Department of Infectious Diseases, Research Laboratory of Clinical Virology, National Research Center for Translational Medicine (Shanghai), Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Virulence. 2021 Dec;12(1):2868-2882. doi: 10.1080/21505594.2021.1999130.
Hepatitis B virus (HBV) middle surface antigen (MHBs) mutation or deletion occurs in patients with chronic HBV infection. However, the functional role of MHBs in HBV infection is still an enigma. Here, we reported that 7.33% (11/150) isolates of CHB patients had MHBs start codon mutations compared with 0.00% (0/146) in acute hepatitis B (AHB) patients. Interestingly, MHBs loss accounted for 11.88% (126/1061) isolates from NCBI GenBank, compared with 0.09% (1/1061) and 0.00% (0/1061) for HBV large surface antigen (LHBs) loss and HBV small surface antigen (SHBs) loss, respectively. One persistent HBV clone of genotype B (B56, MHBs loss) from a CHB patient was hydrodynamically injected into BALB/c mice. B56 persisted for >70 weeks in BALB/c mice, whereas B56 with restored MHBs (B56) was quickly cleared within 28 days. Serum cytokine assays demonstrated that CXCL1, CXCL2, IL-6 and IL-33 were significantly increased during rapid HBV clearance in B56 mice. Furthermore, the enhancers and promoters of B56 were proved to be required for B56 persistence in mice. Ablating MHBs expression improved the persistence of a new clone (HBV1.3, genotype B) which was recreated by using enhancers and promoters of B56. These data demonstrated that MHBs deletion can promote the persistence of specific HBV variants in a hydrodynamic mouse model. MHBs re-expression restored a rapid clearance of HBV, which was accompanied by cytokine responses including the elevation of CXCL1, CXCL2, IL-6 and IL-33.
乙型肝炎病毒 (HBV) 中表面抗原 (MHBs) 突变或缺失发生在慢性 HBV 感染患者中。然而，MHBs 在 HBV 感染中的功能作用仍然是一个谜。在这里，我们报道与急性乙型肝炎 (AHB) 患者相比，150 例慢性乙型肝炎 (CHB) 患者中有 7.33%（11/150）的病毒株存在 MHBs 起始密码子突变。有趣的是，与 HBV 大表面抗原 (LHBs) 缺失（0.09%，1/1061）和 HBV 小表面抗原 (SHBs) 缺失（0.00%，0/1061）相比，NCBI GenBank 中 11.88%（126/1061）的病毒株存在 MHBs 缺失。从一名 CHB 患者中持续存在的乙型肝炎病毒 B 基因型 (B56，MHBs 缺失) 克隆被水动力注入 BALB/c 小鼠。B56 在 BALB/c 小鼠中持续存在>70 周，而恢复 MHBs 的 B56 (B56) 在 28 天内被迅速清除。血清细胞因子检测表明，在 B56 小鼠中快速清除 HBV 期间，CXCL1、CXCL2、IL-6 和 IL-33 显著增加。此外，B56 的增强子和启动子被证明是 B56 在小鼠中持续存在所必需的。消除 MHBs 的表达可提高使用 B56 的增强子和启动子重新创建的新克隆 (HBV1.3，B 基因型) 的持续存在。这些数据表明，MHBs 缺失可促进特定 HBV 变异在水动力小鼠模型中的持续存在。MHBs 的重新表达恢复了 HBV 的快速清除，伴随着细胞因子反应，包括 CXCL1、CXCL2、IL-6 和 IL-33 的升高。
