Advances in experimental model systems to study hepatitis E virus genotype 1

Hepatitis E virus (HEV) of the species Paslahepevirus balayani is a leading cause of acute viral hepatitis worldwide. Four HEV genotypes frequently infect humans but differ in their geographical distribution, routes of transmission, host range, clinical manifestations, and pathogenesis. HEV genotype 1 (HEV-1), endemic in many low- and middle-income countries, is predominantly transmitted via the fecal-oral route through contaminated water and is associated with severe disease during pregnancy, resulting in high maternal morbidity and mortality. Despite its public health importance, our understanding of the HEV-1 replication cycle and genotype-specific determinants of pathogenicity remains limited. A key bottleneck in the field is the availability of robust, reproducible in vitro and in vivo model systems that accurately recapitulate HEV-1 infection. In this review, we summarize recent advances in the development of HEV-1 model systems and describe available in vitro and in vivo systems. We also outline remaining gaps and potential directions for model refinement that may facilitate future HEV-1 research.