Structural and molecular biology of hepatitis E virus

Abstract

Hepatitis E virus (HEV) is one of the most common causes of acute viral hepatitis, mainly transmitted by fecal-oral route but has also been linked to fulminant hepatic failure, chronic hepatitis, and extrahepatic neurological and renal diseases. HEV is an emerging zoonotic pathogen with a broad host range, and strains of HEV from numerous animal species are known to cross species barriers and infect humans. HEV is a single-stranded, positive-sense RNA virus in the family Hepeviridae . The genome typically contains three open reading frames (ORFs): ORF1 encodes a nonstructural polyprotein for virus replication and transcription, ORF2 encodes the capsid protein that elicits neutralizing antibodies, and ORF3, which partially overlaps ORF2, encodes a multifunctional protein involved in virion morphogenesis and pathogenesis. HEV virions are non-enveloped spherical particles in feces but exist as quasi-enveloped particles in circulating blood. Two types of HEV virus-like particles (VLPs), small T = 1 (270 Å) and native virion-sized T = 3 (320–340 Å) have been reported. There exist two distinct forms of capsid protein, the secreted form (ORF2 S ) inhibits antibody neutralization, whereas the capsid-associated form (ORF2 C ) self-assembles to VLPs. Four cis -reactive elements (CREs) containing stem-loops from secondary RNA structures have been identified in the non-coding regions and are critical for virus replication. This mini-review discusses the current knowledge and gaps regarding the structural and molecular biology of HEV with emphasis on the virion structure, genomic organization, secondary RNA structures, viral proteins and their functions, and life cycle of HEV.

Identification of Hepatitis E Virus Genotypes 3 and 7 in Israel: A Public Health Concern?

“…Local HEV-7 ORF3 exhibited a single conservative substitution, V92A, in a site located between the two conserved PSAP motifs (amino acids 86-89 and amino acids 95-98). Mutations in these motifs were previously associated with a decrease in HEV replication [5]. Aside from these few amino acid mutations in both ORF2 and ORF3, all other residues which were previously shown to be of relevance to HEV infection, replication and expression of the capsid protein were conserved.…”

“…ORF2 encodes the capsid protein, 2 of 8 which interacts with the host cell receptor. ORF3 encodes a short multifunctional phosphoprotein that can modulate cellular signaling and is related to particle secretion and considered to influence infectivity [5].…”

Molecular Identification and Characterization of a Genotype 3 Hepatitis E Virus (HEV) Strain Detected in a Wolf Faecal Sample, Italy

“…Hepatitis E virus (HEV) is a common cause of human acute viral hepatitis [ 1 ]. HEV is a single-stranded, positive-sense RNA virus of about 6.4–7.2 kb in length, organized in three open reading frames (ORFs) [ 2 ] and classified in the family Hepeviridae [ 3 ]. In the last few years, identification of genetically divergent HEV strains has suggested an update of the classification of the family Hepeviridae into two genera, namely the genus Piscihepevirus (cutthroat trout virus) and Orthohepevirus [ 3 ].…”

Characterization of the hepatitis E virus replicase

“…The HEV genome is a positive-sense, 5'-capped, single-stranded RNA of ~7.2 kb in length. It is organized into 3 open reading frames (ORFs): ORF1, ORF2, and ORF3 (Wang and Meng, 2021). ORF1 encodes the ORF1 nonstructural polyprotein, which contains several functional domains essential for viral replication.…”

“…Rubivirus, Betateravirus and Benyvirus (Koonin et al, 1992). Although several domains such as methyltransferase (Met), helicase (Hel) and RNA-dependent RNA polymerase (RdRp) have been reported to be enzymatically active, the function of the Y and X-domains as well as the highly disordered hypervariable region (HVR) remain elusive (Wang and Meng, 2021) (Figure 1C). In addition, the precise location of the protease region (known as papain-like cysteine protease, PCP) and its enzymatic activity are still a matter of debate (LeDesma et al, 2019;Proudfoot et al, 2019).…”