Impact of Nucleotide Mutations at the HNF3- and HNF4-Binding Sites in Enhancer 1 on Viral Replication in Patients with Chronic Hepatitis B Virus Infection
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Background/Aims: The hepatitis B virus (HBV) genome contains binding sites for hepatocyte nuclear factors (HNF) 3and 4 in the core domain of enhancer 1 (Enh1), and mutations in this domain have a strong impact on virus replication. We aimed to identify frequent base-mutation sites in the core domain of Enh1 and to examine the impact of these mutations on viral replication. Methods: We studied virological characteristics and genetic sequences in 387 patients with chronic hepatitis B. We evaluated functional differences associated with specific mutations within the core domain of Enh1. Results: Mutations in the core domain were found with significant frequency in C1126 (122/387 [31.5%], the binding site for HNF3) and in C1134 (106/387 [27.4%], the binding site for HNF4). A single mutation at nt 1126 (C1126)was identified in 17/123 (13.8%), and 105/123 (85.4%)had double mutations (C1126/1134). The level of HBV DNA (log10 copies/mL) was lower in single mutants (C1126,5.81±1.25) than in wild (6.80±1.65) and double mutants (C1126/1134, 6.81±1.54). Similarly, the relative luciferase activity of C1126 and C1126/C1134 was 0.18 and 1.12times that of the wild-type virus, respectively. Conclusions:Mutations in the HNF3 binding site inhibit viral replication,whereas mutations at the HNF4 binding site restore viral replication.
Abstract
Background/Aims: The hepatitis B virus (HBV) genome contains binding sites for hepatocyte nuclear factors (HNF) 3and 4 in the core domain of enhancer 1 (Enh1), and mutations in this domain have a strong impact on virus replication. We aimed to identify frequent base-mutation sites in the core domain of Enh1 and to examine the impact of these mutations on viral replication. Methods: We studied virological characteristics and genetic sequences in 387 patients with chronic hepatitis B. We evaluated functional differences associated with specific mutations within the core domain of Enh1. Results: Mutations in the core domain were found with significant frequency in C1126 (122/387 [31.5%], the binding site for HNF3) and in C1134 (106/387 [27.4%], the binding site for HNF4). A single mutation at nt 1126 (C1126)was identified in 17/123 (13.8%), and 105/123 (85.4%)had double mutations (C1126/1134). The level of HBV DNA (log10 copies/mL) was lower in single mutants (C1126,5.81±1.25) than in wild (6.80±1.65) and double mutants (C1126/1134, 6.81±1.54). Similarly, the relative luciferase activity of C1126 and C1126/C1134 was 0.18 and 1.12times that of the wild-type virus, respectively. Conclusions:Mutations in the HNF3 binding site inhibit viral replication,whereas mutations at the HNF4 binding site restore viral replication.
참고문헌 (37)
- "Trends in the seroprevalence of hepatitis B surface antigen in the South Korean population", INTERNATIONAL JOURNAL OF INFECTIOUS DISEASES, 16(9), pp.669~672 (2012), ELSEVIER SCI LTD
- Chisari FV, "Molecular pathogenesis of hepatocellular carcinoma in hepatitis B virus transgenic mice", Cell, 59, pp.1145~1156 (1989)
- Kosovsky MJ, "Purification and properties of rat liver nuclear proteins that interact with the hepatitis B virus enhancer 1", J Biol Chem, 271, pp.21859~21869 (1996)
- Schaller H, "Transcriptional control of hepadnavirus gene expression", Curr Top Microbiol Immunol, 168, pp.21~39 (1991)
- Bock CT, "The enhancer I core region contributes to the replication level of hepatitis B virus in vivo and in vitro", J Virol, 74, pp.2193~2202 (2000)
- Long Y, "The correlation of hepatocyte nuclear factor 4 alpha and 3 beta with hepatitis B virus replication in the liver of chronic hepatitis B patients", J Viral Hepat, 16, pp.537~546 (2009)
- Banks KE, "Hepatocyte nuclear factor 3beta inhibits hepatitis B virus replication in vivo", J Virol, 76, pp.12974~12980 (2002)
- Tang H, "Mechanisms of inhibition of nuclear hormone receptor-dependent hepatitis B virus replication by hepatocyte nuclear factor 3beta", J Virol, 76, pp.8572~8581 (2002)
- Tang H, "Transcriptional regulation of hepatitis B virus by nuclear hormone receptors is a critical determinant of viral tropism", Proc Natl Acad Sci U S A, 98, pp.1841~1846 (2001)
- Thompson Coon J, "Surveillance of cirrhosis for hepatocellular carcinoma: systematic review and economic analysis", Health Technol Assess, 11, pp.1~206 (2007)
- Kimura M, "A simple method for estimating evolutionary rates of base substitutions through comparative studies of nucleotide sequences", J Mol Evol, 16, pp.111~120 (1980)
- Chisari FV, "Hepatitis B virus immunopathogenesis", Annu Rev Immunol, 13, pp.29~60 (1995)
- Lee WM, "Hepatitis B virus infection", N Engl J Med, 337, pp.1733~1745 (1997)
- Ganem D, "Hepatitis B virus infection: natural history and clinical consequences", N Engl J Med, 350, pp.1118~1129 (2004)
- Feld JJ, "Hepatitis B virus DNA prediction rules for hepatitis B e antigen-negative chronic hepatitis B", Hepatology, 46, pp.1057~1070 (2007)
- Papatheodoridis GV, "Longitudinal changes in serum HBV DNA levels and predictors of progression during the natural course of HBeAg-negative chronic hepatitis B virus infection", J Viral Hepat, 15, pp.434~441 (2008)
- Zacharakis G, "The role of serial measurement of serum HBV DNA levels in patients with chronic HBeAg(-) hepatitis B infection: association with liver disease progression. A prospective cohort study", J Hepatol, 49, pp.884~891 (2008)
- Carman WF, "Mutation preventing formation of hepatitis B e antigen in patients with chronic hepatitis B infection", Lancet, 2, pp.588~591 (1989)
- Omata M, "Mutations in the precore region of hepatitis B virus DNA in patients with fulminant and severe hepatitis", N Engl J Med, 324, pp.1699~1704 (1991)
- Brunetto MR, "Wild-type and e antigen-minus hepatitis B viruses and course of chronic hepatitis", Proc Natl Acad Sci U S A, 88, pp.4186~4190 (1991)
- Ehata T, "Variations in codons 84-101 in the core nucleotide sequence correlate with hepatocellular injury in chronic hepatitis B virus infection", J Clin Invest, 89, pp.332~338 (1992)
- Chuang WL, "Precore mutations and core clustering mutations in chronic hepatitis B virus infection", Gastroenterology, 104, pp.263~271 (1993)
- Okamoto H, "Hepatitis B virus with mutations in the core promoter for an e antigen-negative phenotype in carriers with antibody to e antigen", J Virol, 68, pp.8102~8110 (1994)
- Laskus T, "Hepatitis B virus core promoter sequence analysis in fulminant and chronic hepatitis B", Gastroenterology, 109, pp.1618~1623 (1995)
- Yu MW, "Hepatitis B virus genotype and DNA level and hepatocellular carcinoma: a prospective study in men", J Natl Cancer Inst, 97, pp.265~272 (2005)
- Chan HL, "Genotype C hepatitis B virus infection is associated with an increased risk of hepatocellular carcinoma", Gut, 53, pp.1494~1498 (2004)
- Iloeje UH, "Predicting cirrhosis risk based on the level of circulating hepatitis B viral load", Gastroenterology, 130, pp.678~686 (2006)
- Chu CM, "Sex difference in chronic hepatitis B virus infection: an appraisal based on the status of hepatitis B e antigen and antibody", Hepatology, 3, pp.947~950 (1983)
- Chan HL, "High viral load and hepatitis B virus subgenotype ce are associated with increased risk of hepatocellular carcinoma", J Clin Oncol, 26, pp.177~182 (2008)
- Chen CJ, "Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level", JAMA, 295, pp.65~73 (2006)
- Wu CF, "Long-term tracking of hepatitis B viral load and the relationship with risk for hepatocellular carcinoma in men", Carcinogenesis, 29, pp.106~112 (2008)
- Fattovich G, "Natural history of chronic hepatitis B: special emphasis on disease progression and prognostic factors", J Hepatol, 48, pp.335~352 (2008)
- Fan W, "Comparison of hepatitis B X gene mutation between patients with hepatocellular carcinoma and patients with chronic hepatitis B", Virus Genes, 42, pp.162~170 (2011)
- Utama A, "Association of core promoter mutations of hepatitis B virus and viral load is different in HBeAg(+) and HBeAg(-) patients", World J Gastroenterol, 17, pp.708~716 (2011)
- Akarca US, "Detection of precore hepatitis B virus mutants in asymptomatic HBsAg-positive family members", Hepatology, 19, pp.1366~1370 (1994)
- Song BC, "Sequential accumulation of the basal core promoter and the precore mutations in the progression of hepatitis B virus-related chronic liver disease", Intervirology, 49, pp.266~273 (2006)
- Ikegami T, "Impact of determination of hepatitis B virus subgenotype and pre-core", core-promoter mutation for the prediction of acute exacerbation of asymptomatic carriers, 2009, pp.39, 341~345