Distribution of hepatitis B viral genotypes and mutations in the core promoter and precore regions in acute forms of liver disease in patients from Chiba, Japan

Imamura, Takaaki; Yokosuka, Osamu; Kurihara, Tomoko; Kanda, Tatsuo; Fukai, Kenichi; Imazeki, Fumio; Saisho, Hiromitsu

doi:10.1136/gut.52.11.1630

Cited by 88 publications

(89 citation statements)

References 47 publications

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“…In multivariate analysis, HBeAg-negative, HBV/Bj, and the precore stop-codon mutation for G1896A were independent risk factors for the development of fulminant hepatitis (Table 4). Various mutations at nt 1753 for enhanced HBV replication, 36 as well as those adjacent at nt 1754 prevailing in patients with fulminant hepatitis, 37 occurred more frequently in patients with fulminant than acute self-limited hepatitis. Host factors, such as age and total bilirubin, contributed to the development of fulminant hepatitis as well (Table 4).…”

Section: Discussionmentioning

confidence: 98%

Influence of genotypes and precore mutations on fulminant or chronic outcome of acute hepatitis B virus infection

et al. 2006

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The outcome of acute hepatitis B virus (HBV) infection is variable, influenced by host and viral factors. From 1982 through 2004, 301 patients with acute HBV infection entered a multi-center cross-sectional study in Japan. Patients with fulminant hepatitis (n ‫؍‬ 40) were older (44.7 ؎ 16.3 vs. 36.0 ؎ 14.3 years, P < .0017), less predominantly male (43% vs. 71%, P ‫؍‬ .0005), less positive for hepatitis B e antigen (HBeAg) (23% vs. 60%, P < .0001), less infected with subgenotype Ae (0% vs. 13%, P < .05), and more frequently with Bj (30% vs. 4%, P < .0001) than those with acute self-limited hepatitis (n ‫؍‬ 261). Precore (G1896A) and core-promoter (A1762T/G1764A) mutations were more frequent in patients with fulminant than acute self-limited hepatitis (53% vs. 9% and 50% vs. 17%, P < .0001 for both). HBV infection persisted in only three (1%) patients, and they represented 2 of the 23 infected with Ae and 1 of the 187 with the other subgenotypes (9% vs. 0.5%, P ‫؍‬ .032); none of them received antiviral therapy. In multivariate analysis, age 34 years or older, Bj, HBeAg-negative, total bilirubin 10.0 mg/dL or greater, and G1896A mutation were independently associated with the fulminant outcome. In in vitro transfection experiments, the replication of Bj clone was markedly enhanced by introducing either G1896A or A1762T/G1764A mutation. In conclusion, persistence of HBV was rare (1%) and associated with Ae, whereas fulminant hepatitis was frequent (13%) and associated with Bj and lack of HBeAg as well as high replication due to precore mutation in patients with acute HBV infection.

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Section: Discussionmentioning

confidence: 98%

Influence of genotypes and precore mutations on fulminant or chronic outcome of acute hepatitis B virus infection

et al. 2006

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“…A low replication capacity combined with very efficient virion secretion could enable rapid spread of wild-type genotype C isolates without provoking a strong immune response, thus predisposing the individual to persistent infection. Indeed, in adulthood, acute infection with genotype C is more likely to progress to chronic infection than genotype B infection (13,51). The doubling time of HBV DNA was 3.4 days for genotype A but only 1.9 days for genotype C in experimentally infected chimpanzees (17).…”

Section: Discussionmentioning

confidence: 99%

“…The prevalence of genotype C relative to genotype B increases as the infection progresses from asymptomatic carriage status through chronic hepatitis to liver fibrosis/cirrhosis (7,15,40,46). On the other hand, genotype B is more likely implicated in fulminant hepatitis and acute-on-chronic liver failure than genotype C (13,30,34). In Taiwan and China, genotype B (B2) infection might be associated with earlier hepatocellular carcinoma (HCC) development (15,47).…”

Section: Discussionmentioning

confidence: 99%

Hepatitis B Virus Genotype C Isolates with Wild-Type Core Promoter Sequence Replicate Less Efficiently than Genotype B Isolates but Possess Higher Virion Secretion Capacity

Qin

Tang

Garcia

et al. 2011

J Virol

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Infection by hepatitis B virus (HBV) genotype C is associated with a prolonged viremic phase, delayed hepatitis B e antigen (HBeAg) seroconversion, and an increased incidence of liver cirrhosis and hepatocellular carcinoma compared with genotype B infection. Genotype C is also associated with the more frequent emergence of core promoter mutations, which increase genome replication and are independently associated with poor clinical outcomes. We amplified full-length HBV genomes from serum samples from Chinese and U. S. patients with chronic HBV infection and transfected circularized genome pools or dimeric constructs of individual clones into Huh7 cells. The two genotypes could be differentiated by Western blot analysis due to the reactivities of M and L proteins toward a monoclonal pre-S2 antibody and slightly different S-protein mobilities. Great variability in replication capacity was observed for both genotypes. The A1762T/G1764A core promoter mutations were prevalent in genotype C isolates and correlated with increased replication capacity, while the A1752G/T mutation frequently found in genotype B isolates correlated with a low replication capacity. Importantly, most genotype C isolates with wild-type core promoter sequence replicated less efficiently than the corresponding genotype B isolates due to less efficient transcription of the 3.5-kb RNA. However, genotype C isolates often displayed more efficient virion secretion. We propose that the low intracellular levels of viral DNA and core protein of wild-type genotype C delay immune clearance and trigger the subsequent emergence of A1762T/G1764A core promoter mutations to upregulate replication; efficient virion secretion compensates for the low replication capacity to ensure the establishment of persistent infection by genotype C.The hepatitis B virus (HBV) is a hepatotropic enveloped DNA virus. The virion-associated relaxed circular DNA is converted to covalently closed circular DNA (cccDNA) in the nucleus of infected hepatocytes to serve as a template for viral gene expression and genome replication. The four genes are arranged on this 3.2-kb circular genome in the order of core, polymerase (P), surface, and X, with the P gene overlapping with the other three. Besides the core, P, small envelope (S), and hepatitis B X (HBx) proteins, the extra in-frame AUG codons upstream of the surface and core genes permit the expression of large (L) and middle (M) envelope proteins as well as the precore/core protein. The precore/core protein is processed by proteolytic cleavage and secreted as hepatitis B e antigen (HBeAg). The seven viral proteins are translated from five mRNAs generated from the cccDNA template: the 3.5-kb precore RNA for HBeAg, the slightly shorter 3.5-kb pregenomic (pg) RNA for core and P, and subgenomic RNAs of 2.4 kb for L protein, 2

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“…An estimated 20z to 30z of HBsAg carriers may experience reactivation of hepatitis B with elevation of biochemical levels and high serum DNA levels with or without seroconversion to HBeAg. HBV reactivation is usually asymptomatic, but it may mimic active viral hepatitis (20,26,27).…”

Section: -1 Clinical Differences Of Hbv Genotypesmentioning

confidence: 99%

Correlation between Hepatitis B Virus Genotypes and Clinical Outcomes

Shi¹

2012

Jpn J Infect Dis

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Distribution of hepatitis B viral genotypes and mutations in the core promoter and precore regions in acute forms of liver disease in patients from Chiba, Japan

Cited by 88 publications

References 47 publications

Influence of genotypes and precore mutations on fulminant or chronic outcome of acute hepatitis B virus infection

Influence of genotypes and precore mutations on fulminant or chronic outcome of acute hepatitis B virus infection

Hepatitis B Virus Genotype C Isolates with Wild-Type Core Promoter Sequence Replicate Less Efficiently than Genotype B Isolates but Possess Higher Virion Secretion Capacity

Correlation between Hepatitis B Virus Genotypes and Clinical Outcomes

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