Xue Yuan, Wang Ming-Jie, Yang Zhi-Tao, Yu De-Min, Han Yue, Huang Dao, Zhang Dong-Hua, Zhang Xin-Xin
Clinical Virology Research Laboratory, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China.
Department of Infectious Diseases, Institute of Infectious and Respiratory Diseases, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China.
Emerg Microbes Infect. 2017 Mar 22;6(3):e15. doi: 10.1038/emi.2017.2.
Coexistence of the hepatitis B surface antigen (HBsAg) and hepatitis B surface antibody (anti-HBs) is an uncommon phenomenon, and the underlying mechanisms remain largely unknown. Amino-acid (aa) substitution from glycine to arginine at aa 145 (G145R), in the major hydrophilic region, has been reported in patients with HBsAg and anti-HBs coexistence. However, there is limited knowledge about the clinical features and viral quasispecies characteristics associated with G145R mutant hepatitis B virus (HBV) infection. We herein describe the dynamic changes in the serological and virological markers in a case of hepatitis B with coexisting HBsAg and anti-HBs, caused by a G145R immune escape mutant (genotype C). Entecavir was administered during the 4th week after admission. Alanine aminotransferase peaked in the 16th week, while both the HBsAg and HBeAg declined rapidly. HBsAg clearance and hepatitis B e antigen (HBeAg)/hepatitis B e antibody (anti-HBe) seroconversion were achieved in the 36th week, and then entecavir was withdrawn. A follow-up of 96 weeks showed that HBV DNA remained undetectable and that anti-HBs was maintained above 100 mIU/mL. The quasispecies characteristics of the G145R mutant HBV were investigated via ultra-deep sequencing. The complexity and genetic distance of the S and RT regions were much higher in the 8th week than at baseline or in the 4th week. Moreover, the frequencies of mutations (L173P, Q181R and A184V) in cytotoxic T lymphocyte epitopes increased before entecavir treatment. These findings extend understanding of the evolution of HBV under host immune pressure and of the clinical outcomes of affected patients.
乙肝表面抗原（HBsAg）与乙肝表面抗体（抗-HBs）共存是一种罕见现象，其潜在机制在很大程度上仍不清楚。在HBsAg与抗-HBs共存的患者中，已报道在主要亲水区第145位氨基酸（aa）处发生了从甘氨酸到精氨酸的替换（G145R）。然而，关于与G145R突变型乙型肝炎病毒（HBV）感染相关的临床特征和病毒准种特征的了解有限。我们在此描述了1例由G145R免疫逃逸突变株（C基因型）引起的HBsAg与抗-HBs共存的乙型肝炎病例中血清学和病毒学标志物的动态变化。入院后第4周开始给予恩替卡韦。丙氨酸氨基转移酶在第16周达到峰值，而HBsAg和HBeAg均迅速下降。在第36周实现了HBsAg清除和乙肝e抗原（HBeAg）/乙肝e抗体（抗-HBe）血清学转换，随后停用恩替卡韦。96周的随访显示HBV DNA仍未检测到，且抗-HBs维持在100 mIU/mL以上。通过超深度测序研究了G145R突变型HBV的准种特征。第8周时S区和RT区的复杂性和遗传距离比基线或第4周时高得多。此外，在恩替卡韦治疗前，细胞毒性T淋巴细胞表位中的突变（L173P、Q181R和A184V）频率增加。这些发现扩展了对宿主免疫压力下HBV进化以及受影响患者临床结局的认识。
