Genetic determinants of host- and virus-derived insertions for hepatitis E virus replication

作者：Michael Hermann Wißing, Toni Luise Meister, Maximilian K. Nocke, André Gömer, Mejrema Masovic, Leonard Knegendorf, Yannick Brüggemann, Verian Bader, Anindya Siddharta, C.–Thomas Bock, Alexander Ploß, Scott P. Kenney, Konstanze F. Winklhofer, Patrick Behrendt, Heiner Wedemeyer, Eike Steinmann, Daniel Tödt · 发表于：Nature Communications · 年份：2024 · DOI：10.1038/s41467-024-49219-8 · 被引用次数：8 · 研究领域：Hepatitis Viruses Studies and Epidemiology、Viral gastroenteritis research and epidemiology、Liver Disease and Transplantation

Hepatitis E virus (HEV) is a long-neglected RNA virus and the major causative agent of acute viral hepatitis in humans. Recent data suggest that HEV has a very heterogeneous hypervariable region (HVR), which can tolerate major genomic rearrangements. In this study, we identify insertions of previously undescribed sequence snippets in serum samples of a ribavirin treatment failure patient. These insertions increase viral replication while not affecting sensitivity towards ribavirin in a subgenomic replicon assay. All insertions contain a predicted nuclear localization sequence and alanine scanning mutagenesis of lysine residues in the HVR influences viral replication. Sequential replacement of lysine residues additionally alters intracellular localization in a fluorescence dye-coupled construct. Furthermore, distinct sequence patterns outside the HVR are identified as viral determinants that recapitulate the enhancing effect. In conclusion, patient-derived insertions can increase HEV replication and synergistically acting viral determinants in and outside the HVR are described. These results will help to understand the underlying principles of viral adaptation by viral- and host-sequence snatching during the clinical course of infection.