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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 0.0060, <0.01) to >1 year after seroconversion (0.0103 0.0068, <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 0.0106, = 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.

背景与目的

我们旨在利用下一代测序（NGS）技术，研究乙肝病毒（HBV）全基因组的准种如何响应HBeAg血清学转换和病毒控制而发生进化及多样化。

方法

招募了50例HBeAg阳性慢性乙型肝炎患者，其中包括18例初治患者和32例接受干扰素（IFN）治疗的患者。通过NGS分析血清中的连续HBV全基因组，以确定序列特征和病毒准种。

结果

以核苷酸多样性衡量的HBV准种多样性与病毒载量和肝炎活动度呈负相关。自发HBeAg血清学转换者在血清学转换前>1年（0.0112±0.0060，P<0.01）至血清学转换后>1年（0.0103±0.0068，P<0.01）期间，其病毒准种多样性显著高于初治未发生血清学转换者。IFN诱导的HBeAg血清学转换者在治疗过程中病毒遗传多样性往往高于未发生血清学转换者。特别是，定义为IFN诱导的HBeAg血清学转换且病毒血症较低的IFN应答者，在IFN治疗后6个月时HBV全基因组的遗传多样性显著高于IFN无应答者（0.0148±0.0106，P=0.048）。此外，自发HBeAg血清学转换者和IFN应答者表现出显著更高的进化速率和更多的宿主内单核苷酸变异。有趣的是，在自发HBeAg血清学转换者和IFN应答者中，HBV基因组存在明显的进化模式。