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The replication of hepatitis B virus (HBV) may be modulated by a variety of cell signaling pathways, including the phosphatidylinositol 3‑kinase (PI3K)‑RAC‑α serine/threonine‑protein kinase (AKT)‑serine/threonine‑protein kinase mTOR (mTOR) pathway. The aim of the present study was to determine the regulatory effects of this pathway on the infection and replication of HBV. The results indicated that the HBV entry process may activate the AKT pathway, as demonstrated by AKT phosphorylation in HBV natural infection. However, inhibition of AKT phosphorylation by short‑term treatment with AKT inhibitors was unable to block HBV entry, which suggested that AKT activation induced by HBV infection is not essential for viral entry process. Prolonged treatment with PI3K‑AKT‑mTOR pathway inhibitors markedly promoted HBV replication in HBV replicating and natural infection models. The PI3K‑AKT‑mTOR pathway was therefore identified to be a negative regulator of HBV replication. These inhibitors enhanced the replication and transcription of HBV in an HBx‑dependent way. The results additionally indicated that a PI3K inhibitor, Ly294002, inhibited the secretion of the small surface antigen of HBV in a PI3K‑AKT‑independent manner. The inhibitor Ly294002 may be used as a tool for the drug development of surface antigen secretion inhibitors. [ABSTRACT FROM AUTHOR]

The aim of the present study was to investigate the in vitro effects of hepatitis B virus surface antigen (HBsAg) on the immune function of human monocyte-derived dendritic cells (MD-DCs), and the moderating role of T cell immunoglobulin and mucin domain-containing molecule-3 (Tim-3) signaling molecule. The monocytes, obtained from healthy adult peripheral blood, were incubated with recombinant human granulocyte-macrophage colony-stimulating factor and interleukin (IL)-4 to induce DCs. DC-associated cell markers were detected using flow cytometry. MD-DCs were treated with HBsAg (5 μg/ml) in vitro for 48 h and subsequently, cell markers, lymphocyte stimulatory capacity, signaling protein and downstream cytokines were assessed. In addition, a Tim-3 monoclonal antibody was used to inhibit the Tim-3 signaling pathway, and subsequently the immune responses of MD-DCs to HBsAg stimulation were determined using the aforementioned method. The cell phenotype expressions of MD-DCs were all significantly increased with cluster of differentiation (CD)11c at 70.09±0.57%, human leukocyte antigen-DR at 79.83±2.12%, CD80 at 48.33±7.34% and CD86 at 44.21±5.35%. The treatment of MD-DCs with HBsAg resulted in a CD80 and CD86 enhanced expression, enhanced lymphocyte stimulatory capacity, upregulated expression of Tim-3 and nuclear factor-κB (NF-κB), as well as enhanced cytokine secretion of IL-6, IL-10 and interferon (IFN)-γ. However, a reduced immune response of MD-DCs in response to HBsAg stimulation was observed when the Tim-3 signaling pathway was inhibited prior to stimulation. The expression of NF-κB was decreased and the cytokine secretion level of IL-6, IL-10 and IFN-γ were downregulated. The treatment with HBsAg in vitro resulted in an enhanced immune response of MD-DCs, which may be positively regulated by the Tim-3 signaling molecule. [ABSTRACT FROM AUTHOR]