Hepatitis E Virus (HEV) is a positive-sense RNA virus responsible for acute hepatic failure, jaundice and neurological complications, particularly in pregnant women and the immunocompromised. There are eight known genotypes, including obligate human pathogens, non-human pathogens and zoonotic pathogens that can be transmitted between animals and humans, raising the risk of future human spillover events. Despite this, there are limited available treatments for HEV. The HEV genome contains three conserved open reading frames (ORFs) with ORF1 encoding a polyprotein (pORF1) that contains multiple functional domains necessary and required for viral RNA synthesis. One pORF1 domain, the hypervariable region (HVR), is a disordered region which has been proposed to increase viral host range and in part dictate replication efficiency in vitro and in vivo. In particular, a naturally occurring insertion of sequences derived from the human ribosomal protein S17 stimulated replication of  HEV by an undetermined mechanism. Here we use HEV sub-genomic replicons (SGRs) encoding a nano-luciferase reporter to investigate how the HVR and S17 insertions contribute to both host range and replication efficacy. We generated chimeric replicons between obligate human and zoonotic viral genotypes and tested replication efficacy in a panel of human and animal cell types. Chimeras showed an increase in replicative fitness when containing ~80 amino acids of S17 in human liver cell lines. Ongoing work is developing additional SGRs with novel HVR sequences to elucidate the mechanism by which the HVR impacts replication.