Hepatitis B e antigen negative chronic active hepatitis: hepatitis B virus core mutations occur predominantly in known antigenic determinants

Abstract

In chronic hepatitis B virus (HBV) infection seroconversion from hepatitis B e antigen (HBeAg) to hepatitis B e antibody (HBeAb) may be followed either by remission of the disease with low-level viraemia, or by continuing inflammation with high-level viraemia. In both situations the virus may acquire a mutation in the precore sequence which prevents it from encoding HBeAg. We now show that the number of amino acid substitutions in the HBV core is low in viral sequences from patients with HBeAg positive chronic liver disease and HBeAg negative HBeAb positive patients in remission, but the frequency of substitutions is high in HBeAg, negative HBeAb positive patients with active liver disease. Furthermore we show that these substitutions cluster in the promiscuous CD4+ T-helper-cell epitope and in HBV core/e antibody binding determinants, but are not found in regions recognized by major histocompatability complex (MHC) restricted cytotoxic T lymphocytes. Sequential viral sequences from patients before and after HBeAg/HbeAb seroconversion shows that core mutations arise either at the same time or after the precore stop mutation which prevents the virus from encoding HBeAg. These results are consistent with the hypothesis that after clearance of HBeAg, mutations in regions of the virus recognized by CD4+ helper T cells and B cells allow persistence of the HBe negative virus in HBeAb positive patients with viraemia and active hepatitis.

Association of human leukocyte antigen-DRB1 alleles with chronic hepatitis B virus infection in the Han Chinese of Northeast China

“…The association of HLA alleles with the susceptibility of individuals to HBV infection and disease progression varies since multiple factors, such as geography and ethnicity, affect this association (6,(8)(9)(10). To investigate the association of the frequency of HLA-DRB1 alleles with the susceptibility of individuals to HBV infection in the Han Chinese of Northeast China, we characterized the genotypes of 396 patients with ASC, CHB, HBV-related liver cirrhosis or HCC and 400 healthy subjects.…”

“…Previous research has shown that the HLA-I genes are in linkage disequilibrium with CHB and the polymorphisms of HLA-II alleles are associated with susceptibility to CHB (7). However, the association is racially and geographically dependent (6,(8)(9)(10).…”

“…Previous research has shown that the HLA-I genes are in linkage disequilibrium with CHB and the polymorphisms of HLA-II alleles are associated with susceptibility to CHB (7). However, the association is racially and geographically dependent (6,(8)(9)(10).The prevalence of HBV infection is extremely high in China and many people with HBV infections develop CHB and some progress to the onset of cirrhosis (11). A follow-up study (1-18.4 years) revealed that 23 and 4.4% of CHB patients with hepatitis B early antigen (HBeAg)-negative serological status progress to the deve lopment of cirrhosis and HCC, respectively (12,13).…”

HBV Surface Ag mutations in chronic carriers are rare in Baloochstan provinces of Iran: a community with a low rate of HBV-related cirrhosis and HCC

“…Besides, from a total of 18 amino acid mutations, 5 (27.5%) and 13 (72.5%) amino acid mutations occurred in anti-HBe and HBeAg groups, respectively. However, previous data (25)(26)(27) indicated that HBeAg seroconversion led to the higher number of amino acid substitutions. Occurrence of 18 amino acid mutations in 11 positions indicated that there were not any hotspot residues for these substitutions.…”

Nucleotide mutations associated with hepatitis B e antigen negativity

“…It has been reported that amino acid substitutions in immunogenic epitopes in the core protein are found most frequently during or after seroconversion from HBeAg to anti-HBe [Carman et al, 1995;Akarca and Lok, 1995]. We found two mutations in the core gene, but these mutations did not cause amino acid substitutions.…”