Impact of hepatitis E virus ORF1 mutations on virus replication and disease severity

Hepatitis E virus (HEV) Open Reading Frame 1 (ORF1) encodes a non-structural polyprotein. It has domains of methyl transferase, Y domain, fatty acid binding domain, hypervariable domain, X domain, helicase, and RNA-dependent RNA polymerase. Meta-analysis of virus-host interaction and immunological studies suggested that HEV ORF1 plays a significant role in HEV pathogenesis. Many virus-host interaction studies suggest that potential open reading frame 1 (pORF1) domains interact with host factors involved in various pathways, such as metabolism, innate immune pathways, etc. Interestingly, many in vitro studies showed that the mutations in ORF1 regions alter the virus replication efficiency in cell culture; this suggests the importance of ORF1 in virus pathogenesis. Similarly, the genome sequence analysis of HEV-infected patients reveals that specific amino acid mutations in ORF1 contribute to the disease severity. Studies have empirically proven the association of specific ORF1 mutations in fulminant hepatitis failure (FHF) patients and their effects on HEV replication efficiency using reverse genetic systems. These ORF1 amino acid mutations enhance viral fitness and likely contribute to poor clinical outcomes. Additionally, genotype-specific mutations show different pathogenic significance, contributing to differences in disease outcomes across HEV genotypes. In summary, apart from its role in virus replication, the ORF1 protein interacts with various host factors and contributes to pathogenesis. Mutations in ORF1 are one of the factors that contribute to the development of FHF in HEV-infected patients. This review summarises literature on pORF1 and its role in HEV pathogenesis.