Published online May 28, 2021. doi: 10.3748/wjg.v27.i20.2458
Peer-review started: January 23, 2021
First decision: February 25, 2021
Revised: March 10, 2021
Accepted: April 12, 2021
Article in press: April 12, 2021
Published online: May 28, 2021
Hepatitis E virus (HEV), a fecal-orally transmitted foodborne viral pathogen, causes acute hepatitis in humans and is responsible for hepatitis E outbreaks worldwide. Since the identification of HEV as a zoonotic agent, this virus has been isolated from a variety of hosts with an ever-expanding host range. HEV-open reading frame (ORF) 3, the smallest ORF in HEV genomes, initially had been perceived as an unremarkable HEV accessory protein. However, as novel HEV-ORF3 function has been discovered that is related to the existence of a putative third virion structural form, referred to as “quasi-enveloped” HEV particles, HEV is challenging the conventional virion structure-based classification scheme, which assigns all viruses to two groups, “enveloped” or “non-enveloped”. In this review, we systematically describe recent progress that has identified multiple pathogenic roles of HEV-ORF3, including roles in HEV virion release, biogenesis of quasi-enveloped virus, regulation of the host innate immune response, and interference with host signaling pathways. In addition, implications of HEV-ORF3-associated quasi-enveloped virions are discussed to guide future development of improved vaccines against zoonotic HEV infection.
Core Tip: Hepatitis E virus (HEV)-open reading frame (ORF) 3 was originally though as an accessory protein with limited function which is not essential for HEV replication. This view has been challenged by recent discoveries, such as HEV-ORF3-associated “quasi-enveloped” HEV particles, regulation of the host innate immune response, and interference with host signaling pathways. More novel function of HEV-ORF3 will be revealed.