Hepatitis B virus (HBV) carriers with antibody to hepatitis e antigen comprise asymptomatic carriers (ASCs), who have low replication levels of HBV, and patients with chronic active hepatitis (CAH), who have high levels of viral replication. To investigate whether defects in the X protein might be responsible for this difference in the level of viral replication, nucleotide sequences of X and precore gene regions in serum HBV were analyzed in 19 ASCs and 9 CAH patients. All patients had a point mutation creating a stop codon in the precore region. Seventeen ASCs (87.3%) had identical mutations consisting of 4 noncontiguous 1-bp deletions or an 8-bp deletion, both of which truncate the normal X protein, whereas no CAH patient had an X gene mutation (P < .001). Thus, deletion of the X protein might be responsible for the low levels of viral replication in ASCs.
To determine when the precore mutation at the 83rd nucleotide occurs, leading to the formation of a stop codon in the hepatitis B virus genome in carriers, which would indicate the presence of antibody to hepatitis B e antigen (anti-HBe), we investigated this mutation by direct sequencing and subcloning in 22 young hepatitis B antigen (HBeAg) (+) carriers. These subjects were 7-17 years old and were found during a survey for hepatitis B surface antigen (HBsAg) in three elementary schools, a junior high, and a senior high school. None of these carriers had clinical manifestations, although one-third of them had elevated serum alanine aminotransferase levels. All were HBeAg-positive by radioimmunoassay (RIA), and 6 of them had preserved titers of anti-HBe at the same time. Precore mutations were found in 4 subjects (18.2%), with predominance of the wild type. Although 3 of these 4 had preserved titers of HBeAb, the other had no HBeAb titers. In an other 3 subjects with preserved titers of HBeAb, the precore mutation was not detected, even after the subcloning of viral DNA. The remaining 15 subjects with HBeAg showed no precore mutation. Subjects with ALT levels exceeding 100 IU/l were all HBeAg-positive without the mutation. It was clear that the precore mutation itself occurred in the subjects at an early age during the course of infection. However, the chronological relationship between the emergence of the precore mutation and the onset of hepatitis requires further study.
Perforin and granzyme A are the major effectors of cytotoxic T cells in cell-mediated cytotoxicity. However, there has been no report on these effectors in chronic viral hepatitis. In the present study, the expression of perforin and granzyme A mRNA was investigated by the reverse transcription polymerase chain reaction method using liver biopsy specimens and peripheral mononuclear cells (PBMC) from 21 patients with chronic hepatitis C and 5 control cases. Perforin mRNA was detected only in the liver of chronic hepatitis patients but not in the control livers. Conversely, perforin mRNA was not expressed in PBMC of the patients with chronic hepatitis (P < 0.01). Granzyme A mRNA was detected both in the liver and PBMC of all the cases including control cases. These results indicated that the perforin is an important effector molecule in the hepatocyte lysis in chronic viral hepatitis C.
To understand when the mutation with a stop codon of precore region in hepatitis B virus genome occurs, the prevalence of the mutation of viral DNA clones propagated from sera of school-age carriers was investigated with respect to hepatitis B e antigen (HBeAg)/anti-HBe and sequential changes of mutants along HBeAg seroconversion were analyzed. Of 32 carriers aged 8-18 years, 14 HBeAg(+) patients had 2.2% mutant clones, whereas 8 patients with low titer anti-HBe had a higher rate of 18.1% (P < 0.01) and the highest rate of 61.3% was found in 10 patients with high anti-HBe titer (P < 0.001). By contrast, the amount of viral DNA decreased significantly in patients with anti-HBe. Sequential analysis in six cases revealed three types of seroconversion with time difference of the emergence and increase of mutant clones. It is concluded that mutation occurs at a relatively young age and increases along time and/or HBeAg seroconversion. Hepatitis might precede or accelerate the emergence and increase of mutant population which might be predictive of sustained resolution of the disease.
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