Abstract
Hepatitis E virus (HEV) is one of the most common causes of acute viral hepatitis, mainly transmitted by fecal-oral route but has also been linked to fulminant hepatic failure, chronic hepatitis, and extrahepatic neurological and renal diseases. HEV is an emerging zoonotic pathogen with a broad host range, and strains of HEV from numerous animal species are known to cross species barriers and infect humans. HEV is a single-stranded, positive-sense RNA virus in the family Hepeviridae. The genome typically contains three open reading frames (ORFs): ORF1 encodes a nonstructural polyprotein for virus replication and transcription, ORF2 encodes the capsid protein that elicits neutralizing antibodies, and ORF3, which partially overlaps ORF2, encodes a multifunctional protein involved in virion morphogenesis and pathogenesis. HEV virions are non-enveloped spherical particles in feces but exist as quasi-enveloped particles in circulating blood. Two types of HEV virus-like particles (VLPs), small T = 1 (270 Å) and native virion-sized T = 3 (320–340 Å) have been reported. There exist two distinct forms of capsid protein, the secreted form (ORF2S) inhibits antibody neutralization, whereas the capsid-associated form (ORF2C) self-assembles to VLPs. Four cis-reactive elements (CREs) containing stem-loops from secondary RNA structures have been identified in the non-coding regions and are critical for virus replication. This mini-review discusses the current knowledge and gaps regarding the structural and molecular biology of HEV with emphasis on the virion structure, genomic organization, secondary RNA structures, viral proteins and their functions, and life cycle of HEV.
Highlights
Hepatitis E was first recognized in the 1980 s as a ‘non-A, non-B hepatitis’ associated with waterborne outbreaks in India
Chronic hepatitis E has become a significant clinical problem since the majority of hepatitis E virus (HEV) infections in immunosuppressed individuals can progress into chronicity which requires antiviral treatment, and otherwise chronic infection leads to cirrhosis that needs transplantation [6]
It is believed that the eHEV and neHEV exploited distinct virus entry mechanisms: eHEV enters cells via a dynamindependent, clathrin-mediated endocytosis, which requires small GTPases Ras-related proteins Rab5 and Rab7, and the lipid membrane is degraded by a lysosomal protein Niemann-Pick disease type C1 (NPC1)
Summary
Hepatitis E was first recognized in the 1980 s as a ‘non-A, non-B hepatitis’ associated with waterborne outbreaks in India. The determination of the high-resolution three-dimensional structure of HEV virus-like particle (VLP) and capsid protein helps understand HEV morphogenesis and pathogenesis [12]; the development of various reverse genetic systems for HEV allows to delineate the structural and functional relationship of HEV genes [13]; the establishment of more efficient cell culture systems and relevant animal models for HEV provided tools to understand the molecular mechanisms of HEV life cycle and virus-host interactions [2] In this mini review, we highlight the recent advances that unveil the structural and molecular biology of HEV
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