Hepatitis E Virus: What More Do We Need to Know?

Abstract

Hepatitis E virus (HEV) infection is typically a self-limiting, acute illness that spreads through the gastrointestinal tract but replicates in the liver. However, chronic infections are possible in immunocompromised individuals. The HEV virion has two shapes: exosome-like membrane-associated quasi-enveloped virions (eHEV) found in circulating blood or in the supernatant of infected cell cultures and non-enveloped virions ("naked") found in infected hosts' feces and bile to mediate inter-host transmission. Although HEV is mainly spread via enteric routes, it is unclear how it penetrates the gut wall to reach the portal bloodstream. Both virion types are infectious, but they infect cells in different ways. To develop personalized treatment/prevention strategies and reduce HEV impact on public health, it is necessary to decipher the entry mechanism for both virion types using robust cell culture and animal models. The contemporary knowledge of the cell entry mechanism for these two HEV virions as possible therapeutic target candidates is summarized in this narrative review.

Keywords: HEV; antiviral treatment; chronic infection; inhibitors; pregnancy; viral cell entry.

Figure 1

Hepatitis E virus (HEV) genome and virion structure. The figure illustrates the genomic organization and virion structure of the Hepatitis E virus (HEV). (A) Genomic Organization: The HEV genome is a 7.2 kilobase positive-sense single-stranded RNA molecule. It is organized with nonstructural genes at the 5′ end and a methyl guanosine cap (m7G), as well as structural genes at the 3′ end with polyadenylated (PolyA) tail. The 5′ untranslated region of HEV is 28 nucleotides long, with bases 2–26 having the potential to form a complex secondary structure. Furthermore, the HEV genome is polyadenylated at the 3′ end and consists of three partially overlapping open reading frames (ORFs). It is depicted as a linear arrangement of genetic elements, including these three ORFs. ORF1 produces nonstructural proteins that are required for viral replication. ORF2 produces the viral capsids, which form the viral particle’s capsid. ORF3 is a small multifunctional protein, wrapped by a membrane, which is necessary for virion release and pathogenesis. (B) Virion organization: The HEV virus has two varieties: (1) quasi-enveloped virions, which have an outer membrane analogous to exosomes and have been isolated from HEV-infected cells’ bloodstream and cell culture supernatant; (2) non-enveloped virions found in the feces and bile of infected hosts.

Figure 2

Hepatitis E virus (HEV) viral life cycle. 1. Attachment and Entry: Non-enveloped HEV attaches to specific receptors on the surface of susceptible host cells, including hepatocytes in the liver. This interaction is mediated by clathrin, heparan sulfate, integrin alpha 3, and dynamin 2 molecules. This engagement triggers receptor-mediated endocytosis, leading to viral host cell internalization. Alternatively, evidence shows that quasi-enveloped HEV enters cells via endocytosis followed by degradation of the membrane within the endolysosome. 2. Uncoating and Releasing of Genomic RNA: Once inside the host cell, HEV’s viral capsid undergoes disassembly within the endosome. The precise mechanism of HEV capsid uncoating remains still unclear. 3. Translation and Polyprotein Processing: Within the cytoplasm, the HEV genomic RNA is translated into a large polyprotein. The nonstructural proteins encoded by ORF1 play pivotal roles in viral replication and other processes. 4. Genome Replication and Transcription: The HEV RNA-dependent RNA polymerase (RdRp), a product of ORF1, catalyzes the HEV genome replication and transcription. This step results in the production of novel viral RNA genomes and subgenomic RNA species. 5. Assembly of Viral Particles: The newly synthesized viral genomic RNA is encapsidated by the structural capsid protein encoded by ORF2. This encapsidation process forms complete viral particles within the cytoplasm. 6. Maturation and Transport: The mature viral particles undergo structural changes and assemble into quasi-enveloped, spherical virions. The process of viral release from the host cell likely involves the endosomal sorting complexes required for transport (ESCTR) machinery. 7. Circulation and Transmission: After the fusion of multivesicular bodies (MVB) with plasma membranes, viral particles are released via the exosomal pathway so that only quasi-enveloped enters the bloodstream. Canalicular bile salts cause the degradation of the coating membrane and the production of naked particles. These particles reach the environment through bile secretion into the intestine, becoming the major source of contamination and transmission.