Chowdhury Shruti, Jacobsen Carina, Depledge Daniel P, Wedemeyer Heiner, Sandmann Lisa, Kefalakes Helenie
Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Carl-Neuberg-Str. 1, Hannover 30625, Germany.
Cluster of Excellence RESIST, EXC-2155, Hannover Medical School, Carl-Neuberg-Str. 1, Hannover 30625, Germany.
Virus Evol. 2025 Feb 27;11(1):veaf012. doi: 10.1093/ve/veaf012. eCollection 2025.
Sequence diversity of the hepatitis D virus (HDV) may impact viral clearance, contributing to the development of chronic infection. T-Cell-induced selection pressure and viral recombination can induce diversity throughout the viral genome including coding and noncoding regions, with the former potentially impacting viral pathogenicity and the latter exerting regulatory functions. Here, we aim to assess sequence variations of the HDV genome within and across HDV genotypes. Sequences from 721 complete HDV genomes and 793 large hepatitis D antigen (L-HDAg) regions belonging to all eight genotypes and published through December 2023 were compiled. Most retrieved sequences belonged to Genotype 1, whereas for Genotype 8, the fewest sequences were available. Alignments were conducted using Clustal Omega and Multiple Alignment using Fast Fourier Transform. Phylogeny was analysed using SplitsTree4, and recombination sites were inspected using Recombination Detection Program 4. All reported sequences were aligned per genotype to retrieve consensus and reference sequences based on the highest similarity to consensus per genotype. L-HDAg alignments of the proposed reference sequences showed that not only conserved but also highly variable positions exist, which was also reflected in the epitope variability across HDV genotypes. Importantly, binding prediction analysis showed that CD8 T-cell epitopes mapped for Genotype 1 may not bind to major histocompatibility complex class I when examining their corresponding sequence in other genotypes. Phylogenetic analysis showed evidence of recombinant genomes within each individual genotype as well as between two different HDV genotypes, enabling the identification of common recombination sites. The identification of conserved regions within the L-HDAg allows their exploitation for genotype-independent diagnostic and therapeutic strategies, while the harmonized use of the proposed reference sequences may facilitate efforts to achieve HDV control.
丁型肝炎病毒（HDV）的序列多样性可能会影响病毒清除，从而导致慢性感染的发生。T细胞诱导的选择压力和病毒重组可在整个病毒基因组（包括编码区和非编码区）诱导多样性，前者可能影响病毒致病性，后者发挥调节功能。在此，我们旨在评估HDV基因型内部和不同基因型之间HDV基因组的序列变异。我们汇编了截至2023年12月已发表的属于所有八种基因型的721个完整HDV基因组序列和793个大丁型肝炎抗原（L-HDAg）区域序列。检索到的大多数序列属于基因型1，而基因型8的序列最少。使用Clustal Omega进行比对，使用快速傅里叶变换进行多序列比对。使用SplitsTree4分析系统发育，使用重组检测程序4检查重组位点。每个基因型的所有报告序列进行比对，以根据与每个基因型共识序列的最高相似度检索共识序列和参考序列。对提议的参考序列进行的L-HDAg比对表明，不仅存在保守位点，也存在高度可变位点，这也反映在HDV各基因型的表位变异性上。重要的是，结合预测分析表明，在检查其他基因型中的相应序列时，基因型1定位的CD8 T细胞表位可能无法与主要组织相容性复合体I类结合。系统发育分析显示，在每个个体基因型内部以及两种不同的HDV基因型之间均存在重组基因组的证据，从而能够识别常见的重组位点。L-HDAg内保守区域的识别有助于开发不依赖基因型的诊断和治疗策略，而统一使用提议的参考序列可能有助于实现HDV控制。
