Abstract
There are approximately 20 million events of hepatitis E virus (HEV) infection worldwide annually. The genome of HEV is a single-strand, positive-sense RNA containing 5’ and 3’ untranslated regions and three open reading frames (ORF). HEV genome has 5’ cap and 3’ poly(A) tail to mimic host mRNA to escape the host innate immune surveillance and utilize host translational machineries for viral protein translation. The replication mechanism of HEV is poorly understood, especially how the viral polymerase distinguishes viral RNA from host mRNA to synthesize new viral genomes. We hypothesize that the HEV genome contains cis-acting elements that can be recognized by the virally encoded polymerase as “self” for replication. To identify functional cis-acting elements systematically across the HEV genome, we utilized an ORF1 transcomplementation system. Ultimately, we found two highly conserved cis-acting RNA elements within the ORF1 and ORF2 coding regions that are required for viral genome replication in a diverse panel of HEV genotypes. Synonymous mutations in the cis-acting RNA elements, not altering the ORF1 and ORF2 protein sequences, significantly impaired production of infectious viral particles. Mechanistic studies revealed that the cis-acting elements form secondary structures needed to interact with the HEV ORF1 protein to promote HEV replication. Thus, these cis-acting elements function as a scaffold, providing a specific “signal” that recruits viral and host factors to assemble the viral replication complex. Altogether, this work not only facilitates our understanding of the HEV life cycle and provides novel, RNA-directed targets for potential HEV treatments, but also sheds light on the development of HEV as a therapeutic delivery vector.
Highlights
Hepatitis E virus (HEV) remains a considerable health problem in both developing and developed countries, causing an estimated 60,000 deaths and 3,000 stillbirths a year [1, 2]
Functional cis-acting RNA elements required for HEV replication analysis, decision to publish, or preparation of the manuscript
Using an ORF1 transcomplementation system to identify functional cisacting RNA elements in the HEV genome required for viral replication
Summary
Hepatitis E virus (HEV) remains a considerable health problem in both developing and developed countries, causing an estimated 60,000 deaths and 3,000 stillbirths a year [1, 2]. HEV can establish chronic infections and induce liver cirrhosis in immunosuppressed patients, such as organ-transplant recipients and individuals infected with human immunodeficiency virus (HIV) [3, 4]. The overall fatality rate of HEV infection in the general population is about 1%, in pregnant women, it can be an extremely serious illness with a mortality rate of up to 30% during the third trimester [5, 6]. The mechanisms underlying this severe pathogenesis remain incompletely understood. Many important questions about HEV biology are still not well elucidated
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