Early secretory pathway localization and lack of processing for hepatitis E virus replication protein pORF1

Perttilä, Julia; Spuul, Pirjo; Ahola, Tero

doi:10.1099/vir.0.049577-0

Cited by 65 publications

(73 citation statements)

References 42 publications

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“…Proteases encoded by positive-stranded RNA viruses are generally involved in the processing of viral polyproteins. However, while apparently truncation of HEV ORF1 proteins was observed in some early studies [32–34], only full-length ORF1 proteins have been detected using robust mammalian overexpression systems and HEV replicon cells [35, 36]. ORF1 may be present at low abundance in infected cells and development of high quality antibodies against ORF1 will likely be needed to firmly address if the PCP domain possesses protease activity towards the HEV polyprotein and cellular substrates.…”

Section: Discussionmentioning

confidence: 99%

Hepatitis E virus persists in the presence of a type III interferon response

Yin

Ambardekar

et al. 2017

PLoS Pathog

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The RIG-I-like RNA helicase (RLR)-mediated interferon (IFN) response plays a pivotal role in the hepatic antiviral immunity. The hepatitis A virus (HAV) and the hepatitis C virus (HCV) counter this response by encoding a viral protease that cleaves the mitochondria antiviral signaling protein (MAVS), a common signaling adaptor for RLRs. However, a third hepatotropic RNA virus, the hepatitis E virus (HEV), does not appear to encode a functional protease yet persists in infected cells. We investigated HEV-induced IFN responses in human hepatoma cells and primary human hepatocytes. HEV infection resulted in persistent virus replication despite poor spread. This was companied by a type III IFN response that upregulated multiple IFN-stimulated genes (ISGs), but type I IFNs were barely detected. Blocking type III IFN production or signaling resulted in reduced ISG expression and enhanced HEV replication. Unlike HAV and HCV, HEV did not cleave MAVS; MAVS protein size, mitochondrial localization, and function remained unaltered in HEV-replicating cells. Depletion of MAVS or MDA5, and to a less extent RIG-I, also diminished IFN production and increased HEV replication. Furthermore, persistent activation of the JAK/STAT signaling rendered infected cells refractory to exogenous IFN treatment, and depletion of MAVS or the receptor for type III IFNs restored the IFN responsiveness. Collectively, these results indicate that unlike other hepatotropic RNA viruses, HEV does not target MAVS and its persistence is associated with continuous production of type III IFNs.

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Section: Discussionmentioning

confidence: 99%

Hepatitis E virus persists in the presence of a type III interferon response

Yin

Ambardekar

et al. 2017

PLoS Pathog

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“…ORF1 has been expressed as a full-length 185 kDa polyprotein in mammalian, bacterial, and insect cells 47-50 . Expressing ORF1 in mammalian cells using a vaccinia virus expression system led to two potential processing products of 107 and 78 kDa after extended incubation times 48 , however mutation of the predicted protease catalytic site failed to affect the observed processing, suggesting that the processing may have been an artifact of the vaccinia virus expression system.…”

Section: Hepatitis E and Its Causative Agent Hepatitis E Virusmentioning

confidence: 99%

Therapeutic targets for the treatment of hepatitis E virus infection

Kenney

Meng

2015

Expert Opinion on Therapeutic Targets

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Introduction Hepatitis E virus (HEV) is one of the most common causes of acute viral hepatitis in the world with an estimated 20 million infections per year. Although the mortality rate is less than 1% among the general population, pregnant women can have a fatality rate of up to 30%. Additionally, chronic hepatitis E has increasingly become a significant clinical problem in immunocompromised individuals. Effective antivirals against HEV are needed. Areas covered This review article addresses the current state of knowledge of HEV infections with regard to animal and cell culture model systems that are important for antiviral discovery and testing, our current understanding of the molecular mechanisms of virus replication, our understanding of how each viral protein functions, and areas that can potentially be exploited as therapeutic targets. Expert opinion Lack of an efficient cell culture system for HEV propagation, the limited knowledge of HEV lifecycle, and the inherent self-limiting infection within the normal populace make the development of new therapeutic agents against HEV challenging. There are many promising therapeutic targets, and the tools for identifying and testing potential antivirals are rapidly evolving. The development of effective therapeutics against HEV in immunocompromised and pregnant patient populations is warranted.

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“…37.1). Current data indicate that ORF1 protein is not subject to proteolytic processing (Perttila et al 2013).HEV belongs to the genus Hepevirus in the Hepeviridae family (King et al 2011). This family contains HEV variants infecting humans and several animals including mammals, birds and fish.…”

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confidence: 97%

Hepatitis E: The Commonest Viral Zoonosis Worldwide?

Dalton

Izopet

Banks³

et al. 2014

Zoonoses - Infections Affecting Humans and Animals

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Until recently, HEV was thought not to occur in developed countries. It is now clear that locally acquired HEV is common in many developed countries. HEV infection acquired in these areas differs from that in developing countries in a number of important aspects: it is caused by genotype 3 (and 4 in China and Japan); it mainly affects middle-aged/elderly males; it is zoonotic with a porcine primary host. Pig herds worldwide are infected with HEV genotype 3 and HEV has been found in the human food chain in a number of developed countries. However, the route of transmission is not fully understood, since most cases are not obviously associated with pigs/pig products. HEV can be transmitted by blood transfusion and surprisingly high numbers of asymptomatic blood donors are viraemic at the time of donation.Our understanding of the clinical phenotype of HEV infection in humans has undergone a sea-change in recent years. Previously, HEV was thought to cause only acute self-limiting hepatitis. However, HEV may cause persistent disease in the immunocompromised. Patients with chronic HEV infection have no symptoms, but some develop rapidly progressive liver cirrhosis. The full clinical spectrum of HEV is still emerging. HEV has important extra-hepatic manifestations, which deserve further investigation. For example, HEV can cause a wide range of neurological illness. In particular, very recent data suggests that Guillain-Barré syndrome and neuralgic amyotrophy are associated with locally acquired HEV in approximately 5% and 10% of cases respectively. Overview of Virology of HEVHEV is a small non-enveloped virus with an icosahedral capsid and a size of 27-34 nm. The virus has a positive-sense, single-stranded RNA 7.2-kilobases-long genome which is capped and polyadenylated at the 5' and 3'-termini, respectively (Reyes et al. 1990;Tam et al. 1991). The HEV genome contains three open reading frames (ORF). ORF1 encodes a protein of 1693 amino acids containing functional domains present in the non-structural proteins of other positive-stranded RNA viruses (Koonin et al. 1992). These functional domains include methyltransferase, cysteine protease, RNA helicase and RNA-dependent RNA polymerase. ORF2 encodes the viral capsid protein of 660 amino acids that is responsible for virion assembly (Li et al. 1997), interaction with target cells (He et al. 2008;Kalia et al. 2009), and immunogenicity (Xing et al. 2011). The ORF2 protein consists of three linear domains, the shell domain (S) (amino acids 129-319), the middle domain (M) (amino acids 320-455), and protruding domain (P) (amino acids 456-606) harbouring the neutralizing epitope(s) (Guu et al. 2009;Tang et al. 2011;Xing et al. 2010;Yamashita et al. 2009). ORF3, which overlaps ORF2, encodes a small protein of 113 or 114 amino acids involved in virion morphogenesis and release (Emerson et al. 2010;Yamada et al. 2009). HEV replicates in the cytoplasm, with a subgenomic RNA producing OFR2 and OFR3 proteins and the full genomic RNA encoding non-structural proteins and ser...

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Early secretory pathway localization and lack of processing for hepatitis E virus replication protein pORF1

Cited by 65 publications

References 42 publications

Hepatitis E virus persists in the presence of a type III interferon response

Hepatitis E virus persists in the presence of a type III interferon response

Therapeutic targets for the treatment of hepatitis E virus infection

Hepatitis E: The Commonest Viral Zoonosis Worldwide?

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