to enable the elimination of infected cells by redirecting endogenous non‐HBV‐specific T cells, bypassing exhausted HBV‐specific T cells. This represents a promising therapeutic option in the treatment of chronic hepatitis B, with our lead candidate now entering trials.

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Section: Resultsmentioning

confidence: 87%

Immune‐Mobilizing Monoclonal T Cell Receptors Mediate Specific and Rapid Elimination of Hepatitis B–Infected Cells

et al. 2020

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“…Genomic integration of HBV sequence can be detected frequently in young patients with IT disease and has been associated with clonal hepatocyte expansion-in fact the rate of HBV integration has been reported to be similar to that in older patients [38]. The frequency of integration events is proportional to HBV viral load, and viral suppression by NA will reduce the risk of integration events [39,40]. Liver carcinogenesis may therefore start during the IT phase of CHB, with pro-oncogenic events accumulating throughout the natural history of disease.…”

Section: "Treatment For All"-a Public Health Approach To Chbmentioning

confidence: 99%

“…NA will reduce the risk of integration events [39,40]. Liver carcinogenesis may therefore start during the IT phase of CHB, with pro-oncogenic events accumulating throughout the natural history of disease.…”

Section: "Treatment For All"-a Public Health Approach To Chbmentioning

confidence: 99%

The Yin and the Yang of Treatment for Chronic Hepatitis B—When to Start, When to Stop Nucleos(t)ide Analogue Therapy

Hall

Howell

Visvanathan

et al. 2020

Viruses

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Over 257 million individuals worldwide are chronically infected with the Hepatitis B Virus (HBV). Nucleos(t)ide analogues (NAs) are the first-line treatment option for most patients. Entecavir (ETV) and tenofovir disoproxil fumarate (TDF) are both potent, safe antiviral agents, have a high barrier to resistance, and are now off patent. They effectively suppress HBV replication to reduce the risk of cirrhosis, liver failure, and hepatocellular carcinoma (HCC). Treatment is continued long-term in most patients, as NA therapy rarely induces HBsAg loss or functional cure. Two diverging paradigms in the treatment of chronic hepatitis B have recently emerged. First, the public health focussed “treat-all” strategy, advocating for early and lifelong antiviral therapy to minimise the risk of HCC as well as the risk of HBV transmission. In LMICs, this strategy may be cost saving compared to monitoring off treatment. Second, the concept of “stopping” NA therapy in patients with HBeAg-negative disease after long-term viral suppression, a personalised treatment strategy aiming for long-term immune control and even HBsAg loss off treatment. In this manuscript, we will briefly review the current standard of care approach to the management of hepatitis B, before discussing emerging evidence to support both the “treat-all” strategy, as well as the “stop” strategy, and how they may both have a role in the management of patients with chronic hepatitis B.

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“…Upon BLAT analysis of the identi ed HBV regions against human reference genome, Region 2 was found in intronic regions of several human genes while Region 1 was not. Evaluation of 192 DNA sequences from tumor and corresponding non-tumor samples revealed direct repeat region (DR1), the most common fusion breakpoint of HBV genome [30]. Integration of the HBV "Region 2" into human genome, unlike "Region 1", may result from its close proximity to DR1.…”

Section: Centrosomal Protein 76 Kda (Cep76)mentioning

confidence: 99%

Implications of HBV-Driven Epigenetic Remodeling and Its Targets in Liver Cancer Stem Cells

Demir

Benvenuto

Karacicek³

et al. 2020

Preprint

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Background: Elevated levels of STIM1, an endoplasmic reticulum Ca2+ sensor/buffering protein, appear to be correlated with poor cancer prognosis where microRNAs are also known to be involved. We investigated a possible viral origin of specific microRNAs identified in Huh-7 human liver cancer stem cells with enhanced STIM1 expression. Methods: Computational strategies including phylogenetic analyses were performed on miRNome data obtained from Huh-7 liver cancer stem cells with enhanced STIM1 and/or Orai1 expression originally cultured in the present study. Results: Results revealed two putative regions in HBV genome based on apparent clustering pattern of stem loop sequences of microRNAs, including miR3653. Reciprocal analysis of these regions revealed critical human genes of which their transcripts are among the predicted targets of miR3653 which was increased significantly by STIM1 enhancement. Conclusion: This study presents a phylogenetic evidence for an HBV-driven epigenetic remodeling to alter gene expression pattern associated with Ca2+ homeostasis in STIM1-overexpressing liver cancer stem cells for a possible mutual survival outcome. A novel region on HBV-X protein may affect liver carcinogenesis in a genotype-dependent manner. Therefore, detection of the HBV genotype would have a clinical impact on prognosis.

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Genomic modeling of hepatitis B virus integration frequency in the human genome

Cited by 36 publications

References 27 publications

Immune‐Mobilizing Monoclonal T Cell Receptors Mediate Specific and Rapid Elimination of Hepatitis B–Infected Cells

Immune‐Mobilizing Monoclonal T Cell Receptors Mediate Specific and Rapid Elimination of Hepatitis B–Infected Cells

The Yin and the Yang of Treatment for Chronic Hepatitis B—When to Start, When to Stop Nucleos(t)ide Analogue Therapy

Implications of HBV-Driven Epigenetic Remodeling and Its Targets in Liver Cancer Stem Cells

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