The hepatitis E virus (HEV) is the causative agent of hepatitis E. It is a member of the genus Hepevirus that belongs to the Hepeviridae family. It is a nonenveloped, single-stranded positive-sense RNA virus. The genome of HEV contains 3 Open reading frames: ORF 1, ORF 2, and ORF 3. The RNA genome acts as a template for viral replication, structural and nonstructural protein synthesis. Five different genotypes have been identified, all belonging to the same serotype. Depending on the genotype, epidemiological and clinical manifestations will be different: genotypes 1 and 2 only cause disease in humans, and are transmitted through water and fecal-oral route, while genotypes 3 and 4 cause disease in animals, having humans as accidental hosts, and are transmitted through the consumption of undercook meat. The HEV replicates within the host cell’s cytoplasm, however, its cellular receptor, and mechanism of entry remain unknown.

Viruses; ssRNA viruses; ssRNA positive-strand viruses; Hepeviridae; Hepevirus; Hepatitis E virus^[1]

The viral particles are 27 to 34 nanometers in diameter, nonenveloped, and contain a single-strand of positive-sense RNA that is approximately 7200 bases in length, polyadenylated at the 3′ terminus, and capped at the 5’terminus.^[3][4][5]

The genome of HEV contains 3 Open reading frames:

• ORF1 – encodes functional motifs and non-structural protein domains for replication and protein processing, including:^[3][6]

• Cysteine protease
• Methyltransferase
• RNA helicase
• RNA-dependent RNA polymerase

• ORF2 – encodes the protein of the viral capsid, with neutralizing epitopes, responsible for:^[7]

• Assembly of virions^[8]
• Target cell interaction^[9]
• Immunogenicity^[10]
• Mutations in the viral capsid may attenuate the virus and lead to the development of a vaccine

• ORF3 – encodes a small protein involved in the morphogenesis and release of the virions.^[11][12]

In order to study the biology of the virus and develop new treatment drugs, HEV must be grown in culture systems, such as:

• PLC/PRF/5 cell line of hepatic carcinoma, A549 cell line of lung carcinoma, and fecal samples from an infected patient^[13]
• HepG2/C3A cell line of hepatoma^[14]

Molecular studies of HEV lead to the classification of the virus into 4 genotypes:^{[3][15][16][17][18][6][19][20][21]}

Despite the epidemiological and clinical differences, the different genotypes are thought to belong to one same serotype, after studies with cross-neutralization.^[22] Evidence shows that HEV has evolved and adapted to a series of hosts, until finally being able to infect humans. HEV subgenotypes in humans and pigs have been associated, also suggesting zoonotic transmission.^[3][23][24]

The hepatitis E virus replicates in the cytoplasm of the host cell. The genomic RNA serves as template chain for replication and encodes nonstructural proteins, while subgenomic RNA produces capsid proteins. Different recombination events may lead to changes in viral replication, tissue tropism and pathogenesis of the virus.^[7]

Hepatitis D shows tropism for hepatocytes, however, the host cell receptor has not been identified.^[9]

The natural reservoir of HEV is yet to be identified. Different observations have suggested different reservoirs:

• Prolonged fecal shedding from patients with history of the disease has been suggested. However, the duration of viral shedding in feces is not compatible with this hypothesis.^[25]
• Environmental reservoir was suggested following detection of HEV in sewages.^[26]
• Continuous fecal shedding from asymptomatic patients was suggested as a form of maintenance of the virus, contaminating water supplies.^[27]
• The existence of an animal reservoir is supported by the detection of anti-HEV antibodies in different animal species.^[27]