The hepatitis E virus capsid protein forms amyloid-like fibrils that sequester TANK-binding kinase 1 to dampen antiviral responses.

Hepatitis E virus (HEV) is the leading cause of viral hepatitis worldwide. We find that the HEV ORF2 capsid protein contains intrinsically disordered regions (IDRs) at its N terminus that promote condensate formation through liquid-liquid phase separation both in vitro and in cellulo. Using correlative light and electron microscopy/tomography of HEV-infected cells, we observe that ORF2 forms higher order assemblies composed of orderly stacked tubular filaments resembling amyloid fibrils. By light microscopy, we detect ORF2 fibrils in multiple HEV-infected cell types, including human induced pluripotent stem cell-derived hepatocytes and neurons. Moreover, we discover that the central adapter protein TANK-binding kinase 1 is sequestered by ORF2 fibrils, thereby enabling immune evasion and enhancing viral replication. Together, our findings uncover a previously unrecognized mechanism by which HEV modulates host defense pathways and place HEV among the growing repertoire of viruses that exploit dynamic phase behavior as a broader strategy to regulate virus-host interactions.