Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2018 Nov 29;7(1):196.
doi: 10.1038/s41426-018-0198-7.

Life Cycle and Morphogenesis of the Hepatitis E Virus

Free PMC article

Life Cycle and Morphogenesis of the Hepatitis E Virus

Kiyoshi Himmelsbach et al. Emerg Microbes Infect. .
Free PMC article


Hepatitis E virus (HEV) is transmitted primarily via contaminated water and food by the fecal oral route and causes epidemics in developing countries. In industrialized countries, zoonotic transmission of HEV is prevalent. In addition, HEV is the major cause of acute hepatitis in healthy adults and can cause chronic hepatitis in immunocompromised patients, with pregnant HEV-infected women having increased mortality rates of approximately 25%. HEV was once an understudied and neglected virus. However, in recent years, the safety of blood products with respect to HEV has increasingly been considered to be a public health problem. The establishment of HEV infection models has enabled significant progress to be made in understanding its life cycle. HEV infects cells via a receptor (complex) that has yet to be identified. The HEV replication cycle is initiated immediately after the (+) stranded RNA genome is released into the cell cytosol. Subsequently, infectious viral particles are released by the ESCRT complex as quasi-enveloped viruses (eHEVs) into the serum, whereas feces and urine contain only nonenveloped infectious viral progeny. The uncoating of the viral envelope takes place in the biliary tract, resulting in the generation of a nonenveloped virus that is more resistant to environmental stress and possesses a higher infectivity than that of eHEV. This review summarizes the current knowledge regarding the HEV life cycle, viral morphogenesis, established model systems and vaccine development.

Conflict of interest statement

The authors declare that they have no conflict of interest.


Fig. 1
Fig. 1
Schematic illustration of nonenveloped HEV (found in the feces of infected patients) and of the quasi-enveloped form (found in the serum of infected patients and in cell culture supernatant of HEV-replicating cells)
Fig. 2
Fig. 2. Genome organization of the hepatitis E virus.
The 5′ end of the (+)-stranded RNA genome is capped with 7-methylguanosine (7 mG), while the 3′ end is polyadenylated (poly(A)). Open reading frame 1 (ORF1) encodes nonstructural proteins, including a methyltransferase (MT), papain-like cysteine protease (Pro), hypervariable region (HVR), helicase (Hel), and an RNA-dependent RNA polymerase (RdRp), as well as two regions of unknown function (Y-domain (Y), and X-/Macrodomain (X)). ORF2 encodes the core protein that forms the capsid, and the ORF3 protein is essential for viral release via the ESCRT pathway
Fig. 3
Fig. 3. Schematic representation of the MVB-dependent release of the hepatitis E virus via exosomes.
The PXXP motifs in the ORF3 protein interact with components of the cellular ESCRT machinery to facilitate the release of quasi-enveloped viruses into the bloodstream. After encountering bile, the viral envelope is removed and the nonenveloped virus is released via feces and urine

Similar articles

See all similar articles

Cited by 2 articles


    1. Yang C., Yu W., Bi Y., Long F., Li Y., Wei D., Hao X., Situ J., Zhao Y., Huang F. Increased oestradiol in hepatitis E virus-infected pregnant women promotes viral replication. Journal of Viral Hepatitis. 2018;25(6):742–751. doi: 10.1111/jvh.12865. - DOI - PubMed
    1. Aslam, A., Susheela, A., Iriana, S., Chan, S. S. & Lau, D. Acute hepatitis E superinfection leading to chronic hepatitis B reactivation. BMJ Case Rep.2018, pii: bcr-2017–223616 (2018). - PMC - PubMed
    1. Blasco-Perrin H, et al. Hepatitis E virus in patients with decompensated chronic liver disease. A prospective UK/French study. Aliment. Pharmacol. Ther. 2015;42:574–581. doi: 10.1111/apt.13309. - DOI - PubMed
    1. Debing Y, Moradpour D, Neyts J, Gouttenoire J. Update on hepatitis E virology. Implications for clinical practice. J. Hepatol. 2016;65:200–212. doi: 10.1016/j.jhep.2016.02.045. - DOI - PubMed
    1. Horvatits T, et al. Hepatitis E seroprevalence in the Americas. A systematic review and meta-analysis. Liver Int. 2018;38:1951–1964. doi: 10.1111/liv.13859. - DOI - PubMed