SUMMARY A new antigen-antibody system associated with the hepatitis B virus and immunologically distinct from the HB surface, core, and e systems is reported. The new antigen, termed 3, was detected by direct immunofluorescence only in the liver cell nuclei of patients with HBsAg positive chronic liver disease. At present, the intrahepatic expression of HBcAg and 6 antigen appears to be mutually exclusive. No ultrastructural aspect corresponding to the antigen could be identified under the electron microscope. 8 antibody was found in the serum of chronic HBsAg carriers, with a higher prevalence in patients with liver damage. The nuclear fluorescence patterns of HBcAg and antigen were similar; it is only possible to discriminate between the two antigens by using the respective specific antisera.While studying liver biopsies from patients who were seropositive for the hepatitis B surface antigen (HBsAg) in direct immunofluorescence, it was noted that an antiserum against the hepatitis B core antigen (HBcAg), as well as staining specimens in which core particles could be demonstrated by the electron microscope (EM), also reacted with additional biopsies which did not contain core particles (at electron microscopy) and were negative with other reference antisera against HBcAg.When the EM core positive and core negative specimens were tested with several HBsAg positive sera, it soon became apparent that some sera reacted with either one or the other liver substrate; this suggested that there were two distinct nuclear antigenic specificities.The identification of this new antigen and of its antibody as an immunological system independent of other known reactions associated with the HB virus is reported in this communication. Provisionally, we propose that it should be called 6.

Using an oligonucleotide hybridization assay, we studied the clinical implication of wild-type hepatitis B virus (HBV) and a HBV mutant that is unable to secrete hepatitis B e antigen (HBeAg) because of a translational defect due to a stop codon in the pre-C region in 106 hepatitis B surface antigen-positive patients with chronic hepatitis B. Wild-type HBV was detected in 31 of42 (73.8%) HBeAg-positive patients, whereas a mixed viral population was present in 10 (23.8%). Significant differences in the severity and outcome of liver disease were not observed in the two groups of patients. However, the emergence of HBeAg-minus HBV in wild-type HBV carriers was associated with an exacerbation of liver disease and was followed by the presence of antibodies against HBeAg (anti-HBe) in serum in 50% of the cases. In 61 of 64 (95.3%) anti-HBe-positive patients, HBeAg-minus HBV was the predominant virus: HBeAg-minus HBV was detected in 42 patients (65.6%), whereas both wild-type and HBeAg-minus HBV were present in 19 (29.7%). HBeAg-minus HBV was associated with a course of hepatitis characterized by flare-ups of liver cell necrosis interspersed with periods of asymptomatic HBV carriage (P < 0.01). These data support the hypothesis that genetic heterogeneity of HBV significantly influences the course and outcome of chronic hepatitis B. Wild-type HBV secreting HBeAg induces immunologic tolerance and causes chronic infection. HBeAg-minus HBV might be unable to induce chronic infection without the helper function of wildtype HBV, but it appears to be more pathogenic. Once chronic infection is established, HBeAg-minus HBV variants may prevail and displace wild-type virus.Hepatitis B e antigen (HBeAg) is a partially degraded nonparticulate form of hepatitis B nucleocapsid protein secreted into the serum during florid hepatitis B virus (HBV) infection (1-3). HBeAg and polypeptides composing the viral nucleocapsid result from translation of a single open reading frame (C gene) containing two start codons, which identify pre-C and C regions (1-3). Initiation of translation from the first codon (pre-C) yields a secretory protein (HBeAg) with a signal peptide cleaved off during maturation (1-3). In carriers of HBV, disappearance of HBeAg and the presence of antibodies against HBeAg (anti-HBe) in serum is associated with clearance of HBV DNA from serum, hepatitis B core antigen from liver, and the resolution of histological activity (4,5). In areas with high or intermediate HBV endemicity, viral replication and liver damage persist in about 10% of anti-HBe-positive carriers (6-12). HBV mutants unable to secrete HBeAg because of translational defects in the pre-C region have been isolated in these patients (13)(14)(15)(16)(17)(18)(19)(20)(21). In the great majority of them (>90%), an unusual HBV strain was characterized with a G -* A mutation at nucleotide 1896, which generates a stop codon in the pre-C sequence (13-21).In our area, an additional mutation (G --A) at position 1899 was consistently associated with the stop codon...

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