High Rate of Mutations in the Hepatitis B Core Gene During the Immune Clearance Phase of Chronic Hepatitis B Virus Infection

Abstract

rates of changes were found during the immune clearCross-sectional studies reported that hepatitis B core ance of chronic hepatitis B infection. Interferon therapy gene mutations are associated with active liver disease did not induce a higher rate or specific pattern of mutaand responsiveness to interferon therapy. In view of the tions in the hepatitis B core gene. Response to interferon heterogeneity in published sequences, it is not possible therapy in HBeAg positive patients was unrelated to the to tell whether the differences in sequences observed number or location of hepatitis B core gene mutations. were true mutations that developed during the course (HEPATOLOGY 1996;24:32-37.) of infection. We conducted a longitudinal study to determine the rate of hepatitis B core gene mutations and the timing of these mutations in relation to hepatitis B virus Naturally occurring mutations in the hepatitis B virus replication, activity of liver disease, hepatitis B e antigen (HBV) genome have been attributed to play a role in the (HBeAg) seroconversion, and interferon therapy. Serial activity of HBV-related liver disease and in the persistence sera from 55 patients with chronic hepatitis B infection of HBV infection. were analyzed by direct sequencing of the hepatitis BWe and others have reported that mutations in the HBV precore/core gene to identify the nucleotide and amino core gene can be frequently detected in patients with chronic acid changes that emerged during follow-up. Patients HBV infection and that these mutations were significantly who remained HBeAg positive and had normal aminoassociated with the appearance of precore stop codon mutatransferase levels (Group I) maintained higher serum tion (G-A, nucleotide 1896), hepatitis B e antigen (HBeAg) hepatitis B virus (HBV) DNA levels but significantly negativity, and active liver disease. 1-8 These findings suggest lower rates of both nucleotide and amino acid changes that mutations in the HBV core gene sequence may affect during follow-up compared with patients who remained immune clearance of HBV and activity of liver disease. HowHBeAg positive but had elevated aminotransferase levever, most reports were based on cross-sectional studies in els (Group II) and patients who cleared HBeAg (Group which sequences of individual patients were compared III). The rates of nucleotide and amino acid changes in against published sequences. In view of the heterogeneity in Groups I, II, and III patients were: 0.4 { 0.1, 1.9 { 0.3, published sequences, it is not possible to tell whether the and 2.4 { 0.4/nucleotide position/year; and 0.04 { 0.02, nucleotide or amino acid differences observed were true mu-0.21 { 0.05, and 0.38 { 0.07/codon/year, respectively. Most tations that developed in the individual patients. In a recent of the amino acid changes in Groups II and III patients study comparing the HBV core gene sequences among hepatioccurred during or shortly after flares in aminotransfertis B surface antigen positive family members, we found that ase levels, before HB...

Low-Level Secretion of Human Hepatitis B Virus Virions Caused by Two Independent, Naturally Occurring Mutations (P5T and L60V) in the Capsid Protein

“…The acquisition of a mutation at position 5 or 60 has been reported using serum samples in several longitudinal studies (2,6,38). It is interesting to ask how the low-secretion variants, such as mutants P5T and L60V, can be secreted into circulation and eventually predominate over the existing WT HBV population in a natural infection.…”

“…14,15,18,28,29,36). Finally, a very frequent mutation of HBcAg occurs at codon 5, changing a conserved proline (P) to a threonine (T) (1,2,6,11,13,14,18,22,33,38). While the most common mutation found at HBcAg codon 5 is from P to T, other less frequent changes have also been reported, such as proline to serine (S).…”

Predominance of precore mutations and clinical significance of basal core promoter mutations in chronic hepatitis B virus infection in Indonesia

“…Mutations in B-and T-cell epitopes are associated with viral persistence, affecting the host immune response (45)(46)(47). The inflammatory activity produced by viral adaptive mechanisms may persist in up to 15% of cases, leading to the development of cirrhosis (48).…”

“…A previous study by Hosono et al (20) suggested that core mutations in HBV accumulated more errors in tumors compared to non-tumors. The aa 120-140 in the core region exposed on the surface of mature HBeAg and HBcAg are related to the recognition of helper T cells (49)(50)(51) and the immunodominant B-cell recognition sites within the HBcAg have also been found around residues 126-135 (45,46). One of the frequent core mutations is at aa 130, predominated by Thr130 [67 out of 96 (70%)].…”

Reduced Secretion of Virions and Hepatitis B Virus (HBV) Surface Antigen of a Naturally Occurring HBV Variant Correlates with the Accumulation of the Small S Envelope Protein in the Endoplasmic Reticulum and Golgi Apparatus

“…HBV variants are often found in chronically infected patients (19,37). The most common naturally occurring mutation in human HBV core protein is at amino acid (aa) 97, changing a highly conserved isoleucine (HBsAg subtype adr) or phenylalanine (HBsAg subtype ayw) to a leucine (L) (3,(12)(13)(14)(15)20). In contrast to the established dogma of preferential virion secretion of mature genome for wild-type (WT) hepadnaviruses (17,33,40,44,47,48), the 97L mutation results in secretion of virions containing an immature genome into the medium and is characterized by excessive amounts of minus-strand DNA (47, 48).…”