Genomic plasticity: Role of Hepatitis E virus genome insertions in viral fitness, resistance and immune escape

• Applicant: Dr. Daniel Todt
• Subject Area: Virology ; Gastroenterology
• Term: from 2020 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 448974291

RNA viruses such as the Hepatitis E virus (HEV) diversify into populations with high intrahost variability, providing a potential benefit to the virus population across changing environments (e.g. immune response, antiviral therapy). We recently observed that ribavirin (RBV) therapy is associated with a marked increase in viral heterogeneity and further observed of human genomic fragments or HEV sequence duplications in the sequence encoding the hypervariable region (HVR). Given these and previously identified insertions into the genome of HEV originate from chronic patients, insertions into the HVR are likely to reflect a-yet-unknown aspect of HEV viral pathogenesis. Interestingly, the sequence derived from chronic patients as well as the previously described insertion contain predicted nuclear localization signal (NLS), implying a common functionality. This project aims to examine molecular mechanisms of host genome insertions into the HVR as well as the functional role of different insertions regarding viral fitness, resistance and immune escape. We apply an integrated research approach combining next generation sequencing methods to identify novel patient derived sequence insertions into the HVR of HEV and perform an in-depth characterization of the molecular functions HVR insertions using novel state-of-the-art HEV cell culture system.

• DFG Programme: Research Grants