Hepatitis E Virus Mutations: Functional and Clinical Relevance

Abstract

Hepatitis E virus (HEV) infection is a major cause of acute hepatitis and affects more than 20 million individuals, with three million symptomatic cases and 56,000 recognized HEV-related deaths worldwide. HEV is endemic in developing countries and is gaining importance in developed countries, due to increased number of autochthone cases. Although HEV replication is controlled by the host immune system, viral factors (especially specific viral genotypes and mutants) can modulate HEV replication, infection and pathogenesis. Limited knowledge exists on the contribution of HEV genome variants towards pathogenesis, susceptibility and to therapeutic response. Nonsynonymous substitutions can modulate viral proteins structurally and thus dysregulate virus-host interactions. This review aims to compile knowledge and discuss recent advances on the casual role of HEV heterogeneity and its variants on viral morphogenesis, pathogenesis, clinical outcome and antiviral resistance.

Keywords: HEV infection; HEV mutation; HEV replication; HEV treatment failure; HEV variability; Hepatitis E virus.

Fig. 1

Schematic description of the HEV genome and viral proteins. The figure shows linear, ssRNA (+) genome of ~ 7.2 kb HEV genome and corresponding viral proteins. The 5′-end is capped and the 3′-terminus is polyadenylated. ORF1 encodes the nonstructural polyprotein, including methyltransferase (Met), Y-domain (Y), papain-like cysteine protease (PCP), hypervariable region (HVR), macro-domain (X), RNA helicase (Hel) and RNA-dependent RNA polymerase (RdRp). ORF2 encodes the capsid protein (CP), containing S domain (S), M domain (M) and P domain (P). The glycosylation sites of ORF2 are indicated (Asn137, Asn310, and Asn562). ORF3 encodes a small multifunctional protein (MFP) including hydrophobic regions (D1, D2) and proline-rich regions (P1, P2). The phosphorylation site (Ser80) and the SH3-binding domain are indicated. ORF2 is translated by leaky scanning from the bicistronic ORF3-2 ~ 2.0 kb subgenomic RNA. JR is ORF2 and ORF3 overlapping/intergenic-junction region; CRE is cis-reactive element; SP is signal peptide. Nucleotide positions are relative to the HEV-1 Burmese strain (Acc. No. M73218)/HEV-3 47832 strain (Acc. No. KC618402). Asterisk (*) indicates the hot spot region for clinical mutations (adapted from (Cao and Meng, 2012, Chandra et al., 2008b).

Fig. 2

Effect of mutations on HEV replication cycle and clinical significance. Schematic description of the HEV replication cycle and effect of mutations occurring in the HEV genome (red boxes; domain and region are indicated) on the transcriptional/translational machinery (blue dotted box) of HEV. Asterisks (***) indicate mutations described in the text. The possible effect of mutations on HEV replication is denoted at the side, described clinical outcome below the red boxes.