Adenovirus Vector Harboring the HBcAg and Tripeptidyl Peptidase II Genes Induces Potent Cellular Immune Responses In Vivo.

BACKGROUND

Chronic hepatitis B virus (HBV) infection is associated with a weak but specific cellular immune response of the host to HBV. Tripeptidyl peptidaseⅡ (TPPⅡ), an intracellular macromolecule and proteolytic enzyme, plays an important complementary and compensatory role for the proteasome during viral protein degradation and major histocompatibility complex class I antigen presentation by inducing a specific cellular immune response in vivo. Based on a previous study, we aimed to explore the role of MHC class I antigen presentation in vivo and the mechanisms that may be involved.

METHODS

In this study, recombinant adenoviral vectors harboring the hepatitis B core antigen (HBcAg) and the TPPII gene were constructed (Adv-HBcAg and Adv-HBcAg-TPPII), and H-2Kd HBV-transgenic BALB/c mice and HLA-A2 C57BL/6 mice were immunized with these vectors, respectively. We evaluated the specific immune responses induced by Adv-HBcAg-TPPII in the HBV transgenic BALB/c mice and HLA-A2 C57BL/6 mice as well as the anti-viral ability of HBV transgenic mice, and we explored the underlying mechanisms.

RESULTS

We found that immunization with Adv-HBcAg-TPPII induced the secretion of the cytokines interleukin-2 (IL-2), interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) as well as the activities of IFN-γ-secreting CD8+ T cells and CD4+ T cells. In addition, HBcAg-specific CTL activity in C57/BL mice and HBV transgenic animals was significantly enhanced in the Adv-HBcAg-TPPII group. Furthermore, Adv-HBcAg-TPPII decreased the hepatitis B surface antigen (HBsAg) and HBV DNA levels and the amount of HBsAg and HBcAg in liver tissues. Moreover, Adv-HBcAg-TPPII enhanced the expression of T-box transcription factor (T-bet) and downregulated GATA-binding protein 3 (GATA-3) while increasing the expression levels of JAK2, STAT1, STAT4 and Tyk2.

CONCLUSIONS

These results suggested that the JAK/STAT signaling pathway participates in the CTL response that is mediated by the adenoviral vector encoding TPPII. Adv-HBcAg-TPPII could therefore break immune tolerance and stimulate HBV-specific cytotoxic T lymphocyte activity and could have a good therapeutic effect in transgenic mice.