We previously identified that hepatitis B virus (HBV) encodes a microRNA (HBV-miR-3) that restrains HBV replication by targeting the HBV transcript. However, whether HBV-miR-3 affects host innate immunity to modulate HBV replication remains unclear. Here, we examined the vital functions of HBV-miR-3 in the innate immune response after HBV infection. We found that HBV-miR-3 expression gradually increased in a dose- and time-dependent manner in HBV-infected HepG2-NTCP cells. HBV-miR-3 activated the JAK/STAT signaling pathway by downregulating SOCS5 in hepatocytes, thereby enhancing the IFN-induced anti-HBV effect. In addition, HBV-miR-3 in exosomes facilitated the M1 polarization of macrophages. Furthermore, exosomes containing HBV-miR-3 enhanced the secretion of IL-6 via inhibiting the SOCS5-mediated ubiquitination of EGFR. In short, these results demonstrate that HBV-miR-3 activates the innate immune response to restrain HBV replication by multiple pathways, which may suppress HBV-induced acute liver cell injury and affect the progression of persistent HBV infection.

中文翻译：

---

HBV 编码的 miRNA 可激活先天免疫，限制 HBV 复制。

我们之前发现，乙型肝炎病毒 (HBV) 编码一种 microRNA (HBV-miR-3)，可通过靶向 HBV 转录本来抑制 HBV 复制。然而，HBV-miR-3是否影响宿主先天免疫来调节HBV复制仍不清楚。在这里，我们检查了 HBV-miR-3 在 HBV 感染后先天免疫反应中的重要功能。我们发现，在 HBV 感染的 HepG2-NTCP 细胞中，HBV-miR-3 表达以剂量和时间依赖性方式逐渐增加。HBV-miR-3通过下调肝细胞中的SOCS5激活JAK/STAT信号通路，从而增强IFN诱导的抗HBV作用。此外，外泌体中的 HBV-miR-3 促进了巨噬细胞的 M1 极化。此外，含有 HBV-miR-3 的外泌体通过抑制 SOCS5 介导的 EGFR 泛素化来增强 IL-6 的分泌。总之，这些结果表明，HBV-miR-3激活先天免疫反应，通过多种途径抑制HBV复制，这可能抑制HBV诱导的急性肝细胞损伤并影响持续性HBV感染的进展。