Whole genome deep sequencing analysis of viral quasispecies diversity and evolution in HBeAg seroconverters

JHEP Reports

You-Yu Lin¹  Fang-Yi Wu²  Huei-Ru Cheng²  Tung-Hung Su³  Chun-Jen Liu⁴  Hurng-Yi Wang⁵  Su-Ru Lin⁶  Hung-Chih Yang⁶  Pei-Jer Chen⁶  Ta-Yu Yang⁶  Yueh-Chi Shen⁷  I-Jung Liu⁷  Jia-Horng Kao⁸  Chia-Yen Dai⁸  Tai-Chung Tseng⁸  Ding-Shinn Chen⁸  Cheng-Yuan Peng⁹ 

[1] Department of Internal Medicine, Center for Digestive Medicine, China Medical University Hospital, Taichung, Taiwan;Hepatitis Research Center, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan;Hepato-Biliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan;Cardinal Tien Junior College of Healthcare and Management, New Taipei City, Taiwan;Department of Internal Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan;Department of Microbiology, National Taiwan University, Taipei, Taiwan;Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan;Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan;School of Medicine, China Medical University, Taichung, Taiwan;

关键词: Chronic hepatitis B;    HBeAg seroconversion;    Intra-host single nucleotide variants;   

DOI  :  

来源: DOAJ

【 摘 要 】

Summary:Background & Aims: We aimed to investigate how viral quasispecies of the HBV whole genome evolves and diversifies in response to HBeAg seroconversion and viral control utilising next-generation sequencing (NGS). Methods: Fifty HBeAg-positive chronic hepatitis B patients, including 18 treatment-naïve and 32 interferon (IFN)-treated individuals, were recruited. Serial HBV whole genomes in serum were analysed by NGS to determine sequence characteristics and viral quasispecies. Results: HBV quasispecies diversity, measured by nucleotide diversity, was negatively correlated with viral load and hepatitis activity. Spontaneous HBeAg seroconverters exhibited significantly greater viral quasispecies diversity than treatment-naïve non-seroconverters from >1 year before seroconversion (0.0112 vs. 0.0060, p <0.01) to >1 year after seroconversion (0.0103 vs. 0.0068, p <0.01). IFN-induced HBeAg seroconverters tended to have higher viral genetic diversity than non-seroconverters along with treatment. Particularly, the IFN responders, defined as IFN-induced HBeAg seroconversion with low viraemia, exhibited significantly greater genetic diversity of whole HBV genome at 6 months post-IFN treatment than IFN non-responders (0.0148 vs. 0.0106, p = 0.048). Moreover, spontaneous HBeAg seroconverters and IFN responders exhibited significantly higher evolutionary rates and more intra-host single-nucleotide variants. Interestingly, in spontaneous HBeAg seroconverters and IFN responders, there were distinct evolutionary patterns in the HBV genome. Conclusions: Higher HBV quasispecies diversity is associated with spontaneous HBeAg seroconversion and IFN-induced HBeAg seroconversion with low viraemia, conferring a favourable clinical outcome. Lay summary: HBeAg seroconversion is a landmark in the natural history of chronic HBV infection. Using next-generation sequencing, we found that the nucleotide diversity of HBV was negatively correlated with viral load and hepatitis activity. Patients undergoing HBeAg seroconversion had more diverse HBV genomes and a faster viral evolution rate. Our findings suggest HBeAg seroconversion is driven by host selection pressure, likely immune selection pressure.

【 授权许可】

Unknown