Genetic characteristics of hepatitis B virus genotypes as a factor for interferon‐induced HBeAg clearance

Hou, Jinlin; Schilling, R; Janssen, Harry L.A.; Hansen, Bettina E.; Heijtink, R. A.; Sablon, Erwin; Williams, Roger L.; Lau, George; Schalm, Solko W.; Naoumov, Nikolai V.

doi:10.1002/jmv.20935

Cited by 36 publications

(32 citation statements)

References 53 publications

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“…Recent clinical studies have shown that patients infected with HBV genotype A or B, each of which transcribes 2.2DS-RNA, have less severe symptoms and liver pathology and higher rates of viral clearance in response to IFN-␣ therapy than patients infected with HBV genotype C or D, each of which is 2.2DS-RNA deficient (7,9,61,62). Our prior study found that relatively high levels of 2.2DS-RNAs were present in CHB patients with genotype A infection but not in those with genotype D infection (25).…”

Section: Discussionmentioning

confidence: 99%

Doubly Spliced RNA of Hepatitis B Virus Suppresses Viral Transcription via TATA-Binding Protein and Induces Stress Granule Assembly

Tsai

Chong

Chou

et al. 2015

J Virol

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The risk of liver cancer in patients infected with the hepatitis B virus (HBV) and their clinical response to interferon alpha therapy vary based on the HBV genotype. The mechanisms underlying these differences in HBV pathogenesis remain unclear. In HepG2 cells transfected with a mutant HBV G2335A expression plasmid that does not transcribe the 2.2-kb doubly spliced RNA (2.2DS-RNA) expressed by wild-type HBV genotype A, the level of HBV pregenomic RNA (pgRNA) was higher than that in cells transfected with an HBV genotype A expression plasmid. By using cotransfection with HBV genotype D and 2.2DS-RNA expression plasmids, we found that a reduction of pgRNA was observed in the cells even in the presence of small amounts of the 2. T he hepatitis B virus (HBV) causes acute and chronic liver diseases in humans. Millions of people worldwide suffer from HBV-induced liver disorders, and HBV infection increases the risk of hepatic cirrhosis and hepatocellular carcinoma (1, 2). Type I interferons (IFNs), including IFN-␣ and IFN-␤, exert antiviral activity and important immunomodulatory effects in the innate immune response against HBV infection (3-5). However, the mechanism through which HBV evades the host immune response in chronically infected patients has not been fully elucidated.In addition to the factors such as viral load and naturally occurring mutants, the HBV genotype, classified as A through J based on genomic sequence, has been shown to be associated with disease progression and responses to IFN-based therapy (6). Previous studies have shown that chronic hepatitis B patients infected with genotype A or B exhibit higher rates of seroclearance of HBV e antigen (HBeAg) and viral DNA in response to IFN-␣ therapy than patients with genotype C or D infection (7-9) and that chronically infected children with HBV genotype A infection have lower viral DNA loads and exhibit less severe symptoms than patients with genotype D infection (10, 11). Clinical studies have also shown that differences between HBV genotypes correlate with deoxycytidine analog resistance (12) and hepatic pathogenesis (13).

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Section: Discussionmentioning

confidence: 99%

Doubly Spliced RNA of Hepatitis B Virus Suppresses Viral Transcription via TATA-Binding Protein and Induces Stress Granule Assembly

Tsai

Chong

Chou

et al. 2015

J Virol

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“…Native Alaskans with chronic HBV infection are infected with genotypes A, B, C, D, and F. In this patient population, where the host genetic background and age at the time of infection are similar, genotype A was associated with faster HBeAg clearance than other HBV genotypes (36). Recent clinical trials showed that genotype A was also associated with a higher rate of HBeAg loss than other genotypes (B, C, and D) after interferon but not lamivudine therapy (15,23,24,30). It remains to be established whether such differences are related to the different molecular forms of HBeAg produced from genotype A, the difference in HBeAg titer, or the reduced ability of genotype A to switch off HBeAg expression.…”

Section: Discussionmentioning

confidence: 99%

Characterization of Genotype-Specific Carboxyl-Terminal Cleavage Sites of Hepatitis B Virus e Antigen Precursor and Identification of Furin as the Candidate Enzyme

Ito

Kim

Lok

et al. 2009

J Virol

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Hepatitis B e antigen (HBeAg) is a secreted version of hepatitis B virus (HBV) core protein that promotes immune tolerance and persistent infection. It is derived from a translation product of the precore/core gene by two proteolytic cleavage events: removal of the amino-terminal signal peptide and removal of the carboxylterminal arginine-rich sequence. Four RXXR motifs are present at the carboxyl terminus of the HBeAg precursor, with the first two fused as 151 Approximately 2 billion people worldwide have been exposed to hepatitis B virus (HBV), and 350 million of them remain chronically infected. The long-term consequences of HBV infection include liver cirrhosis and hepatocellular carcinoma (21). The risk of developing chronic HBV infection correlates inversely with the age of transmission. In areas where HBV infection is endemic, such as China where over 10% of people are chronic carriers of the virus, HBV is transmitted both horizontally during early childhood and vertically from hepatitis B e antigen (HBeAg)-positive mothers during birth (68). In countries of intermediate HBV incidence such as South Africa, infection is acquired primarily horizontally during early childhood (28). In Western countries, HBV is transmitted mostly by drug abuse or unprotected sex during adulthood, and the majority of carriers will recover from the acute infection. In this regard, HBeAg is implicated as a major viral factor contributing to chronic infection following neonatal transmission (41).HBeAg was discovered by Magnius and Espmark over 30 years ago as a new serological marker for HBV infection (38), supplementing the then available assays for HBcAg (HBV core antigen or core protein) and HBsAg (HBV surface antigen or envelope protein). Soon after its discovery, the presence of HBeAg was found to correlate with liver diseases, whereas the loss of HBeAg followed by the rise of corresponding antibody (anti-HBe) was associated with normalization of liver function (22,65). Later studies further revealed a correlation of HBeAg with high viremia titer and anti-HBe with reduced viral load.

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“…They consistently found that HBV genotype B and younger age were independent factors associated with sustained response, and suggested low-dose IFN regimen might be cost-effective for the treatment of younger genotype B patients. In addition, Hou et al prospectively investigated the relationship between HBV genetic characteristics and the outcome of short (16 weeks) or prolonged (32 weeks) treatment with standard IFN in 103 European HBeAg-positive patients and found that HBV genotype A responded earlier to IFN than other genotypes, which was associated with its molecular characteristics [115]. Collectively, the optimal duration of interferon treatment for chronic hepatitis B may vary among different HBV genotypes.…”

Section: Genotypesmentioning

confidence: 99%

Role of viral factors in the natural course and therapy of chronic hepatitis B

Kao

2007

Hepatol Int

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Hepatitis B virus (HBV) infection is a global health problem that causes a wide spectrum of liver disease, including acute or fulminant hepatitis, inactive carrier state, chronic hepatitis, cirrhosis, and hepatocellular carcinoma (HCC). The pathogenesis of hepatocyte damage associated with HBV is mainly through immune-mediated mechanisms. On the basis of the virus and host interactions, the natural history of HBV carriers who are infected in early life can be divided into four dynamic phases. The frequency, extent, and severity of hepatitis flares or acute exacerbation in the second immune clearance and/or fourth reactivation phase predict liver disease progression in HBV carriers. In the past decade, hepatitis B viral factors including serum HBV DNA level, genotype, and naturally occurring mutants predictive of clinical outcomes have been identified. The higher the serum HBV DNA level after the immune clearance phase, the higher the incidence of adverse outcomes over time. In addition, high viral load, genotype C, basal core promoter mutation, and pre-S deletion correlate with increased risk of cirrhosis and HCC development. As to the treatment of chronic hepatitis B, patients with high HBV DNA level and genotype C or D infection are shown to have a worse response to interferon therapy. In conclusion, serum HBV DNA level, genotype, and naturally occurring mutants are identified to influence liver disease progression and therapy of chronic hepatitis B. More investigations are needed to clarify the molecular mechanisms of the viral factors involved in the pathogenesis of each stage of liver disease and the response to antiviral treatments.

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Genetic characteristics of hepatitis B virus genotypes as a factor for interferon‐induced HBeAg clearance

Cited by 36 publications

References 53 publications

Doubly Spliced RNA of Hepatitis B Virus Suppresses Viral Transcription via TATA-Binding Protein and Induces Stress Granule Assembly

Doubly Spliced RNA of Hepatitis B Virus Suppresses Viral Transcription via TATA-Binding Protein and Induces Stress Granule Assembly

Characterization of Genotype-Specific Carboxyl-Terminal Cleavage Sites of Hepatitis B Virus e Antigen Precursor and Identification of Furin as the Candidate Enzyme

Role of viral factors in the natural course and therapy of chronic hepatitis B

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