Differences in the entire nucleotide sequence between hepatitis B virus genomes from carriers positive for antibody to hepatitis B e antigen with and without active disease

Abstract

The entire nucleotide sequence was determined for eight hepatitis B virus (HBV) genomes from three symptom-free carriers, two patients with chronic persistent hepatitis and one patient with chronic active hepatitis, who were positive for antibody to hepatitis B e antigen (HBeAg). The two patients with chronic persistent hepatitis were tested again after they developed chronic active or fulminant hepatitis, making a total of eight samples. Six had a point mutation in the preC region prohibiting the encoding of HBeAg precursor, while the remaining two had a deletion of 8 or 21 nucleotides within the X gene upstream of the preC transcription initiation sites which would affect the X gene and the putative preC/C promoter. Most genomes from the three symptom-free carriers and the two patients with chronic persistent hepatitis, with HBV DNA levels of 10(2)-10(3)/ml, had deletion, frameshift mutation, initiation failure or a premature stop codon, rendering them replication-incompetent. In contrast, such mutations were rarely seen in HBV genomes from the two patients with chronic persistent hepatitis after they had developed active or fulminant hepatitis and from the patient with chronic active hepatitis, all of whom had vigorous HBV replication with serum HBV DNA from 10(6) to 10(9)/ml. Unique mutations for amino acid changes were more frequent in HBV genomes with a higher replicative activity. These results indicate two kinds of HBV genomes with an HBeAg-minus phenotype, one with defects seriously affecting viral replication and the other without such defects, which would account for different clinical profiles in carriers with antibody to HBeAg.

The hepatitis B virus X gene: analysis of functional domain variation and gene phylogeny using multiple sequences

“…The most obvious difference was the eight nucleotide deletion in the strain infecting patient 16, similar to a deletion in a strain from a symptom-free HBV carrier (accession no. D23677) described by Horikita et al (1994), and to at least one other strain described by Okamoto et al (1994). These authors described several point mutations within the core promoter which were also seen in the present study.…”

High Prevalence of 1762T 1764A Mutations in the Basic Core Promoter of Hepatitis B Virus Isolated From Black Africans With Hepatocellular Carcinoma Compared With Asymptomatic Carriers

“…1-3, Table 4). These mutations have rarely been reported to occur alone in previous studies, whereas the double mutant has been described in ASCs 17 and patients with chronic hepatitis, [15][16][17][18][19][20] fulminant hepatitis, [14][15][16][21][22][23] and HCC. 17,27 The frequency of 1764 A alone was similar in ASCs and patients with HCC, but the prevalence of 1762 T 1764 A was significantly higher in HCC patients (P Ͻ .0001).…”

“…The BCP, mapping between nucleotides 1742 and 1849, controls the transcription of both precore messenger RNA (mRNA), which codes for the protein that is the precursor of the e antigen, and pregenomic RNA (pgRNA), which controls HBV replication. 11 A pair of mutations in the BCP that is associated with a reduced level of HBeAg expression was first described in Japanese patients [12][13][14] : an adenine (A) to thymine (T) transversion at position 1762 together with a guanine (G) to A transition at 1764 in the second AT-rich region of the BCP are often present in patients with chronic hepatitis B [15][16][17][18][19][20] and fulminant hepatitis B, [14][15][16][21][22][23] and less often in asymptomatic carriers (ASCs), 17 immunosuppressed patients, 24 and carriers without serological HBV markers. 25,26 These two mutations have also been reported in HBV DNA from sera 17 and tumor and liver tissue from patients with HBV-related hepatocellular carcinoma (HCC), 27 although the significance of this finding is yet to be determined.…”

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

“…23,24 Nevertheless, there remains lingering concerns that HBeAg seroconversion associated with the development of A1896 is less likely to result in remission of liver disease. Similarly, early studies reported that core promoter mutations were mainly found in patients with fulminant hepatitis or chronic active hepatitis, 12,13,15,25 but later studies showed that TA changes were also found in asymptomatic carriers. 12,14 Thus, it is unclear if TA changes influence the severity or course of liver disease after HBeAg seroconversion.…”

“…2). [12][13][14][15] In some patients, the TA changes were not associated with A1896, suggesting that mutations in the core promoter region alone may play a role in HBeAg clearance. This hypothesis is supported by in vitro observations that the TA changes decrease transcription of precore mRNA and secretion of HBeAg.…”