Impact of Hepatitis B Virus (HBV) X Gene Mutations on Hepatocellular Carcinoma Development in Chronic HBV Infection

Abstract Background: It has been reported that polymorphisms of signal transducer and activator of transcription (STAT) 3 and STAT4 might be associated with susceptibility to hepatitis B virus (HBV) infection and risk of chronic hepatocellular carcinoma (HCC). Owing to limitation of sample size and inconclusive results, we conducted a meta-analysis to clarify the association. Methods: We identified relevant studies by a systematic search of Medline/PubMed, Embase, Web of Science and the Cochrane Library up to 20 February 2019. The strength of the association measured by odds ratios (OR) with 95% confidence intervals (CIs) was studied. All the statistical analyses were conducted based on Review Manager 5.3 software. Results: A total of 5242 cases and 2717 controls from five studies were included for the STAT3 polymorphism, 5902 cases and 7867 controls from nine studies for the STAT4 polymorphism. Our results suggested that STAT3 rs1053004 polymorphism was a significant risk factor of chronic HBV infection (C vs. T: OR = 1.17, 95% CI: 1.07–1.29, PA=0.0007; CC + CT vs. TT: OR = 1.38, 95% CI: 1.09–1.76, PA=0.008). Validation with all the genetic models revealed that rs7574865 polymorphism of STAT4 gene was closely associated with chronic HBV infection (PA<0.01) and chronic hepatitis B (CHB)-related HCC (PA<0.05). Meanwhile, the authenticity of the above meta-analysis results was confirmed by trial sequential analysis (TSA). Conclusions: The meta-analysis showed that STAT3 rs1053004 polymorphism may be the risk for developing chronic HBV infection but not associated with HCC. The present study also indicates that STAT4 rs7574865 polymorphism increased the risk of chronic HBV infection and HCC.

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Hepatitis B Virus

10.2310/im.5483 ◽

2021 ◽

Author(s):

Ming V. Lin ◽

April Wall

Keyword(s):

Hepatocellular Carcinoma ◽

Hepatitis B Virus ◽

Hepatitis B ◽

Chronic Infection ◽

Treatment Options ◽

Hbv Infection ◽

Chronic Hbv Infection ◽

Chronic Hepatitis B Virus ◽

B Virus ◽

Chronic Hbv

Chronic hepatitis B virus (HBV) infection is a major health burden worldwide, with approximately 257 million people with chronic infection. HBV is a small partially double-stranded DNA virus that replicates within the nucleus of the hepatocyte and commonly leads to chronic infection. Chronic HBV infection can cause cirrhosis, hepatocellular carcinoma, and extrahepatic manifestations such as glomerulonephritis or vasculitis. The latter is due to deposition of circulating immune complex in the different tissues. The natural history of HBV infection can be conceptualized as a spectrum encompassing different phases, including immune tolerance, immune clearance, inactive carrier, and reactivation and resolution. The diagnosis of the different phases of chronic HBV infection relies on various HBV serologies, liver enzyme levels, and histology findings. There are currently eight therapies approved for the treatment of HBV. Tenofovir alafenamide was the most recently approved therapy with a better side effect profile compared with tenofovir disoproxil fumarate. With the recent advances in the basic research in hepatitis B, new treatment options may become available in the near-future. This review contains 9 figures, 11 tables and 80 references Key words: cirrhosis, entecavir, Hepadnaviridae, hepatitis B virus, hepatocellular carcinoma, precore mutation, tenofovir

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Hepatitis B Virus

10.2310/em.5483 ◽

2021 ◽

Author(s):

Ming V. Lin ◽

April Wall

Keyword(s):

Hepatocellular Carcinoma ◽

Hepatitis B Virus ◽

Hepatitis B ◽

Chronic Infection ◽

Treatment Options ◽

Hbv Infection ◽

Chronic Hbv Infection ◽

Chronic Hepatitis B Virus ◽

B Virus ◽

Chronic Hbv

Chronic hepatitis B virus (HBV) infection is a major health burden worldwide, with approximately 257 million people with chronic infection. HBV is a small partially double-stranded DNA virus that replicates within the nucleus of the hepatocyte and commonly leads to chronic infection. Chronic HBV infection can cause cirrhosis, hepatocellular carcinoma, and extrahepatic manifestations such as glomerulonephritis or vasculitis. The latter is due to deposition of circulating immune complex in the different tissues. The natural history of HBV infection can be conceptualized as a spectrum encompassing different phases, including immune tolerance, immune clearance, inactive carrier, and reactivation and resolution. The diagnosis of the different phases of chronic HBV infection relies on various HBV serologies, liver enzyme levels, and histology findings. There are currently eight therapies approved for the treatment of HBV. Tenofovir alafenamide was the most recently approved therapy with a better side effect profile compared with tenofovir disoproxil fumarate. With the recent advances in the basic research in hepatitis B, new treatment options may become available in the near-future. This review contains 9 figures, 11 tables and 80 references Key words: cirrhosis, entecavir, Hepadnaviridae, hepatitis B virus, hepatocellular carcinoma, precore mutation, tenofovir

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Hepatitis B virus (HBV) X gene expression in human cells and anti-HBx antibodies detection in chronic HBV infection

Virology ◽

10.1016/0042-6822(90)90079-7 ◽

1990 ◽

Vol 174 (1) ◽

pp. 299-304 ◽

Cited By ~ 24

Author(s):

Massimo Levrero ◽

O. Jean-Jean ◽

C. Balsano ◽

H. Will ◽

M. Perricaudet

Keyword(s):

Gene Expression ◽

Hepatitis B Virus ◽

Hepatitis B ◽

Human Cells ◽

Hbv Infection ◽

Chronic Hbv Infection ◽

B Virus ◽

Chronic Hbv ◽

X Gene ◽

Antibodies Detection

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Impact of Hepatitis B Virus (HBV) X Gene Mutations on Hepatocellular Carcinoma Development in Chronic HBV Infection

Clinical and Vaccine Immunology ◽

10.1128/cvi.00474-10 ◽

2011 ◽

Vol 18 (6) ◽

pp. 914-921 ◽

Cited By ~ 33

Author(s):

Jong-Han Lee ◽

Kwang-Hyub Han ◽

Jae Myun Lee ◽

Jeon Han Park ◽

Hyon-Suk Kim

Keyword(s):

Hepatocellular Carcinoma ◽

Risk Factor ◽

Hepatitis B Virus ◽

Hepatitis B ◽

Hbv Infection ◽

Regulatory Pathways ◽

Chronic Hbv Infection ◽

B Virus ◽

Chronic Hbv ◽

The Impact

ABSTRACTThe hepatitis B virus (HBV) PreS mutations C1653T, T1753V, and A1762T/G1764A were reported as a strong risk factor of hepatocellular carcinoma (HCC) in a meta-analysis. HBV core promoter overlaps partially with HBx coding sequence, so the nucleotide 1762 and 1764 mutations induce HBV X protein (HBx) 130 and 131 substitutions. We sought to elucidate the impact of HBx mutations on HCC development. Chronically HBV-infected patients were enrolled in this study: 42 chronic hepatitis B (CHB) patients, 23 liver cirrhosis (LC) patients, and 31 HCC patients. Direct sequencing showed HBx131, HBx130, HBx5, HBx94, and HBx38 amino acid mutations were common in HCC patients. Of various mutations, HBx130+HBx131 (double) mutations and HBx5+HBx130+HBx131 (triple) mutations were significantly high in HCC patients. Double and triple mutations increased the risk for HCC by 3.75-fold (95% confidence interval [CI] = 1.101 to 12.768,P= 0.033) and 5.34-fold (95% CI = 1.65 to 17.309,P= 0.005), respectively, when HCC patients were compared to CHB patients. Functionally, there were significantly higher levels of NF-κB activity in cells with the HBx5 mutant and with the double mutants than that of wild-type cells and the triple-mutant cells. The triple mutation did not increase NF-κB activity. Other regulatory pathways seem to exist for NF-κB activation. In conclusion, a specific HBx mutation may contribute to HCC development by activating NF-κB activity. The HBx5 mutation in genotype C2 HBV appears to be a risk factor for the development of HCC and may be used to predict the clinical outcomes of patients with chronic HBV infection.

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Hepatitis B Virus

10.2310/fm.5483 ◽

2021 ◽

Author(s):

Ming V. Lin ◽

April Wall

Keyword(s):

Hepatocellular Carcinoma ◽

Hepatitis B Virus ◽

Hepatitis B ◽

Chronic Infection ◽

Treatment Options ◽

Hbv Infection ◽

Chronic Hbv Infection ◽

Chronic Hepatitis B Virus ◽

B Virus ◽

Chronic Hbv

Chronic hepatitis B virus (HBV) infection is a major health burden worldwide, with approximately 257 million people with chronic infection. HBV is a small partially double-stranded DNA virus that replicates within the nucleus of the hepatocyte and commonly leads to chronic infection. Chronic HBV infection can cause cirrhosis, hepatocellular carcinoma, and extrahepatic manifestations such as glomerulonephritis or vasculitis. The latter is due to deposition of circulating immune complex in the different tissues. The natural history of HBV infection can be conceptualized as a spectrum encompassing different phases, including immune tolerance, immune clearance, inactive carrier, and reactivation and resolution. The diagnosis of the different phases of chronic HBV infection relies on various HBV serologies, liver enzyme levels, and histology findings. There are currently eight therapies approved for the treatment of HBV. Tenofovir alafenamide was the most recently approved therapy with a better side effect profile compared with tenofovir disoproxil fumarate. With the recent advances in the basic research in hepatitis B, new treatment options may become available in the near-future. This review contains 9 figures, 11 tables and 80 references Key words: cirrhosis, entecavir, Hepadnaviridae, hepatitis B virus, hepatocellular carcinoma, precore mutation, tenofovir

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Hepatitis B Virus Demethylates PD-1 and Modulates the Changes of the Tumor Microenvironment in Hepatocellular Carcinoma Patients

10.21203/rs.3.rs-793418/v1 ◽

2021 ◽

Author(s):

Weiguang Lian ◽

Ruixue Lai ◽

Jianhua Wu ◽

Jingjing Zhang ◽

Shengchao Li ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Dna Methylation ◽

T Cells ◽

Hepatitis B Virus ◽

Tumor Microenvironment ◽

Hepatitis B ◽

Hbv Infection ◽

Chronic Hbv Infection ◽

B Virus ◽

Chronic Hbv

Abstract Background: Hepatitis B virus (HBV) constitutes a major global health burden. Previously study has found the expression of programmed cell death 1 (PD-1) is up-regulated during the chronic HBV infection. However, the mechanism of how HBV infection modulates the expression of PD-1 on CD8+T cells are not well understood. In the present study, we aimed to analyzed the role of DNA methylation in regulating the expression of PD-1 on CD8+T cells during HBV infection, we also aimed to evaluate the HBV induced changes of tumor microenvironment (TME).Methods: The methylation microarray was used to assess the profile changes of gene methylation upon chronic HBV infection. CD8+T cells were separated from peripheral blood of health volunteers and HCC patients including HBV related HCC (HBV-HCC) and non-viral HCC. The immune microenvironments of hepatocellular carcinoma (HCC) was interrogated by using Immunofluorescence staining. The PD-1 expression of CD8+T cells from peripheral blood were examined by western blot and flow cytometry. T cells function was determined by cytokine measurement. Sequenom MassARRAY platform was used to detected the DNA methylation status of PD-1 promoter.Results: HBV could drive 413 genes methylated while 3,023 genes including PD-1 demethylated, the reduced PD-1 expression and increased PD-1 demethylation was proved in HBV-HCC tissue. The subsequent analysis indicate that the expression of PD-1 differed by stages of HBV infection, it reduced on the cell membrane of HBV-transfected CD8+T cells upon transient HBV plasmid transfection which might mimic acute HBV infection, while upregulated on the HBV specific CD8+T cells by demethylation during chronic HBV infection. Interferon-gamma increased in the medium of HBV transfected CD8+T cells and interleukin-10 increased in the blood of chronic HBV infection patients. Increased tumor associated macrophage (TAM) cells and T regulatory cells (Tregs) invasion was identified in HBV-HCC tissue when compared with those from non-viral HCC tissue Conclusion: Our data suggested that the expression of PD-1 varies upon the stage of HBV infection, chronic HBV infection could drove the TME more immunosuppressive through PD-1 demethylation related CD8+T cells exhaustion as well as promotion of invaded Treg and TAM cells thereby to attenuating therapy of immune checkpoint inhibitors.

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Hepatitis B Virus

10.2310/gastro.5483 ◽

2021 ◽

Author(s):

Ming V. Lin ◽

April Wall

Keyword(s):

Hepatocellular Carcinoma ◽

Hepatitis B Virus ◽

Hepatitis B ◽

Chronic Infection ◽

Treatment Options ◽

Hbv Infection ◽

Chronic Hbv Infection ◽

Chronic Hepatitis B Virus ◽

B Virus ◽

Chronic Hbv

Chronic hepatitis B virus (HBV) infection is a major health burden worldwide, with approximately 257 million people with chronic infection. HBV is a small partially double-stranded DNA virus that replicates within the nucleus of the hepatocyte and commonly leads to chronic infection. Chronic HBV infection can cause cirrhosis, hepatocellular carcinoma, and extrahepatic manifestations such as glomerulonephritis or vasculitis. The latter is due to deposition of circulating immune complex in the different tissues. The natural history of HBV infection can be conceptualized as a spectrum encompassing different phases, including immune tolerance, immune clearance, inactive carrier, and reactivation and resolution. The diagnosis of the different phases of chronic HBV infection relies on various HBV serologies, liver enzyme levels, and histology findings. There are currently eight therapies approved for the treatment of HBV. Tenofovir alafenamide was the most recently approved therapy with a better side effect profile compared with tenofovir disoproxil fumarate. With the recent advances in the basic research in hepatitis B, new treatment options may become available in the near-future. This review contains 9 figures, 11 tables and 80 references Key words: cirrhosis, entecavir, Hepadnaviridae, hepatitis B virus, hepatocellular carcinoma, precore mutation, tenofovir

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Hepatitis B Virus Infection in Pregnancy: Immunological Response, Natural Course and Pregnancy Outcomes

Journal of Clinical Medicine ◽

10.3390/jcm10132926 ◽

2021 ◽

Vol 10 (13) ◽

pp. 2926

Author(s):

Sirinart Sirilert ◽

Theera Tongsong

Keyword(s):

Hepatitis B Virus ◽

Hepatitis B ◽

Pregnancy Outcomes ◽

Natural Course ◽

Hbv Infection ◽

Chronic Hbv Infection ◽

B Virus ◽

Chronic Hbv ◽

Adverse Pregnancy ◽

The Impact

This review aimed to provide an update on the impact of pregnancy on the natural course of hepatitis B virus (HBV) infection and also on the impact of HBV infection on adverse pregnancy outcomes, including mother-to-child transmission (MTCT). For the literature review, original research articles, review articles, and guidelines were narratively reviewed and comprehensively validated. The databases of PubMed, EMBASE, and CINAHL were carefully searched for articles in English on topics related to HBV infection, pregnancy, and vertical transmission from 1960 to May 2021. Immunological changes during pregnancy such as suppression of Th1 response and induction of Th2 immunity lead to an impaired immune reaction to HBV and stimulate viral activity along with the reduction of CD8 T cells to escape immune detection. The impact of pregnancy on the natural course of chronic HBV infection seems to be minimal, while pregnancy can increase morbidity and mortality in the case of advanced HBV hepatitis or cirrhosis. Importantly, hepatitis flare or alanine aminotransferase (ALT) flare can occur during pregnancy and is more common during the postpartum period due to the interaction between HBV and the immune response. Interestingly, the impact of HBV infection on adverse pregnancy outcomes is more serious than ever thought. Updated evidence indicates that pregnancies with chronic HBV infection increase the risk of preterm birth and gestational diabetes, especially in cases of positive hepatitis e antigen (HBeAg).

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