Core Antigen Mutations of Human Hepatitis B Virus in Hepatomas Accumulate in MHC Class II-Restricted T Cell Epitopes

Abstract

Despite the extensive molecular information on serum-derived human hepatitis B viruses (HBV), liver-derived replicative HBV genomes have remained largely uninvestigated. We have examined the sequences of the entire core antigen (nucleocapsid) of liver-derived HBVs in 15 different hepatoma patients. Bona fide mutations, rather than subtype polymorphism, have been identified based on the high-frequency occurrence of structural differences from wild type at the highly evolutionarily conserved positions, instead of at the positions known to contain genetic heterogeneity among different isolates from different geographic locations. The distribution of these naturally occurring mutations of HBV core gene appears to be nonrandom and is found predominantly within three major (I, IV, and V) and four minor domains (II, III, VI, and VII). In general, domain IV mutations correlate with domain V mutations. The replicative HBV DNAs tend to accumulate a higher number of mutated core domains than the integrated HBV DNAs. At the domain level, there is no significant difference in HBV core mutation frequencies between the liver tumors and the adjacent nontumorous livers. Strikingly, domains I, III, and V coincide with three major known T cell epitopes within the core protein in acute and chronic hepatitis B patients. Furthermore, these domains coincide with HLA class II-restricted T cell epitopes, rather than with the conventional HLA class I-restricted epitopes of cytotoxic T lymphocytes. Our results support the hypothesis that HBV core antigen variants can accomplish immunoevasion via accumulated escape mutations. In addition, they also provide a potential molecular explanation for the maintenance of persistent infection of human hepatitis B virus in chronic carriers.

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

“…These BCP mutations may be detected with or without PC mutations (17)(18)(19). Core mutations, particularly amino acid (aa) at position 130 exposed on the surface of mature HBeAg, were observed in the course of disease progression and accumulate in the B-and T-cell epitopes (20,21). These findings emphasize the possibility that the mutations in the T-or B-cell epitopes exert a significant effect on T-cell function or subsequent cytokine release and on the association between the host immunological reaction and viral persistence.…”

“…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).…”

Molecular, immunological and clinical properties of mutated hepatitis B viruses

“…The precore-Cys-23 was found to be highly conserved in Taiwanese hepatomas [16] while in Italian hepatomas this Cys could be changed [108,109].…”

Replication efficiency and sequence analysis of full‐length hepatitis B virus isolates from hepatocellular carcinoma tissues

“…8 As shown in Figure 2, there were 5 "hot-spots" mutations in the core region, which were all located in the B cell epitopes (codons 76 -89, 130 -135, 146 -159) and T cell epitopes (61-85, 81-105, 117-131). 9 Furthermore, 2 isolates showed a stop-codon mutation in the precore region, which abolished HBeAg expression.…”