PROLIFERATIVE RESPONSE OF CD4(+) T-CELLS AND HEPATITIS-B VIRUS CLEARANCE IN CHRONIC HEPATITIS WITH OR WITHOUT HEPATITIS-B E-MINUS HEPATITIS-B VIRUS MUTANTS

To assess the significance of cell-mediated immunity, T cells were derived from the peripheral blood and liver tissue of hepatitis B virus (HBV)-infected patients and controls. The analysis of the SH-thymidine-uptake in response to a panel of recombinant HBV antigens revealed that peripheral blood mononuclear cells (PBMC) of the 25 viremic patients with inflammatory active, chronic hepatitis B, 16 with wild-type and nine with HBe-minus HBV mutant infection, showed stronger proliferative responses to HBe and HBe antigens than 16 asymptomatic nonviremic HBsAg carriers with normal aminotransferase levels (HBsAg: SI 19.3 +/- 3.9 vs. 13.0 +/- 3.2 vs, 8.0 +/- 1.2; P < .01 and HBe: SI 16.6 +/- 4.0 vs. 10.7 +/- 3.5 vs. 6.9 +/- 1.5; P < .05). In 15 patients with acute self-limited hepatitis B, however, significantly stronger HBc antigen-specific T-cell responses were observed during HBV clearance and HBe/anti-HBe seroconversion, whereas in nine completely HBV-immunized patients only minor proliferative responses to HBV antigens were observed. Six HBe/ HBcAg- and two HBeAg-specific CD4(+) T-cell lines could be expanded from liver tissue and peripheral blood of six viremic patients with chronic hepatitis B. Irrespectively of HBV mutations the HBV-specific activation of the T-cell lines was restricted by the presence of HLA-DR molecules and resulted in the release of Th1-like cytokine patterns. Follow-up of interferon (IFN) recipients showed simultaneous short-term increase of HBc/HBe-specific T-cell reactivities in responder patients during HBV clearance and HBe/anti-HBe seroconversion, whereas in nonresponders high virus load and HBV-specific immune responses were in imbalance, In conclusion, HBe/HBc-specific CD4(+) helper T cells are related to disease activity. From patients with HBe-minus HBV mutants HBeAg-specific T cells could be obtained in vitro, suggestive of viral escape from the host immune response. We speculate that HBe/HBcAg-specific T helper cells are required to mount an efficient immune response in HBV infection.