Toll-Like Receptor Signaling Inhibits Hepatitis B Virus Replication In Vivo

ABSTRACT Toll-like receptors (TLR) play a key role in innate immunity. To examine the ability of diverse TLRs to modulate hepatitis B virus (HBV) replication, HBV transgenic mice received a single intravenous injection of ligands specific for TLR2, TLR3, TLR4, TLR5, TLR7, and TLR9. All of the ligands except for TLR2 inhibited HBV replication in the liver noncytopathically within 24 h in a α/β interferon-dependent manner. The ability of these TLR ligands to induce antiviral cytokines at the site of HBV replication suggests that TLR activation could represent a powerful and novel therapeutic strategy for the treatment of chronic HBV infection.

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Antiviral l-Nucleosides Specific for Hepatitis B Virus Infection

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.45.1.229-235.2001 ◽

2001 ◽

Vol 45 (1) ◽

pp. 229-235 ◽

Cited By ~ 132

Author(s):

Martin L. Bryant ◽

Edward G. Bridges ◽

Laurent Placidi ◽

Abdesslem Faraj ◽

Anna-Giulia Loi ◽

...

Keyword(s):

Viral Load ◽

Hepatitis B Virus ◽

Hepatitis B ◽

Hepatitis Virus ◽

Hbv Infection ◽

Virus Surface ◽

Chronic Hbv Infection ◽

Hbv Replication ◽

B Virus ◽

Chronic Hbv

ABSTRACT A unique series of simple “unnatural” nucleosides has been discovered to inhibit hepatitis B virus (HBV) replication. Through structure-activity analysis it was found that the 3′-OH group of the β-l-2′-deoxyribose of the β-l-2′-deoxynucleoside confers specific antihepadnavirus activity. The unsubstituted nucleosides β-l-2′-deoxycytidine, β-l-thymidine, and β-l-2′-deoxyadenosine had the most potent, selective, and specific antiviral activity against HBV replication. Human DNA polymerases (α, β, and γ) and mitochondrial function were not affected. In the woodchuck model of chronic HBV infection, viral load was reduced by as much as 108 genome equivalents/ml of serum and there was no drug-related toxicity. In addition, the decline in woodchuck hepatitis virus surface antigen paralleled the decrease in viral load. These investigational drugs, used alone or in combination, are expected to offer new therapeutic options for patients with chronic HBV infection.

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Interferons Accelerate Decay of Replication-Competent Nucleocapsids of Hepatitis B Virus

Journal of Virology ◽

10.1128/jvi.00918-10 ◽

2010 ◽

Vol 84 (18) ◽

pp. 9332-9340 ◽

Cited By ~ 79

Author(s):

Chunxiao Xu ◽

Haitao Guo ◽

Xiao-Ben Pan ◽

Richeng Mao ◽

Wenquan Yu ◽

...

Keyword(s):

Hepatitis B Virus ◽

Hepatitis B ◽

Dependent Manner ◽

Hbv Replication ◽

B Virus ◽

Cellular Antiviral Response ◽

Ifn Γ ◽

Antiviral Mechanism ◽

Murine Hepatocyte

ABSTRACT Alpha interferon (IFN-α) is an approved medication for chronic hepatitis B. Gamma interferon (IFN-γ) is a key mediator of host antiviral immunity against hepatitis B virus (HBV) infection in vivo. However, the molecular mechanism by which these antiviral cytokines suppress HBV replication remains elusive. Using an immortalized murine hepatocyte (AML12)-derived cell line supporting tetracycline-inducible HBV replication, we show in this report that both IFN-α and IFN-γ efficiently reduce the amount of intracellular HBV nucleocapsids. Furthermore, we provide evidence suggesting that the IFN-induced cellular antiviral response is able to distinguish and selectively accelerate the decay of HBV replication-competent nucleocapsids but not empty capsids in a proteasome-dependent manner. Our findings thus reveal a novel antiviral mechanism of IFNs and provide a basis for a better understanding of HBV pathobiology.

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The Enhancer I Core Region Contributes to the Replication Level of Hepatitis B Virus In Vivo and In Vitro

Journal of Virology ◽

10.1128/jvi.74.5.2193-2202.2000 ◽

2000 ◽

Vol 74 (5) ◽

pp. 2193-2202 ◽

Cited By ~ 39

Author(s):

C.-Thomas Bock ◽

Nisar P. Malek ◽

Hans L. Tillmann ◽

Michael P. Manns ◽

Christian Trautwein

Keyword(s):

Liver Transplantation ◽

Hepatitis B Virus ◽

Hepatitis B ◽

Transcriptional Activity ◽

Hbv Infection ◽

Chronic Hbv Infection ◽

Hbv Replication ◽

B Virus ◽

Mutant Strains ◽

Chronic Hbv

ABSTRACT Chronic hepatitis B virus (HBV) infection can lead to liver cirrhosis and hepatocellular carcinoma. Long-term interaction of the immune system with the virus results in the selection of escape mutants and viral persistence. In this work we characterize mutations in the enhancer I region isolated prior to liver transplantation from the HBV genomes of 10 patients with chronic HBV infection. The HBV-genomes were sequenced, and the enhancer I region was cloned into luciferase reporter constructs to determine the transcriptional activity. Functional studies were performed by transfecting HBV replication-competent plasmids into hepatoma cells. Analyses of the replication fitness of the mutant strains were conducted by biochemical analysis. In all HBV genomes the enhancer I region was mutated. Most of these mutations resulted in decreased transcriptional activity. The strongest effects were detectable in strains with mutations in the hepatocyte nuclear factor 3 and 4 (HNF3 and HNF4) binding sites of the enhancer I core domain. Replication-competent HBV constructs containing these mutations demonstrated up to 10-fold-reduced levels of virus replication. Before liver transplantation, when the mutant strains were detected in the patients' sera, low HBV DNA levels were found. After transplantation and reinfection with a wild-type virus, the levels of replication were up to 240-fold higher. Our results show that mutations in the enhancer I region of HBV have a major impact on HBV replication. These mutations may also determine the switch from high to low levels of viral replication which is frequently observed during chronic HBV infection.

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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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G‐to‐A Hypermutation in Hepatitis B Virus (HBV) and Clinical Course of Patients with Chronic HBV Infection

The Journal of Infectious Diseases ◽

10.1086/598951 ◽

2009 ◽

Vol 199 (11) ◽

pp. 1599-1607 ◽

Cited By ~ 16

Author(s):

Chiemi Noguchi ◽

Michio Imamura ◽

Masataka Tsuge ◽

Nobuhiko Hiraga ◽

Nami Mori ◽

...

Keyword(s):

Hepatitis B Virus ◽

Hepatitis B ◽

Clinical Course ◽

Hbv Infection ◽

Chronic Hbv Infection ◽

B Virus ◽

Chronic Hbv

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Hepatic expression of hepatitis B virus (HBV) genome in chronic HBV infection

Hepatology ◽

10.1016/0270-9139(93)91988-5 ◽

1993 ◽

Vol 18 (4) ◽

pp. A115

Author(s):

Keyword(s):

Hepatitis B Virus ◽

Hepatitis B ◽

Hbv Infection ◽

Chronic Hbv Infection ◽

Hepatic Expression ◽

B Virus ◽

Chronic Hbv

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Anti-Hepatitis B Virus Activity of Esculetin from Microsorium fortunei In Vitro and In Vivo

Molecules ◽

10.3390/molecules24193475 ◽

2019 ◽

Vol 24 (19) ◽

pp. 3475 ◽

Cited By ~ 3

Author(s):

Si-Xin Huang ◽

Jun-Fei Mou ◽

Qin Luo ◽

Qing-Hu Mo ◽

Xian-Li Zhou ◽

...

Keyword(s):

Hepatitis B Virus ◽

Hepatitis B ◽

Hepatitis B Surface Antigen ◽

Antiviral Drug ◽

Liver Carcinoma ◽

Dependent Manner ◽

Duck Hepatitis ◽

B Virus

Coumarins are widely present in a variety of plants and have a variety of pharmacological activities. In this study, we isolated a coumarin compound from Microsorium fortunei (Moore) Ching; the compound was identified as esculetin by hydrogen and carbon spectroscopy. Its anti-hepatitis B virus (HBV) activity was investigated in vitro and in vivo. In the human hepatocellular liver carcinoma 2.2.15 cell line (HepG2.2.15) transfected with HBV, esculetin effecting inhibited the expression of the HBV antigens and HBV DNA in vitro. Esculetin inhibited the expression of Hepatitis B virus X (HBx) protein in a dose-dependent manner. In the ducklings infected with duck hepatitis B virus (DHBV), the levels of DHBV DNA, duck hepatitis B surface antigen (DHBsAg), duck hepatitis B e-antigen (DHBeAg), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) decreased significantly after esculetin treatment. Summing up the above, the results suggest that esculetin efficiently inhibits HBV replication both in vitro and in vivo, which provides an opportunity for further development of esculetin as antiviral drug.

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A Method to Detect Hepatitis B Virus-specific Cytotoxic T Lymphocytes in Patients with Acute and Chronic HBV Infection

Viral Hepatitis and Liver Disease ◽

10.1007/978-4-431-68255-4_44 ◽

1994 ◽

pp. 168-172

Author(s):

Geert Leroux-Roels ◽

Els Van Hecke ◽

Jozef Paradijs ◽

Chantal Molitor ◽

Carine Bastin ◽

...

Keyword(s):

Hepatitis B Virus ◽

T Lymphocytes ◽

Hepatitis B ◽

Cytotoxic T Lymphocytes ◽

Hbv Infection ◽

Chronic Hbv Infection ◽

B Virus ◽

Chronic Hbv

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Association of STAT3 and STAT4 polymorphisms with susceptibility to chronic hepatitis B virus infection and risk of hepatocellular carcinoma: a meta-analysis

Bioscience Reports ◽

10.1042/bsr20190783 ◽

2019 ◽

Vol 39 (6) ◽

Cited By ~ 4

Author(s):

Han Shi ◽

Hongyan He ◽

Suvash Chandra Ojha ◽

Changfeng Sun ◽

Juan Fu ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Chronic Hepatitis ◽

Hepatitis B Virus ◽

Hepatitis B ◽

Chronic Hepatitis B ◽

Meta Analysis ◽

Hbv Infection ◽

Chronic Hbv Infection ◽

B Virus ◽

Chronic Hbv

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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