Department of Clinical Laboratory, The People's Hospital of Jiaozuo, China.
Department of Nephrology, The Affiliated Hospital of Henan Polytechnic University, China.
Lab Med. 2021 Sep 1;52(5):439-451. doi: 10.1093/labmed/lmaa110.
T-cell exhaustion in hepatitis B virus (HBV) infection, which results from upregulation of programmed cell death-1 (PD-1), leads to persistent HBV infection and related disease progression. Therefore, agents targeting PD-1 may prove beneficial in the treatment of this condition. MicroRNA-138 (miR-138) possesses an anti-tumor ability in that it targets immune checkpoints, including PD-1. However, the function and underlying mechanisms of miR-138 in patients with HBV infection remains unclear.
Specimens were collected from healthy volunteers (n = 43) and patients with chronic hepatitis B (CHB; n = 52), liver cirrhosis (LC; n = 26), and hepatocellular carcinoma (HCC; n = 31); carriers of HBV who were asymptomatic (n = 51); and patients with CHB receiving antivirus treatment (n = 11). These specimens were then used to study the expression and relationship among miR-138, PD-1, and HBV DNA viral load. To investigate the role of miR-138 in regulating PD-1 expression and determine the effect of miR-138 in regulating T-cell function, a luciferase assay and a transfection assay were each performed with primary CD3+ T cells.
We found that PD-1 was upregulated and miR-138 was downregulated in patients with CHB, LC, and HCC. Correlations analysis revealed that PD-1 expression was positively correlated with HBV DNA viral load whereas miR-138 was negatively correlated. Luciferase assay results showed that miR-138 directly inhibited PD-1 expression by interacting with the 3'-untranslated region of PD-1. As a result of miR-138 overexpression in primary T cells, PD-1 in these T cells was downregulated and antivirus cytokines secreted by T cells were significantly upregulated. In addition, the expression levels of PD-1 and miR-138 were reversed in patients with CHB who received antivirus treatments.
Results showed that miR-138 can promote T-cell responses within patients with HBV infection by inducing a PD-1 blockade. Such an effect suggests that miR-138 may serve as a new therapeutic target for the treatment of HBV infection.
乙型肝炎病毒（HBV）感染导致的 T 细胞耗竭是由于程序性细胞死亡-1（PD-1）的上调，导致 HBV 持续感染和相关疾病进展。因此，靶向 PD-1 的药物可能在治疗这种疾病方面是有益的。MicroRNA-138（miR-138）在靶向免疫检查点方面具有抗肿瘤能力，包括 PD-1。然而，miR-138 在 HBV 感染患者中的功能和潜在机制尚不清楚。
收集健康志愿者（n=43）、慢性乙型肝炎（CHB；n=52）、肝硬化（LC；n=26）和肝细胞癌（HCC；n=31）患者、无症状 HBV 携带者（n=51）和接受抗病毒治疗的 CHB 患者（n=11）的标本。然后使用这些标本研究 miR-138、PD-1 和 HBV DNA 病毒载量之间的表达和关系。为了研究 miR-138 调节 PD-1 表达的作用，并确定 miR-138 调节 T 细胞功能的效果，我们分别用原代 CD3+T 细胞进行了荧光素酶检测和转染实验。
我们发现 CHB、LC 和 HCC 患者的 PD-1 上调，miR-138 下调。相关性分析显示，PD-1 表达与 HBV DNA 病毒载量呈正相关，而 miR-138 与病毒载量呈负相关。荧光素酶检测结果显示，miR-138 通过与 PD-1 的 3'-UTR 相互作用直接抑制 PD-1 表达。由于原代 T 细胞中 miR-138 的过表达，这些 T 细胞中的 PD-1 下调，T 细胞分泌的抗病毒细胞因子明显上调。此外，接受抗病毒治疗的 CHB 患者的 PD-1 和 miR-138 表达水平逆转。
结果表明，miR-138 通过诱导 PD-1 阻断，可促进 HBV 感染患者的 T 细胞反应。这种作用表明，miR-138 可能成为治疗 HBV 感染的新治疗靶点。
