Mutations in the pre-core region of hepatitis B virus serve to enhance the stability of the secondary structure of the pre-genome encapsidation signal.

Lok, Anna S.; Akarca, Ulus Salih; Greene, Sheila

doi:10.1073/pnas.91.9.4077

Cited by 362 publications

(309 citation statements)

References 35 publications

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“…Thus, the worldwide detection of the 145 glycine-to-arginine mutation may be explained by the development of compensatory changes that permit its occurrence in all HBV genotypes in contrast to the precore stop codon mutation (A1896), which is restricted to geographical areas where the predominant HBV genotypes have T at nucleotide 1858. [28][29][30] In summary, we found that mutations in the HBV S gene, in particular the 'a' determinant, were common in OLT recipients who developed HBV reinfection despite HBIG prophylaxis. The significant correlation between the development of these mutations and the duration of HBIG therapy, the absence of these mutations pre-OLT, and the reversal of these mutations after withdrawal of HBIG suggest that these mutations were induced or selected by prolonged exposure to high levels of anti-HBs.…”

Section: Discussionmentioning

confidence: 99%

Hepatitis B virus S mutants in liver transplant recipients who were reinfected despite hepatitis B immune globulin prophylaxis†

Ghany¹,

Ayola²,

Villamil³

et al. 1998

Hepatology

307

225

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Early studies found that orthotopic liver transplantation (OLT) for hepatitis B virus (HBV)-related liver failure was associated with a very high rate of reinfection and severe and rapidly progressive liver disease, resulting in a significant decrease in graft and patient survival compared with patients transplanted for other causes of liver disease. 1,2 Various measures have been tried in an attempt to reduce the rate of reinfection. The most promising results have come from the use of long-term (Ն 6 months) high-dose hepatitis B immune globulin (HBIG). 3,4 However, this regimen is expensive, and a significant reduction in the rate of reinfection is mainly seen in patients who have nonreplicative infection pre-OLT. Reinfection despite HBIG immunoprophylaxis may be caused by inadequate neutralization of overwhelming amounts of wildtype HBV, or to breakthrough infection by immune escape mutants.The major B-cell epitopes of hepatitis B surface antigen (HBsAg) have been shown to reside in the 'a' determinant region located at amino acid positions 124-149. 5,6 This region is conformational and is thought to consist of two loops held by disulfide bridges between cysteines 124 and 137, and cysteines 138 and 147. 7 The second loop is more conserved and confers most of the antigenicity of the 'a' determinant; this loop is sometimes referred to as the major hydrophilic region (MHR). HBV can be classified into four major subtypes: adr, adw, ayr, and ayw. Antibodies to the 'a' determinant confer protection against all subtypes of HBV. 8 Mutations in the HBV S gene have been reported in OLT recipients who developed HBV reinfection despite prophylaxis with monoclonal or polyclonal hepatitis B surface antibody (anti-HBs). McMahon et al. found amino acid substitutions in the 'a' determinant in all three patients who were reinfected despite monoclonal anti-HBs prophylaxis, 9 while the incidence of mutations in the 'a' determinant in OLT recipients who were reinfected despite HBIG prophylaxis varied from 0% to 33%. 10-12 Some of these mutations, including the glycine-to-arginine substitution at codon 145, have been shown to decrease binding to monoclonal antiHBs, suggesting that the breakthrough infections were caused by immune escape mutants. 9,11,13 The number of patients cited in the above studies ranged from three to seven patients; therefore, the significance of S escape mutants in HBV reinfection post-OLT remains unclear. It is also possible that additional mutations may be present in the HBV S gene outside the 'a' determinant in patients who received polyclonal anti-HBs (HBIG). Unfortunately, there are very few data on the sequence in the rest of the S gene. In addition, to date, there are no data on the reversibility of these mutations after withdrawal of HBIG therapy.

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Section: Discussionmentioning

confidence: 99%

Hepatitis B virus S mutants in liver transplant recipients who were reinfected despite hepatitis B immune globulin prophylaxis†

Ghany¹,

Ayola²,

Villamil³

et al. 1998

Hepatology

307

225

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“…9,10 In our previous studies of Chinese patients from Hong Kong, we found that only 60% of patients were infected with HBV genotypes that have T1858. 4 Nevertheless, patients infected with HBV genotypes that have C1858, which precludes the development of A1896, appeared to clear HBeAg at rates similar to those infected with HBV genotypes that have T1858. 11 Recent studies reported that mutations in the core promoter region can be found in many HBeAg-negative patients; the most common mutations involve a two-nucleotide substitution: A-T at nucleotide 1762 and G-A at nucleotide 1764 (TA) (Fig.…”

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confidence: 99%

“…4,[8][9][10] A change from G to A at nucleotide 1896 increases the stability of the stem-loop structure of the pregenome encapsidation sequence (⑀) when the opposite nucleotide at 1858 is a T (T1858), but this change disrupts a pre-existing C-G pair when the nucleotide at 1858 is a C (C1858). 4 The restriction of A1896 to specific HBV genotypes accounts for its high prevalence in Asia and the Mediterranean basin, where the predominant HBV genotypes (B, C, and D) frequently have T1858, and its low prevalence in North America and Europe, where the predominant HBV genotype (A) almost always has C1858. 9,10 In our previous studies of Chinese patients from Hong Kong, we found that only 60% of patients were infected with HBV genotypes that have T1858.…”

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Different Hepatitis B Virus Genotypes Are Associated With Different Mutations in the Core Promoter and Precore Regions During Hepatitis B E Antigen Seroconversion

1999

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Mutations in the core promoter and precore regions are frequently found in hepatitis B e antigen (HBeAg)-negative patients, but precore stop codon mutation is restricted to hepatitis B virus (HBV) genotypes that have T at nucleotide 1858. The aims of this study were to determine the role of core promoter and/or precore mutations in HBeAg seroconversion and their impact on the subsequent course of liver disease, and to determine if core promoter mutations are more frequently selected in patients with HBV genotypes that preclude the development of precore stop codon mutation. Serial sera from 45 patients with chronic HBV infection were polymerase chain reaction (PCR)-amplified, and the HBV core promoter and precore regions were sequenced. Ninety-two percent of patients had core promoter or precore mutations after HBeAg seroconversion: 42% had core promoter changes only, 38% had precore stop codon mutations only, and 12% had changes in both regions. Seventy-three percent of the patients had persistently normal aminotransferases, and only 8% had multiple flares in aminotransferases after HBeAg seroconversion. Core promoter changes were significantly more common in patients infected with HBV who have C at nucleotide 1858 (91% vs. 27%; P F .01), while precore stop codon changes were exclusively found in patients infected with HBV who have T at nucleotide 1858 (87% vs. 0; P F .01). The vast majority of our patients had core promoter and/or precore mutations after HBeAg seroconversion. Nevertheless, most patients had sustained remission of liver disease. Our data suggest that core promoter changes are preferentially selected in patients infected with HBV genotypes that preclude the development of precore stop codon mutation. (HEPATOLOGY 1999;29:976-984.)

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“…The stop codon mutation is found only in patients infected with genotypes that bear a thymidine at nucleotide 1858; thus, accounting for the lower incidence in the United States and Northern Europe where genotype A predominates. [14][15][16] Alfa-interferon is currently the only approved treatment for chronic hepatitis B. 17,18 Several studies have shown that the presence of precore mutations correlates with suboptimal responses to interferon therapy and is associated with a high rate of relapse.…”

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confidence: 99%

Efficacy of Lamivudine in Patients With Hepatitis B E Antigen-Negative/Hepatitis B Virus Dna-Positive (Precore Mutant) Chronic Hepatitis Befficacy of Lamivudine in Patients With Hepatitis B E Antigen-Negative/Hepatitis B Virus Dna-Positive (Precore Mutant) Chronic Hepatitis Befficacy of Lamivudine in Patients With Hepatitis B E Antigen-Negative/Hepatitis B Virus Dna-Positive (Precore Mutant) Chronic Hepatitis Befficacy of Lamivudine in Patients With Hepatitis B E Antigen-Negative/Hepatitis B Virus Dna-Posi

et al. 1999

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This placebo controlled, double-blind study evaluated the efficacy and safety of lamivudine in patients with hepatitis B e antigen (HBeAg)-negative/hepatitis B virus (HBV) DNA-positive chronic hepatitis B. Patients were randomized to receive 100 mg lamivudine orally once daily for 52 weeks (n ‫؍‬ 60) or placebo for 26 weeks (n ‫؍‬ 65). Patients who were HBV DNA positive at week 24 were withdrawn at week 26. The primary efficacy endpoint was loss of serum HBV DNA plus normalization of alanine transaminase (ALT) at week 24. A significantly higher proportion of patients receiving lamivudine (63%) had a complete response at week 24 compared with patients receiving placebo (6%) (P F .001). Secondary efficacy parameters included histological response from baseline to week 52 in the lamivudine-treated patients. At week 52, 60% of lamivudine-treated patients with liver biopsy specimens available showed histological improvement (H2-point reduction in Knodell necro-inflammatory score), 29% showed no change, and 12% worsened. In a ranked assessment of pretreatment and post-treatment biopsy pairs 11% improved, 86% showed no change, and 2% worsened in fibrosis. At week 52, 27% of patients receiving lamivudine had YMDD (tyrosine-methionine-aspartate-aspartate amino acid motif of HBV polymerase) variant HBV. The incidence of adverse events and laboratory abnormalities was similar in both groups. In conclusion, lamivudine treatment results in a significant virological and biochemical improvement compared with placebo, induces an improvement or no change in histology in most patients, and is well tolerated. The response to lamivudine therapy in HBeAg-negative patients is similar to the response reported in previous studies of patients with HBeAg-positive chronic hepatitis B. (HEPATOLOGY 1999;29:889-896.)

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Mutations in the pre-core region of hepatitis B virus serve to enhance the stability of the secondary structure of the pre-genome encapsidation signal.

Cited by 362 publications

References 35 publications

Hepatitis B virus S mutants in liver transplant recipients who were reinfected despite hepatitis B immune globulin prophylaxis†

Hepatitis B virus S mutants in liver transplant recipients who were reinfected despite hepatitis B immune globulin prophylaxis†

Different Hepatitis B Virus Genotypes Are Associated With Different Mutations in the Core Promoter and Precore Regions During Hepatitis B E Antigen Seroconversion

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