cccDNA
恩替卡韦
Jurkat细胞
乙型肝炎病毒
病毒学
免疫系统
肝细胞
HBeAg
溶解循环
生物
化学
分子生物学
乙型肝炎表面抗原
癌症研究
T细胞
病毒
免疫学
拉米夫定
生物化学
体外
作者
Yuichiro Yamamoto,Masatoshi Kakizaki,Takayuki Shioiri,Joaquim Carreras,Tetsuhiro Chiba,Kenji Chamoto,Tatehiro Kagawa,Taku Aoki,Naoya Nakamura,Kiyoshi Ando,Ai Kotani
标识
DOI:10.1093/intimm/dxaa018
摘要
Abstract Chronic hepatitis B is now controllable when treated with nucleoside reverse transcriptase inhibitors (NRTIs), which inhibit hepatitis B virus (HBV) replication. However, once the NRTIs are discontinued, most patients relapse, necessitating lifelong NRTIs treatment. HBV infection relapse is assumed to be caused by the persistent existence of covalently closed circular DNA (cccDNA) in the nuclei of infected hepatocytes. The mechanism by which cccDNA-positive hepatocytes escape immune surveillance during NRTIs treatment remains elusive. Entecavir (ETV), a commonly used NRTI, post-transcriptionally up-regulates programmed cell death-ligand 1 (PD-L1), an immune checkpoint molecule, on the cell surface of hepatocytes regardless of HBV infection. Up-regulation by ETV depends on up-regulation of CKLF-like MARVEL transmembrane domain-containing 6, a newly identified potent regulator of PD-L1 expression on the cell surface. ETV-treated hepatic cells suppressed the activity of primary CD3 T cells and programmed cell death protein-1 (PD-1)-over-expressed Jurkat cells. Finally, ETV induces PD-L1 in primary hepatocytes infected by HBV. These results provide evidence that ETV considerably up-regulates PD-L1 on the cell surface of infected hepatocytes, which may be one of the mechanisms by which infected hepatocytes subvert immune surveillance.
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