THE SECRETED HEPATITIS-B PRECORE ANTIGEN CAN MODULATE THE IMMUNE-RESPONSE TO THE NUCLEOCAPSID - A MECHANISM FOR PERSISTENCE

The hepatitis B precore Ag (HBeAg) is a secreted nonparticulate versio n of the viral nucleocapsid hepatitis B core Ag (HBcAg), and its funct ion is unknown. A proportion of HBeAg-specific Th cells evade deletion /anergy in HBeAg-transgenic (Tg) mite and mediate anti-HBe ''autoantib ody'' (autoAb) production after in vivo activation with the appropriat e Th cell peptide, This model system was used to determine how secreto ry HBeAg may effect deletion of Th cells in the periphery. For this pu rpose, HBeAg-Tg mice were bred with Fas and Fas ligand (FasL)-defectiv e lpr/lpr and gld/gld mutant mice. Fas-FasL interactions mediate activ ation-induced apoptosis in the periphery. In HBeAg-Tg/+ mice, high-tit rated anti-HBe autoAb was produced that was exclusively composed of th e IgG1 isotype (i.e., Th2-like profile), In contrast, HBeAg-Tg/lpr and HBeAg-Tg/gld mice produced significantly less anti-HBe autoAb, and th e IgG isotype patterns were broadened to include IgG2a, IgG2b and IgG3 as wed as IgG1 (i.e., mixed Th1/Th2-1ike profile). These results sugg est that HBeAg-specific Th1 cells are preferentially depleted by Fas-F asL-mediated interactions. The effect of circulating HBeAg on HBcAg-sp ecific Th1 cells was also examined by transferring HBe/HBcAg-specific Th cells into dual HBeAg- and HBcAg-expressing Tg recipient mice. The presence of serum HBeAg ablated the expected Th1-mediated anti-HBc Ab response and shifted it toward a Th2 phenotype. These results suggest that in the context of a hepatitis B viral infection, circulating HBeA g has the potential to preferentially deplete inflammatory HBeAg- and HBcAg-specific Th1 cells that are necessary for viral clearance, there by promoting hepatitis B virus persistence.