Naturally Occurring Mutations within HBV Surface Promoter II Sequences Affect Transcription Activity, HBsAg and HBV DNA Levels in HBeAg-Positive Chronic Hepatitis B Patients
2019
Ran Hao | Kuanhui Xiang | Yan Shi | Dong Zhao | Huifang Tian | Baohong Xu | Yufang Zhu | Huan Dong | Hai Ding | Hui Zhuang | Jie Hu | Tong Li
Mutations in hepatitis B virus (HBV) surface promoter II (SPII) have not been well studied in hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) patients. We aimed to investigate SPII mutations in such patients and their biological and clinical impacts. Direct sequencing was used to detect SPII mutations in 106 HBeAg-positive treatment-naïve CHB patients with genotype C (82.1% (87/106) was C2) HBV infection. Results showed that mutation frequency in transcription factor (TF) unbinding region was significantly higher than that in TF binding region of SPII (C1: 3.4% vs. 1.3%; C2: 2.6% vs. 1.3%; p < 0.0001). Luciferase assay revealed distinct promoter activities among SPII mutants; especially SPII of G120A mutant had a 15-fold higher activity than that of wild-type (p < 0.001). In vitro experiments in HepG2 cells showed that G82A, A115C and G120A mutants increased the hepatitis B surface antigen (HBsAg) levels, while C18T had an opposite effect. G82A, A115C and G120A mutants boosted the intracellular HBV total RNA level. G120A mutation resulted in an increased HBV DNA level in vitro, consistent with the serological results in patients. Thus, novel SPII mutations would affect promoter activity, HBsAg, HBV DNA and HBV total RNA levels, suggesting their potential biological and clinical significances.
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