Occult hepatitis B infection and HBV replicative activity in patients with cryptogenic cause of hepatocellular carcinoma

Wong, Diana; Huang, Fung‐Yu; Lai, Ching–Lung; Poon, Ronnie Tung Ping; Seto, Wai Kay; Fung, James; Hung, Ivan Fan-Ngai; Yuen, Man Fung

doi:10.1002/hep.24551

Cited by 137 publications

(150 citation statements)

References 33 publications

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“…RNA samples were treated with RNase-free DNase (Promega) for 1 h at 37°C to remove genomic DNA. Quantitative measurement of HBV pregenomic RNA was performed using real-time PCR as described previously (31). The primers for the detection of pregenomic were 5′-CTCAATCTCGG-GAATCTCAATGT-3′ (sense) and 5′-TGGATAAAACCTAGCAGGCATAAT-3′ (antisense).…”

mentioning

confidence: 99%

Complete replication of hepatitis B virus and hepatitis C virus in a newly developed hepatoma cell line

Yang

Zuo

Wang

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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The absence of a robust cell culture system for hepatitis B virus (HBV) and hepatitis C virus (HCV) infection has limited the analysis of the virus lifecycle and drug discovery. We have established a hepatoma cell line, HLCZ01, the first cell line, to the authors' knowledge, supporting the entire lifecycle of both HBV and HCV. HBV surface antigen (HBsAg)-positive particles can be observed in the supernatant and the lumen of the endoplasmic reticulum of the cells via electron microscopy. Interestingly, HBV and HCV clinical isolates propagate in HLCZ01 cells. Both viruses replicate in the cells without evidence of overt interference. HBV and HCV entry are blocked by antibodies against HBsAg and human CD81, respectively, and the replication of HBV and HCV is inhibited by antivirals. HLCZ01 cells mount an innate immune response to virus infection. The cell line provides a powerful tool for exploring the mechanisms of virus entry and replication and the interaction between host and virus, facilitating the development of novel antiviral agents and vaccines.cell culture model | primary human hepatocytes | cccDNA | interferon | ISGs M ore than 500 million people worldwide are persistently infected with hepatitis B virus (HBV) and/or hepatitis B virus (HCV) and are at risk of developing chronic liver diseases (1). There is no vaccine against HCV, and many patients who are persistently infected by HBV or HCV do not respond to currently available therapies (2, 3). Improved understanding of the biology and pathogenesis of these infections is required for the development of vaccine and antiviral drugs (4). The inability to grow HBV and HCV efficiently in cell culture has presented a major obstacle to understanding the virus lifecycle and pathogenesis and to developing improved therapeutics.HBV is a member of the hepadnavirus families, and its genome is a relaxed circular, partially double-stranded DNA molecule. The negative strand has an invariable length of ∼3.2 kb, and the positive strand is 50-100% of this length. Several key issues about the biology of HBV remain to be explored, including the identification of the cellular receptors, the role of the X gene, and the mechanisms by which the viral minichromosome is formed. Covalently closed circular DNA (cccDNA) is responsible for the establishment of viral infection and persistence. Understanding the mechanisms underlying cccDNA formation and regulation is critical for understanding the HBV pathogenesis and finding a cure for hepatitis B. HepG2.2.15 cells derived from the hepatoma cell line HepG2 transfected with the full genome of HBV have been used to study HBV replication (5). Primary human hepatocytes (PHH) are susceptible to HBV infection (6, 7), but the use of this model is hampered by the limited availability and unpredictable variability of human liver. Several human hepatoma cell lines support HBV replication after HBV DNA transfection, and overexpression of sodium-taurocholate cotransporting polypeptide (NTCP) in HepG2 and Huh7 cells can render these cells able t...

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mentioning

confidence: 99%

Complete replication of hepatitis B virus and hepatitis C virus in a newly developed hepatoma cell line

Yang

Zuo

Wang

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…OBI has been less investigated in patients with HCV-negative cryptogenic liver disease (CLD). Its prevalence has been reported to range between 20 % and 30 % in subjects with cryptogenic liver disease (Wong et al, 2011). In one study, 12.2 % of patients with chronic hepatitis related to autoimmune disorders proved OBI-positive when serum samples were tested, although this prevalence appeared to significantly increase when viral DNA was also assayed on liver extracts of a number of those patients.…”

Section: Prevalence Of Occult Hepatitis B Virus Infection (Obi)mentioning

confidence: 99%

“…This involvement is also confirmed by the data showing that a long-lasting memory CD4 and CDS cell-responses against HBV antigens are still detectable several years after recovery from acute hepatitis B possibly because during the occult phase of the infection, HBV is still able to synthesize minute amounts of antigens, which are umceteciable by available technical approaches but are sufficient enough to maintain an HBV-specific T cell response (Penna et al, 1996). Indeec, besides HBV cccDNA molecules, all viral transcripts have been detected in the liver of occult-infected individuals (Wong et al, 2011) and real-time PCR quantification has revealed small but still quantifiable amounts of intrahepatic HBV mRNA in these subjects. Therefore, clinical recovery from HBV infection not only implies the lack of complete clearance, of the virus but also reflects the ability of the immune system to keep under tight control leftover viruses in the liver after clinical resolution of disease.…”

Section: Immunological Factorsmentioning

confidence: 99%

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Occult Hepatitis B infection and immunity

2017

Int. J. Curr. Res. Med. Sci.

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Chronic hepatitis B virus (HBV) infection is a major global problem despite the availability of an efficacious vaccine. In Chronic HBV infection, liver cirrhosis and hepatocellular carcinoma (HCC) are associated with considerable morbidity and mortality. The detection of hepatitis B virus surface antigen (HBsAg) in serum remains the mainstay in the diagnosis of Chronic HBV infection and screening for HBV in most developing countries. The majority of individuals positive for HBsAg are also positive for HBV DNA in the serum. Occult HBV infection is characterized by the presence of HBV DNA in the absence of detected HBsAg. Recovery from an acute hepatitis B virus (HBV) infection is associated with loss of HBV DNA from serum, hepatitis Be antigen seroconversion (HBeAg), hepatitis B surface antigen (HBsAg) seroconversion, and normalization of serum aminotransferases. These changes generally imply clearance of virus, but clinical observations have shown that reactivation of HBV infection can occur either spontaneously or after immunosuppression. Recent studies showed that immune response to HBV remains vigorously long after an acute infection. In addition, HBV DNA can be detected by polymerase chain reaction (PCR) assay in serum, liver and peripheral blood mononuclear cells more than a decade after an apparent recovery from HBV infection. These findings suggest that recovery from acute hepatitis B may not result in complete virus elimination but rather the immune system keeps the virus at very low levels. The availability of PCR assays for HBV DNA allows the detection of 10 2 copies /ml compared with 10 6 copies /ml using hybridization assays. Using PCR assays, HBV DNA has been detected in some subjects who are HBsAg negative including those with no serological markers of HBV infection.

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“…As a non-cytopathic virus, HBV infection may induce the host immune responses, producing substantial liver damage and resulting in chronic hepatitis, cirrhosis and hepatocellular carcinoma (HCC) (1). Covalently closed circular DNA (cccDNA), generated from the partially double-stranded genomic DNA (relaxed circular DNA) in the nucleus of infected hepatocytes, represents the transcriptional template for HBV RNA production and has a significant role in the persistence of HBV infection, the infection of liver transplant cases (2) and the pathogenesis of HCC (3). To date, the treatment with nucleoside analogues, such as lamivudine, adefovir (ADV) and entecavir, either as a monotherapy or with interferon-α (INF-α), has been the major intervention capable of eradicating HBV from infected cells (4).…”

Section: Introductionmentioning

confidence: 99%

Cimicifuga foetida L. plus adefovir effectively inhibits the replication of hepatitis B virus in patients with chronic hepatitis B

et al. 2016

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Abstract. The aim of the present study was to assess the anti-hepatitis B virus (HBV) effect of Cimicifuga foetida L. (C. foetida) in the patients with chronic hepatitis B (CHB). A total of 60 randomly selected patients with CHB were recruited and divided into groups I and II. The patients in group I received a monotherapy of adefovir (ADV), and the patients in group II received a combination therapy of ADV and C. foetida for >48 weeks. Intrahepatic (IH) HBV covalently closed circular DNA (cccDNA), serum HBV DNA, hepatitis B surface antigen (HBsAg), alanine aminotransferase levels and serum interferon-γ (IFN-γ) and transforming growth factor-β (TGF-β) levels were quantified during the test. Following the treatment, a significant reduction of the median IH cccDNA level was identified in group II (P=0.017), but not in group I (P=0.05, and P=0.01 between the 2 groups), and a significant reduction of log 10 HBsAg was identified in groups I (P= 0.012) and II (P<0.0001, and P= 0.20 between the 2 groups). A significant increase of the median serum IFN-γ level was found in group II (P=0.0005), but not in group I (P=0.06, and P=0.004 between the 2 groups), and a significant reduction of the median TGF-β level was identified in groups I (P<0.0001) and II (P<0.0001, and P=0.002 between the 2 groups). A total of 24 patients in group I, and 27 patients in group II achieved a sustained virological response (P= 0.0386), and 20 patients in group I and 24 in group II achieved hepatitis B e antigen seroclearance (P=0.0442). In conclusion, C. foetida can effectively inhibit HBV transcription and replication in the patients by stimulating the release of the inflammatory cytokines, such as IFN-γ.

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Occult hepatitis B infection and HBV replicative activity in patients with cryptogenic cause of hepatocellular carcinoma

Cited by 137 publications

References 33 publications

Complete replication of hepatitis B virus and hepatitis C virus in a newly developed hepatoma cell line

Complete replication of hepatitis B virus and hepatitis C virus in a newly developed hepatoma cell line

Occult Hepatitis B infection and immunity

Cimicifuga foetida L. plus adefovir effectively inhibits the replication of hepatitis B virus in patients with chronic hepatitis B

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