Division of Molecular Research and Development, Victorian Infectious Diseases Reference Laboratory, Peter Doherty Institute for Infection and Immunity, Royal Melbourne Hospital, Melbourne, Victoria, Australia.
Department of Microbiology, Monash University, Clayton, Victoria, Australia.
J Viral Hepat. 2022 Aug;29(8):604-615. doi: 10.1111/jvh.13702. Epub 2022 May 28.
Chronic hepatitis B (CHB) is characterized by progression through different phases of hepatitis B virus (HBV) infection and disease. Although not necessary for HBV replication, there is increasing evidence that HBV splice variants are associated with liver disease progression and pathogenesis. However, there have been no studies till date on the frequency or diversity of splice variants for different HBV genotypes across the phases of CHB. Next generation sequencing data from 404 patient samples of HBV genotype A, B, C or D in Phase I, Phase II or Phase IV of CHB was analysed for HBV splice variants using an in house bioinformatics pipeline. HBV splice variants differed in frequency and type by genotype and phase of natural history. Splice variant Sp1 was the most frequently detected (206/404, 51% of patients), followed by Sp13 (151/404 37% of patients). The frequency of variants was generally highest in Phase II (123/165, 75% of patients), a phase typically associated with enhanced immune activation, followed by Phase I (69/99, 70% of patients). Splice variants were associated with reduced hepatitis B e antigen (HBeAg) levels and statistically reduced likelihood of achieving HBsAg loss (functional cure) in Phase II patients for Sp1 and Sp13 (p = .0014 and .0156, respectively). The frequency of HBV splice variants in patient serum differed markedly by HBV genotype and phase of CHB natural history. The increased levels of HBV splice variants detected in CHB phase II patients compared with the higher replicative Phase I in particular warrants further investigation.
慢性乙型肝炎（CHB）的特征是乙型肝炎病毒（HBV）感染和疾病经历不同阶段的进展。尽管 HBV 剪接变异体不是 HBV 复制所必需的，但越来越多的证据表明，HBV 剪接变异体与肝病进展和发病机制有关。然而，迄今为止，还没有研究报道不同 HBV 基因型在 CHB 各阶段的剪接变异体的频率或多样性。使用内部生物信息学管道，对来自处于 CHB Ⅰ期、Ⅱ期或Ⅳ期的 HBV 基因型 A、B、C 或 D 的 404 名患者样本的下一代测序数据进行 HBV 剪接变异体分析。HBV 剪接变异体在基因型和自然史阶段的频率和类型上存在差异。Sp1 剪接变体是最常检测到的（404 例中的 206 例，占患者的 51%），其次是 Sp13（404 例中的 151 例，占患者的 37%）。变体的频率通常在第二期最高（165 例中的 123 例，占患者的 75%），这一阶段通常与增强的免疫激活有关，其次是第一期（99 例中的 69 例，占患者的 70%）。Sp1 和 Sp13 的剪接变体与乙型肝炎 e 抗原（HBeAg）水平降低以及乙型肝炎表面抗原（HBsAg）丢失（功能性治愈）的可能性降低有关（第二期患者的 p 值分别为.0014 和.0156）。HBV 剪接变异体在患者血清中的频率因 HBV 基因型和 CHB 自然史阶段而异。与 HBV 复制较高的第一期相比，CHB 第二期患者中检测到的 HBV 剪接变异体水平升高尤其值得进一步研究。
