HEPATITIS-B E-ANTIGEN NEGATIVE CHRONIC ACTIVE HEPATITIS - HEPATITIS-BVIRUS CORE MUTATIONS OCCUR PREDOMINANTLY IN KNOWN ANTIGENIC DETERMINANTS

In chronic hepatitis B virus (HBV) infection seroconversion from hepat itis Be antigen (HBeAg) to hepatitis B e antibody (HBeAb) may be follo wed either by remission of the disease with low-level viraemia, or by continuing inflammation with high-level viraemia. In both situations t he virus may acquire a mutation in the precore sequence which prevents it from encoding HBeAg, We now show that the number of amino acid sub stitutions in the HBV core is low in viral sequences from patients wit h HBeAg positive chronic liver disease. and HBeAg negative HBeAb posit ive 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 promiscuou s CD4(+) T-helper-cell epitope and in HBV core/e antibody binding dete rminants, but are not found in regions recognized by major histocompat ability complex (MHC) restricted cytotoxic T lymphocytes, Sequential v iral sequences from patients before and after HBeAg/HbeAb seroconversi on shows that core mutations arise either at the same time or after th e 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(+) helpe r T cells and B cells allow persistence of the HBe negative virus in H BeAb positive patients with viraemia and active hepatitis.