Mutations in the basic core promotor and the precore region of hepatitis b virus and their selection in children with fulminant and chronic hepatitis B

The involvement of precore stop codon 1896‐A and base exchanges in the AT‐rich region at positions 1762 and 1764 of the hepatitis B core promotor has been controversely discussed in adults with fulminant hepatitis B. Because no data are currently available on children, we analyzed the basic core promotor (BCP) and precore region in children with chronic and fulminant hepatitis B. The BCP and precore region were sequenced directly and after cloning from mothers and infants. Thirteen children suffered from chronic liver disease, 6 of whom were treated with interferon alfa (IFN‐α). All 13 patients seroconverted from hepatitis B e antigen (HBeAg) to hepatitis B e antigen antibodies (anti‐HBe), and sera were analyzed before and after seroconversion. Nine vertically infected infants developed a fulminant course of hepatitis B. The occurrence of BCP (1762‐T/1764‐A, 7.7%) and precore (1896‐A, 7.7%; 1899‐A, 15%) mutations in chronic hepatitis B was rare. A genotype shift from D to A was observed in 3 patients after development of anti‐HBe. A high number of base exchanges was detected in those infants with fulminant hepatitis B. Eight of nine showed a G‐A exchange at positions 1896/97 (89%), 1899 (56%), and/or mutations at nucleotide (nt) positions 1762 (56%) and 1764 (78%). All virus strains belonged to genotype D, whereas in the only surviving infant, a D‐to‐A shift was detected. Hepatitis B virus (HBV) DNA clones were examined from 3 babies and 5 mothers. Our results showed a heterogeneous virus population in 4 of 5 mothers. In contrast, a homogeneous virus population emerged in the infants. According to our data, the analysis in children with fulminant and chronic hepatitis B revealed a striking presence of BCP and precore mutants in infants with fulminant hepatitis (FH) when compared with clinically inapparent anti‐HBe–positive children (P < .002), which could be one factor in the pathogenesis of fulminant hepatitis B in children

[1]  S. Günther,et al.  Neonatal fulminant hepatitis B: structural and functional analysis of complete hepatitis B virus genomes from mother and infant. , 1998, The Journal of infectious diseases.

[2]  M. Chen,et al.  The secreted hepatitis B precore antigen can modulate the immune response to the nucleocapsid: a mechanism for persistence. , 1998, Journal of immunology.

[3]  S. Günther,et al.  Wild-type levels of pregenomic RNA and replication but reduced pre-C RNA and e-antigen synthesis of hepatitis B virus with C(1653) --> T, A(1762) --> T and G(1764) --> A mutations in the core promoter. , 1998, The Journal of general virology.

[4]  S. Wirth,et al.  Detection of different viral strains of hepatitis B virus in chronically infected children after seroconversion from HBsAg to anti-HBs indicating viral persistence. , 1997, Journal of hepatology.

[5]  A. Kidd,et al.  Hepatitis B virus X gene 1751 to 1764 mutations: implications for HBeAg status and disease. , 1997, The Journal of general virology.

[6]  J. Wands,et al.  Posttranscriptional regulation of hepatitis B virus replication by the precore protein , 1997, Journal of virology.

[7]  P. Angus,et al.  Mutations in the hepatitis B virus precore/core gene and core promoter in patients with severe recurrent disease following liver transplantation , 1996, Hepatology.

[8]  K. Moriyama,et al.  Reduced precore transcription and enhanced core-pregenome transcription of hepatitis B virus DNA after replacement of the precore-core promoter with sequences associated with e antigen-seronegative persistent infections. , 1996, Virology.

[9]  F. Chisari,et al.  The hepatitis B virus (HBV) precore protein inhibits HBV replication in transgenic mice , 1996, Journal of virology.

[10]  M. Chen,et al.  Effects of a naturally occurring mutation in the hepatitis B virus basal core promoter on precore gene expression and viral replication , 1996, Journal of virology.

[11]  H. Will,et al.  Hepatitis B virus genomes of patients with fulminant hepatitis do not share a specific mutation , 1996, Hepatology.

[12]  J. Bartolomé,et al.  Distribution of the Predominant Hepatitis B Virus Precore Variants in Hepatitis B e Antigen-Positive Children and Their Effect on Treatment Response , 1996, Pediatric Research.

[13]  F. Zoulim,et al.  Analysis of hepatitis B virus genotypes and pre‐core region variability during interferon treatment of HBe antigen negative chronic hepatitis B , 1996, Journal of medical virology.

[14]  S. Mishiro,et al.  The precore/core promoter mutant (T1762A1764) of hepatitis B virus: clinical significance and an easy method for detection. , 1995, The Journal of general virology.

[15]  D. Persing,et al.  Hepatitis B virus core promoter sequence analysis in fulminant and chronic hepatitis B. , 1995, Gastroenterology.

[16]  P. Lampertico,et al.  Hepatitis B virus precore mutants in HBeAg carriers with chronic hepatitis treated with interferon , 1995, Journal of viral hepatitis.

[17]  H. Hsu,et al.  Precore mutant of hepatitis B virus in childhood fulminant hepatitis B: an infrequent association. , 1995, The Journal of infectious diseases.

[18]  H. Okamoto,et al.  Hepatitis B Virus Strains with Mutations in the Core Promoter in Patients with Fulminant Hepatitis , 1995, Annals of Internal Medicine.

[19]  Mark George Thomas,et al.  Genomic variations in the hepatitis B core gene: a possible factor influencing response to interferon alfa treatment. , 1995, Gastroenterology.

[20]  H. Blum,et al.  Selective transmission of variant genomes from mother to infant in neonatal fulminant hepatitis B , 1995, Hepatology.

[21]  F Tsuda,et al.  Hepatitis B virus with mutations in the core promoter for an e antigen-negative phenotype in carriers with antibody to e antigen , 1994, Journal of virology.

[22]  M. Brunetto,et al.  Precore Mutant Hepatitis B Virus and Outcome of Chronic Infection and Hepatitis in Hepatitis B e Antigen-Positive Children , 1994, Pediatric Research.

[23]  K. Hasegawa,et al.  Enhanced replication of a hepatitis B virus mutant associated with an epidemic of fulminant hepatitis , 1994, Journal of virology.

[24]  M. Alter,et al.  Hepatitis B virus precore mutation and fulminant hepatitis in the United States. A polymerase chain reaction-based assay for the detection of specific mutation. , 1994, The Journal of clinical investigation.

[25]  Q. Zhang,et al.  Hepatitis B virus genotype A rarely circulates as an HBe-minus mutant: possible contribution of a single nucleotide in the precore region , 1993, Journal of virology.

[26]  H. Zentgraf,et al.  Precore-mediated inhibition of hepatitis B virus progeny DNA synthesis , 1993, Journal of virology.

[27]  E. Tanzi,et al.  Is the course of perinatal hepatitis B virus infection influenced by genetic heterogeneity of the virus? , 1993, Journal of medical virology.

[28]  R. Purcell,et al.  The complete nucleotide sequence of a pre-core mutant of hepatitis B virus implicated in fulminant hepatitis and its biological characterization in chimpanzees. , 1993, Virology.

[29]  D. Samuel,et al.  Low prevalence of precore mutations in hepatitis B virus DNA in fulminant hepatitis type B in France. , 1993, Journal of hepatology.

[30]  S. Mishiro,et al.  Fulminant hepatitis related to transmission of hepatitis B variants with precore mutations between spouses , 1992, Hepatology.

[31]  S. Davies,et al.  High-level expression of hepatitis B viral antigens in fibrosing cholestatic hepatitis. , 1992, Gastroenterology.

[32]  J. Wands,et al.  Association of hepatitis B viral precore mutations with fulminant hepatitis B in Japan. , 1991, Virology.

[33]  O. Yokosuka,et al.  Mutations in the precore region of hepatitis B virus DNA in patients with fulminant and severe hepatitis. , 1991, The New England journal of medicine.

[34]  J. Wands,et al.  A hepatitis B virus mutant associated with an epidemic of fulminant hepatitis. , 1991, The New England journal of medicine.

[35]  H. Will,et al.  Wild-type and e antigen-minus hepatitis B viruses and course of chronic hepatitis. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[36]  K. Takase,et al.  Fulminant hepatitis B: induction by hepatitis B virus mutants defective in the precore region and incapable of encoding e antigen. , 1991, Gastroenterology.

[37]  H. Okamoto,et al.  Hepatitis B Virus Mutants with Precore-Region Defects in Two Babies with Fulminant Hepatitis and Their Mothers Positive for Antibody to Hepatitis B e Antigen , 1991, Pediatric Research.

[38]  P. Roingeard,et al.  Hepatitis B virus core antigen (HBc Ag) accumulation in an HBV nonproducer clone of HepG2-transfected cells is associated with cytopathic effect. , 1990, Virology.

[39]  R. Palmiter,et al.  Immunobiology and pathogenesis of hepatocellular injury in hepatitis B virus transgenic mice. , 1990, Science.

[40]  F Tsuda,et al.  Hepatitis B viruses with precore region defects prevail in persistently infected hosts along with seroconversion to the antibody against e antigen , 1990, Journal of virology.

[41]  R. Palmiter,et al.  Structural and pathological effects of synthesis of hepatitis B virus large envelope polypeptide in transgenic mice. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[42]  F. Galibert,et al.  Nucleotide sequence of the hepatitis B virus genome (subtype ayw) cloned in E. coli , 1979, Nature.

[43]  J. de Groote.  Classification of Chronic Hepatitis. , 1976, Annals of clinical research.