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

Abstract

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.

Efficacy of recombinant adenovirus expressing a fusion gene from GM-CSF and Epstein-Barr virus LMP2A in a mouse tumor model

“…In addition, the adenovirus vector can infect the respiratory tract and intestinal cells, which can be conveniently used to immunize the mucosa and induce the mucosal and systemic immune responses. 12 Adenovirus vectors have a wide range of hosts, are able to infect cells in the dividing, resting, and terminal phases, and are safe for use in humans. They are typically used as carriers in genetic engineering, 13,14 and are considered good vectors for tumor vaccine development that can be used to express other genes.…”

Applications and developments of gene therapy drug delivery systems for genetic diseases

“…Tan et al immunized transgenic mice by constructing a recombinant AdV vector carrying the hepatitis B core antigen (HBcAg) and TPPII genes (Adv-HBcAg-TPPII) to evaluate the specific immune response induced by them and the antiviral ability of the transgenic mice. The results show that Adv-HBcAg-TPPII can break the immune tolerance, stimulate the activity of HBV-specific cytotoxic T lymphocytes, and has a better therapeutic effect in transgenic mice [75] .…”

An Engineered DC-Targeting Lentivector Induces Robust T Cell Responses and Inhibits HBV Replication in HBV Transgenic Mice via Upregulating T Cell Autophagy

“…Eighty H-2K d HBV-transgenic BALB/c mice (40 males and 40 females, 6-8 weeks old) were obtained from the Key Liver Army Laboratory (The No.458 Hospital, Guangzhou, China). The characterization of the mice has been described in detail before [23,24]. All mice were bred under specific pathogen-free conditions in the Experimental Animal Centre of the Shanghai Sixth People's Hospital.…”