core region. The interrelations are formulated in Table 1. In the high replicative phase, the relatively higher expression of precore region than core gene results in translation of a greater amount of precore protein than core protein. The precore protein is then either secreted as HBeAg or transported into nucleus as nuclear HBcAg. This hypothesis is in keeping with the clinical observation of high levels of serum HBV-DNNHBeAg and the predominant localization of HBcAg in hepatocyte nuclei during this phase. In contrast. the expression of the precore region is relatively lower than core gene in the low replicative phase. This results in translation of a greater amount of core protein than precore protein. also in keeping with the clinical observations of the low levels of HBV-DNA and HBeAg in serum and a decreased nuclear HBcAg expression with a concomitant increase of cytoplasmic HBcAg expression in such patients. In the anti-HBe-positive patients with viremia and active hepatitis, point mutation of the precore region prevents HBeAg secretion ( 9 ) and nuclear transport of HBcAg, in keeping with the clinical observations of HBeAg seronegativity and exclusively cytoplasmic HBcAg expression in these patients.
However, these observations have not answered the question of what regulates these changes along the natural course of chronic HBV infection. We have shown that HLA class I antigen (HLA-I), an antigen required for T cell killing of HBV-infected hepatocytes, is undetectable during the immune tolerant phase, but becomes detectable during the immune clearance phase ( 101. As interferon may enhance HLA-I expression, the finding that HLA-I is expressed simultaneously with cytoplasmic HBcAg suggests that the regulatory mechanism of HLA-I, as well as of HBcAg, may be related to interferon. Of interest is that the interferon-sensitive consensus sequence ( 1821 to 1834) locates in the precore region (11). The significance and implications of this association await further molecular biological study.