Copyright ©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. May 28, 2021; 27(20): 2458-2473
Published online May 28, 2021. doi: 10.3748/wjg.v27.i20.2458
Open reading frame 3 protein of hepatitis E virus: Multi-function protein with endless potential
Yong-Lin Yang, Yu-Chen Nan
Yong-Lin Yang, Department of Infectious Diseases, Taizhou People's Hospital, The Fifth Affiliated Hospital of Nantong University, Taizhou 225300, Jiangsu Province, China
Yong-Lin Yang, Department of General Practice, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, Jiangsu Province, China
Yu-Chen Nan, Department of Preventive Veterinary Medicine, Northwest A&F University, Yangling 712100, Shaanxi Province, China
Author contributions: Yang YL and Nan YC prepared the main body of this manuscript; Nan YC reviewed and revised the manuscript, and designed and prepared the figures; all authors approved the manuscript for publication.
Supported by National Natural Science Foundation of China, No. 31672534; Key Project supported by Medical Science and Technology Development Foundation of Nanjing Department of Health, No. ZKX19026.
Conflict-of-interest statement: The authors declare no conflict of interests for this article.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Corresponding author: Yu-Chen Nan, PhD, Associate Professor, Department of Preventive Veterinary Medicine, Northwest A&F University, No. 3 Taicheng Road, Yangling Demonstration Zone, Yangling 712100, Shaanxi Province, China.
Received: January 23, 2021
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.

Keywords: Hepatitis E virus, Zoonosis, Quasi-enveloped virion, Hepatitis E virus-open reading frame 3, Innate immunity

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.