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

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Abstract
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 H‐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 HBc and HBe antigens than 16 asymptomatic nonviremic HBsAg carriers with normal aminotransferase levels (HBc: 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. (HEPATOLOGY 1995; 22:61–68.)