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Immunomodulatory effects of ADV or TDF by inhibition of mTOR pathway
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Kazumoto Murata1,2,
Masaya Sugiyama2,
Masashi Mizokami2 |
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1Division of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, 2Genome Medical Science, National Center for Global Health and Medicine |
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| Nucleos(t)ide analogues (NUC) safely control HBV replication and improve prognosis in HBV patients. However, life-long treatments are required and NUC cannot completely suppress hepatocellular carcinoma (HCC). We recently found that nucleotide analogues (ADV or TDF), not nucleoside analogues (LAM or ETV), induced IFN-λ3 in the gastrointestinal tracts, which inhibited HBsAg production in vitro. We next examined the effects of NUC on lipopolysaccharide (LPS)-mediated cytokine production because orally administrated NUC encounter lymphocytes and LPS in the portal area. Lymphocytes were incubated with NUC and LPS, and cytokine profiles in the supernatant were examined. We found that ADV or TDF initially inhibited LPS-mediated IL-10 production and reciprocally induced IL-12p70 and TNF-α production. These effects were not observed in LAM or ETV. Furthermore, the combination of IFN-α and ADV or TDF synergistically induced LPS-mediated IL-12p70 production. Mechanistic analyses uncovered that cellular metabolites of TDF directly bound the Akt protein and inhibited its translocation to the plasma membrane, thereby inhibiting Akt phosphorylation. These findings theoretically suggest that TDF is superior to ETV in both anti-HBV and anti-HCC effects, which are comparable with recent clinical data that TDF reduced serum HBsAg levels and the incidence of HCC, compared with ETV. Novel therapies utilizing these mechanisms of ADV or TDF should be considered. |
Index Term 1: Nucleotide analogues
Index Term 2: HCC prevention
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