Hepatitis B Virus Pregenomic RNA in Hepatocellular Carcinoma: A Nosological and Prognostic Determinant

Halgand, Boris; Desterke, Christophe; Rivière, Lise; Fallot, Guillaume; Sebagh, Mylène; Caldéraro, Julien; Bioulac‐Sage, Paulette; Neuveut, Christine; Buendía, Marie-Annick; Samuel, Didier; Féray, Cyrille

doi:10.1002/hep.29463

Cited by 46 publications

(48 citation statements)

References 19 publications

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“…We suggested that SOX2 may act as a restriction factor to repress HBV replication, not only during the acute infection, but also in the chronic infection and the development of liver diseases [12,20]. Previous studies have reported that HBV mRNA was lower in the HCC tissues relative to the non-tumor liver tissues [21,22]. In this study, we showed that the level of SOX2 was significantly higher in the HBV-positive HCC tissues.…”

Section: Discussionsupporting

confidence: 50%

SOX2 Represses Hepatitis B Virus Replication by Binding to the Viral EnhII/Cp and Inhibiting the Promoter Activation

Yang

et al. 2020

Viruses

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Hepatitis B virus (HBV) replication is controlled by four promoters (preS1, preS2, Cp, and Xp) and two enhancers (EnhI and EnhII). EnhII stimulates Cp activity to regulate the transcriptions of precore, core, polymerase, and pregenomic RNAs, and therefore, EnhII/Cp is essential for the regulation of HBV replication. This study revealed a distinct mechanism underlying the suppression of EnhII/Cp activation and HBV replication. On the one hand, the sex determining region Y box2 (SOX2), a transcription factor, is induced by HBV. On the other hand, SOX2, in turn, represses the expression levels of HBV RNAs, HBV core-associated DNA, hepatitis B surface antigen (HBsAg), and hepatitis B e antigen (HBeAg), thereby playing an inhibitory role during HBV replication. Further studies indicated that SOX2 bound to the EnhII/Cp DNA and repressed the promoter activation. With the deletion of the high mobility group (HMG) domain, SOX2 loses the ability to repress EnhII/Cp activation, viral RNA transcription, HBV core-associated DNA replication, HBsAg and HBeAg production, as well as fails to enter the nucleus, demonstrating that the HMG domain is required for the SOX2-mediated repression of HBV replication. Moreover, SOX2 represses HBsAg and HBeAg secretion in BALB/c mice sera, and attenuates HBV 3.5 kb RNA transcription and hepatitis B virus core protein (HBc) production in the liver tissues, demonstrating that SOX2 suppresses HBV replication in mice. Furthermore, the results revealed that the HMG domain was required for SOX2-mediated repression of HBV replication in the mice. Taken together, the above facts indicate that SOX2 acts as a new host restriction factor to repress HBV replication by binding to the viral EnhII/Cp and inhibiting the promoter activation through the HMG domain.

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Section: Discussionsupporting

confidence: 50%

SOX2 Represses Hepatitis B Virus Replication by Binding to the Viral EnhII/Cp and Inhibiting the Promoter Activation

Yang

et al. 2020

Viruses

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“…Thus, HBV pgRNA is a sensitive marker for viral replication and the prognosis of hepatocellular carcinoma. Furthermore, detection of HBV pgRNA in patient tumours was correlated with an absence of tumorous microvascular invasion and better patient survival …”

Section: Introductionmentioning

confidence: 95%

“…Furthermore, detection of HBV pgRNA in patient tumours was correlated with an absence of tumorous microvascular invasion and better patient survival. 7 In this work, we investigated the dynamic changes in HBV DNA, ALT and the HBeAg status in CHB patients during NA treatment.…”

mentioning

confidence: 99%

Hepatitis B virus pregenomic RNA status can reveal the long‐term prognoses of chronic hepatitis B patients treated with nucleos(t)ide analogues

Luo

Tan

Kang

et al. 2019

Journal of Viral Hepatitis

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We examined whether the hepatitis B virus (HBV) pregenomic RNA (pgRNA) status after nucleos(t)ide (NA) treatment can predict the long‐time prognoses of chronic hepatitis B patients. Patients with chronic hepatitis B (98) who were treatment‐naïve and had begun a 7‐year NA therapy regimen were enrolled in this study. Biochemical indicators and serological markers of HBV infection were performed during therapy. HBV pgRNA was quantified by real‐time quantitative PCR with specific primers. During treatment, HBV DNA undetectable rates increased. The aminotransferase (ALT) normalization (ALT < 50 IU/L) and HBeAg‐negative rates also increased. After 48 weeks’ NA treatment, 48.28% (28/58) of HBV DNA undetectable patients still had HBV pgRNA‐positive. After 7 years of treatment, more HBV pgRNA‐negative patients (n = 35) achieved HBeAg clearance than the patients who were HBV pgRNA‐positive (n = 63) (19/23 vs 19/56, P < .00). HBV pgRNA‐positive patients also had an increased risk of failing to achieve HBeAg clearance (OR = 9.25, 95% CI: 2.75‐31.08). The median time to HBeAg clearance in the HBV pgRNA‐positive patients was longer than that of the HBV pgRNA‐negative patients (152 weeks vs 72 weeks). The HBV pgRNA‐positive patients also required more time to achieve HBV DNA undetectable (124 weeks, 95% CI: 103.33‐144.67 vs 48 weeks, 95% CI: 34.80‐61.20). The HBV pgRNA status after NA treatment can predict the long‐term prognoses of patients with chronic HBV. Patients who remain HBV pgRNA‐positive after 48 weeks of NA treatment have an increased risk of not achieving HBeAg clearance, need more time to achieve HBeAg clearance and undetectable HBV DNA load.

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“…Indeed, the accuracy of in-silico predictions of neoantigen or viral binding affinity in estimating immune reactivity are at best suboptimal compared to using mass spectroscopy. Also, in comparing viral and neo-epitopes it's important to note that several lines of evidence suggest that the replication status of HBV is dependent on the differentiation status of the cells (15,16). Thus, the virus may hardly replicate in HCC cells and further reduce the viral epitope burden within the tumor.…”

Section: Discussionmentioning

confidence: 99%

Tumor fitness, immune exhaustion and clinical outcomes: impact of immune checkpoint inhibitors

Bubie

Gonzalez-Kozlova

Akers

et al. 2019

Preprint

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Recently proposed tumor fitness measures, based on profiling neoepitopes for reactive viral epitope similarity, have led to improved prediction models of response to immune checkpoint inhibitors in melanoma and small-cell lung cancer.Here we apply these checkpoint based fitness measures in the matched checkpoint-treatment naive TCGA samples where cytolytic activity imparts a known survival benefit. No significant survival predictive power beyond that of overall patient tumor mutational burden is observed in either cohort, and furthermore, there is no observed association between checkpoint based fitness and tumor T-cell infiltration, cytolytic activity (CYT), or abundance (TIL burden).We investigate the key assumption of viral epitope similarity driving immune response in the hepatitis B virally infected liver cancer TCGA cohort, and uncover suggestive evidence that tumor neoepitopes dominate viral epitopes in putative immunogenicity and plausibly drive immune response.Significance: Tumor fitness does not predict patient survival better than tumor mutation burden, unlike a measure of CYT. In checkpoint treatment naive patients, our results suggest TIL recruitment and cytolytic activity are essentially driven by tumor neoepitopes, regardless of the presence of viral epitopes.

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Hepatitis B Virus Pregenomic RNA in Hepatocellular Carcinoma: A Nosological and Prognostic Determinant

Cited by 46 publications

References 19 publications

SOX2 Represses Hepatitis B Virus Replication by Binding to the Viral EnhII/Cp and Inhibiting the Promoter Activation

SOX2 Represses Hepatitis B Virus Replication by Binding to the Viral EnhII/Cp and Inhibiting the Promoter Activation

Hepatitis B virus pregenomic RNA status can reveal the long‐term prognoses of chronic hepatitis B patients treated with nucleos(t)ide analogues

Tumor fitness, immune exhaustion and clinical outcomes: impact of immune checkpoint inhibitors

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