Division of Hematological Malignancy, Institute of Medical Sciences, Tokai University, Isehara, Japan.
Department of Hematology and Oncology, Tokai University School of Medicine, Isehara, Japan.
Int Immunol. 2020 Jul 28;32(8):519-531. doi: 10.1093/intimm/dxaa018.
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.
慢性乙型肝炎现在可以通过核苷（酸）类似物逆转录酶抑制剂（NRTIs）治疗来控制，这些抑制剂可以抑制乙型肝炎病毒（HBV）的复制。然而，一旦停止使用 NRTIs，大多数患者会复发，需要终身接受 NRTIs 治疗。HBV 感染的复发被认为是由于感染肝细胞核内共价闭合环状 DNA（cccDNA）的持续存在所致。在 NRTIs 治疗期间，cccDNA 阳性肝细胞如何逃避免疫监视的机制仍不清楚。恩替卡韦（ETV）是一种常用的 NRTI，它会在不依赖 HBV 感染的情况下，在肝细胞表面转录后上调程序性细胞死亡配体 1（PD-L1），一种免疫检查点分子。ETV 的上调依赖于 CKLF 样 MARVEL 跨膜结构域包含蛋白 6 的上调，这是一种新发现的能够在细胞表面强力调控 PD-L1 表达的蛋白。ETV 处理后的肝细胞会抑制原代 CD3 T 细胞的活性和程序性细胞死亡蛋白 1（PD-1）过表达的 Jurkat 细胞的活性。最后，ETV 会诱导 HBV 感染的原代肝细胞表达 PD-L1。这些结果提供了证据表明，ETV 会显著上调感染肝细胞表面的 PD-L1，这可能是感染肝细胞逃避免疫监视的机制之一。
