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Viruses Jun 2023According to the World Health Organization, approximately 20 million people worldwide are infected annually with the hepatitis E virus (HEV). There are four main... (Review)
Review
According to the World Health Organization, approximately 20 million people worldwide are infected annually with the hepatitis E virus (HEV). There are four main genotypes of HEV. Genotype 1 and genotype 2 are common in developing countries and are transmitted by contaminated water from a fecal-oral route. Genotype 3 and genotype 4 are common in developed countries and can lead to occasional transmission to humans via undercooked meat. Hepatitis E virus 1 and HEV3 can lead to fulminant hepatitis, and HEV3 can lead to chronic hepatitis and cirrhosis in immunocompromised patients. The majority of patients with HEV infection are asymptomatic and usually have spontaneous viral clearance without treatment. However, infection in immunocompromised individuals can lead to chronic HEV infection. Both acute and chronic HEV infections can have extrahepatic manifestations. No specific treatment is required for acute HEV infection, no treatment has been approved in chronic infection, and no HEV vaccine has been approved by the (United States) Food and Drug Administration. This review focuses on the molecular virology (HEV life cycle, genotypes, model systems, zoonosis), pathogenesis, clinical manifestation, and treatment of chronic HEV infection, especially in immunocompromised patients, to provide clinicians a better understanding of the global distribution of these infections and the significant effect they can have on immunocompromised patients.
Topics: Animals; Humans; Hepatitis E virus; Molecular Epidemiology; Hepatitis E; Zoonoses; Hepatitis, Chronic; Genotype
PubMed: 37376687
DOI: 10.3390/v15061389 -
Science Advances Jan 2022Hepatotropic viruses naturally have narrow host and tissue tropisms, challenging the development of robust experimental models. The advent of organoid technology...
Hepatotropic viruses naturally have narrow host and tissue tropisms, challenging the development of robust experimental models. The advent of organoid technology provides a unique opportunity for moving the field forward. Here, we demonstrate that three-dimensional cultured organoids from fetal and adult human liver with cholangiocyte or hepatocyte phenotype support hepatitis E virus (HEV) replication. Inoculation with infectious HEV particles demonstrates that human liver–derived organoids support the full life cycle of HEV infection. By directing organoids toward polarized monolayers in a transwell system, we observed predominantly apical secretion of HEV particles. Genome-wide transcriptomic and tRNAome analyses revealed robust host responses triggered by viral replication. Drug screening in organoids identified brequinar and homoharringtonine as potent HEV inhibitors, which are also effective against the ribavirin resistance variant harboring G1634R mutation. Thus, successful recapitulation of HEV infection in liver-derived organoids shall facilitate the study of virus-host interactions and development of antiviral therapies.
Topics: Antiviral Agents; Hepatitis E; Hepatitis E virus; Host Microbial Interactions; Humans; Organoids
PubMed: 35044825
DOI: 10.1126/sciadv.abj5908 -
Viruses Sep 2019Hepatitis E virus (HEV) infection is a major cause of acute hepatitis worldwide. It is transmitted enterically but replicates in the liver. Recent studies indicate that... (Review)
Review
Hepatitis E virus (HEV) infection is a major cause of acute hepatitis worldwide. It is transmitted enterically but replicates in the liver. Recent studies indicate that HEV exists in two forms: naked, nonenveloped virions that are shed into feces to mediate inter-host transmission, and membrane-cloaked, quasienveloped virions that circulate in the bloodstream to mediate virus spread within a host. Both virion types are infectious, but differ in the way they infect cells. Elucidating the entry mechanism for both virion types is essential to understand HEV biology and pathogenesis, and is relevant to the development of treatments and preventions for HEV. This review summarizes the current understanding of the cell entry mechanism for these two HEV virion types.
Topics: Hepatitis E; Hepatitis E virus; Humans; Lysosomes; Receptors, Virus; Virion; Virus Internalization; Virus Uncoating
PubMed: 31547135
DOI: 10.3390/v11100883 -
Viruses Aug 2019Hepatitis E virus (HEV) is a small quasi-enveloped, (+)-sense, single-stranded RNA virus belonging to the family. There are at least 20 million HEV infections annually... (Review)
Review
Hepatitis E virus (HEV) is a small quasi-enveloped, (+)-sense, single-stranded RNA virus belonging to the family. There are at least 20 million HEV infections annually and 60,000 HEV-related deaths worldwide. HEV can cause up to 30% mortality in pregnant women and progress to liver cirrhosis in immunocompromised individuals and is, therefore, a greatly underestimated public health concern. Although a prophylactic vaccine for HEV has been developed, it is only licensed in China, and there is currently no effective, non-teratogenic treatment. HEV encodes three open reading frames (ORFs). ORF1 is the largest viral gene product, encoding the replicative machinery of the virus including a methyltransferase, RNA helicase, and an RNA-dependent RNA polymerase. ORF1 additionally contains a number of poorly understood domains including a hypervariable region, a putative protease, and the so-called 'X' and 'Y' domains. ORF2 is the viral capsid essential for formation of infectious particles and ORF3 is a small protein essential for viral release. In this review, we focus on the domains encoded by ORF1, which collectively mediate the virus' asymmetric genome replication strategy. We summarize what is known, unknown, and hotly debated regarding the coding and non-coding regions of HEV ORF1, and present a model of how HEV replicates its genome.
Topics: Genome, Viral; Hepatitis E; Hepatitis E virus; Humans; Nucleic Acid Conformation; Open Reading Frames; Regulatory Sequences, Nucleic Acid; Viral Proteins; Virus Replication
PubMed: 31390784
DOI: 10.3390/v11080719 -
Viruses Jun 2019Hepatitis E is an underestimated threat to public health, caused by the hepatitis E virus (HEV). HEV is the most common cause of acute viral hepatitis in the world, with... (Review)
Review
Hepatitis E is an underestimated threat to public health, caused by the hepatitis E virus (HEV). HEV is the most common cause of acute viral hepatitis in the world, with no available direct-acting antiviral treatment. According to a recent WHO report, 20 million people become infected with HEV annually, resulting in 44,000 deaths. However, due to the scarcity of efficient in vitro cell culture systems for HEV, our knowledge of the life cycle of HEV is incomplete. Recently, significant progress has been made towards gaining a more comprehensive view of the HEV life cycle, as several in vitro culturing systems have been developed in recent years. Here, we review current knowledge and recent advances with regard to the HEV life cycle, with a particular focus on the assembly and release of viral particles. We also discuss the knowledge gaps in HEV assembly and release. Meanwhile, we highlight experimental platforms that could potentially be utilized to fill these gaps. Lastly, we offer perspectives on the future of research into HEV virology and its interaction with host cells.
Topics: Animals; Antiviral Agents; Hepatitis E; Hepatitis E virus; Host-Pathogen Interactions; Humans; Life Cycle Stages; Virion; Virus Assembly; Virus Release
PubMed: 31181848
DOI: 10.3390/v11060539 -
ELife Mar 2023A domain in the ORF1 polyprotein of the hepatitis E virus that was previously thought to be a protease is actually a zinc-binding domain.
A domain in the ORF1 polyprotein of the hepatitis E virus that was previously thought to be a protease is actually a zinc-binding domain.
Topics: Hepatitis E virus; Peptide Hydrolases; Polyproteins; Virus Replication
PubMed: 36947136
DOI: 10.7554/eLife.87047 -
Viruses Aug 2016Although most hepatitis E virus (HEV) infections are asymptomatic, some can be severe, causing fulminant hepatitis and extra-hepatic manifestations, including... (Review)
Review
Although most hepatitis E virus (HEV) infections are asymptomatic, some can be severe, causing fulminant hepatitis and extra-hepatic manifestations, including neurological and kidney injuries. Chronic HEV infections may also occur in immunocompromised patients. This review describes how our understanding of the pathogenesis of HEV infection has progressed in recent years.
Topics: Hepatitis E; Hepatitis E virus; Host-Pathogen Interactions; Humans
PubMed: 27527210
DOI: 10.3390/v8080212 -
Viruses Jun 2019Hepatitis E virus (HEV) is an underdiagnosed pathogen with approximately 20 million infections each year and currently the most common cause of acute viral hepatitis.... (Review)
Review
Hepatitis E virus (HEV) is an underdiagnosed pathogen with approximately 20 million infections each year and currently the most common cause of acute viral hepatitis. HEV was long considered to be confined to developing countries but there is increasing evidence that it is also a medical problem in the Western world. HEV that infects humans belongs to the species of the family. Novel HEV-like viruses have been observed in a variety of animals and some have been shown to be able to cross the species barrier, causing infection in humans. Several cell culture models for HEV have been established in the past years, but their efficiency is usually relatively low. With the circulation of this virus and related viruses in a variety of species, several different animal models have been developed. In this review, we give an overview of these animal models, indicate their main characteristics, and highlight how they may contribute to our understanding of the basic aspects of the viral life cycle and cross-species infection, the study of pathogenesis, and the evaluation of novel preventative and therapeutic strategies.
Topics: Animals; Disease Models, Animal; Hepatitis E; Hepatitis E virus
PubMed: 31216711
DOI: 10.3390/v11060564 -
Current Opinion in Microbiology Feb 2021Hepatitis E virus (HEV), the causative agent of hepatitis E, is an understudied but important pathogen. HEV typically causes self-limiting acute viral hepatitis, however... (Review)
Review
Hepatitis E virus (HEV), the causative agent of hepatitis E, is an understudied but important pathogen. HEV typically causes self-limiting acute viral hepatitis, however chronic infection with neurological and other extrahepatic manifestations has increasingly become a significant clinical problem. The discovery of swine HEV from pigs and demonstration of its zoonotic potential led to the genetic identification of very diverse HEV strains from more than a dozen other animal species. HEV strains from pig, rabbit, deer, camel, and rat have been shown to cross species barriers and infect humans. Zoonotic HEV infections through consumption of raw or undercooked animal meat or direct contact with infected animals have been reported. The discovery of a large number of animal HEV variants does provide an opportunity to develop useful animal models for HEV. In this mini-review, we discuss recent advances in HEV host range, and cross-species and zoonotic transmission.
Topics: Animals; Genetic Variation; Hepatitis E; Hepatitis E virus; Host Specificity; Humans; Viral Tropism; Zoonoses
PubMed: 32810801
DOI: 10.1016/j.mib.2020.07.004 -
Archives of Virology Dec 2022Hepatitis E virus (HEV) is a leading cause of acute hepatitis worldwide. Hepatitis E is an enterically transmitted zoonotic disease that causes large waterborne epidemic... (Review)
Review
Hepatitis E virus (HEV) is a leading cause of acute hepatitis worldwide. Hepatitis E is an enterically transmitted zoonotic disease that causes large waterborne epidemic outbreaks in developing countries and has become an increasing public-health concern in industrialized countries. In this setting, the infection is usually acute and self-limiting in immunocompetent individuals, although chronic cases in immunocompromised patients have been reported, frequently associated with several extrahepatic manifestations. Moreover, extrahepatic manifestations have also been reported in immunocompetent individuals with acute HEV infection. HEV belongs to the alphavirus-like supergroup III of single-stranded positive-sense RNA viruses, and its genome contains three partially overlapping open reading frames (ORFs). ORF1 encodes a nonstructural protein with eight domains, most of which have not been extensively characterized: methyltransferase, Y domain, papain-like cysteine protease, hypervariable region, proline-rich region, X domain, Hel domain, and RNA-dependent RNA polymerase. ORF2 and ORF3 encode the capsid protein and a multifunctional protein believed to be involved in virion release, respectively. The novel ORF4 is only expressed in HEV genotype 1 under endoplasmic reticulum stress conditions, and its exact function has not yet been elucidated. Despite important advances in recent years, the biological and molecular processes underlying HEV replication remain poorly understood, primarily due to a lack of detailed information about the functions of the viral proteins and the mechanisms involved in host-pathogen interactions. This review summarizes the current knowledge concerning HEV proteins and their biological properties, providing updated detailed data describing their function and focusing in detail on their structural characteristics. Furthermore, we review some unclear aspects of the four proteins encoded by the ORFs, highlighting the current key information gaps and discussing potential novel experimental strategies for shedding light on those issues.
Topics: Animals; Humans; Hepatitis E virus; Hepatitis E; Open Reading Frames; Viral Proteins; Zoonoses
PubMed: 36098802
DOI: 10.1007/s00705-022-05575-8