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Orosz L, Sárvári KP, Dernovics Á, Rosztóczy A, Megyeri K. Pathogenesis and clinical features of severe hepatitis E virus infection. World J Virol 2024; 13:91580. [PMID: 38984076 PMCID: PMC11229844 DOI: 10.5501/wjv.v13.i2.91580] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2023] [Revised: 02/08/2024] [Accepted: 04/15/2024] [Indexed: 06/24/2024] Open
Abstract
The hepatitis E virus (HEV), a member of the Hepeviridae family, is a small, non-enveloped icosahedral virus divided into eight distinct genotypes (HEV-1 to HEV-8). Only genotypes 1 to 4 are known to cause diseases in humans. Genotypes 1 and 2 commonly spread via fecal-oral transmission, often through the consumption of contaminated water. Genotypes 3 and 4 are known to infect pigs, deer, and wild boars, often transferring to humans through inadequately cooked meat. Acute hepatitis caused by HEV in healthy individuals is mostly asymptomatic or associated with minor symptoms, such as jaundice. However, in immunosuppressed individuals, the disease can progress to chronic hepatitis and even escalate to cirrhosis. For pregnant women, an HEV infection can cause fulminant liver failure, with a potential mortality rate of 25%. Mortality rates also rise amongst cirrhotic patients when they contract an acute HEV infection, which can even trigger acute-on-chronic liver failure if layered onto pre-existing chronic liver disease. As the prevalence of HEV infection continues to rise worldwide, highlighting the particular risks associated with severe HEV infection is of major medical interest. This text offers a brief summary of the characteristics of hepatitis developed by patient groups at an elevated risk of severe HEV infection.
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Affiliation(s)
- László Orosz
- Department of Medical Microbiology, University of Szeged, Szeged 6720, Csongrád-Csanád, Hungary
| | - Károly Péter Sárvári
- Department of Medical Microbiology, University of Szeged, Szeged 6720, Csongrád-Csanád, Hungary
| | - Áron Dernovics
- Department of Medical Microbiology, University of Szeged, Szeged 6720, Csongrád-Csanád, Hungary
| | - András Rosztóczy
- Department of Internal Medicine, Division of Gastroenterology, University of Szeged, Szeged 6725, Csongrád-Csanád, Hungary
| | - Klára Megyeri
- Department of Medical Microbiology, University of Szeged, Szeged 6720, Csongrád-Csanád, Hungary
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Li X, Sun X, Pinpin J, Zhao Q, Sun Y. Multifunctional ORF3 protein of hepatitis E virus. J Med Virol 2024; 96:e29691. [PMID: 38783788 DOI: 10.1002/jmv.29691] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Revised: 04/23/2024] [Accepted: 05/14/2024] [Indexed: 05/25/2024]
Abstract
Hepatitis E virus (HEV) is an emerging zoonotic pathogen that is transmitted primarily through the fecal-oral route and can cause acute hepatitis in humans. Since HEV was identified as a zoonotic pathogen, different species of HEV strains have been globally identified from various hosts, leading to an expanding range of hosts. The HEV genome consists of a 5' noncoding region, three open reading frames (ORFs), and a 3' noncoding region. The ORF3 protein is the smallest but has many functions in HEV release and pathogenesis. In this review, we systematically summarize recent progress in understanding the functions of the HEV ORF3 protein in virion release, biogenesis of quasi-enveloped viruses, antigenicity, and host environmental regulation. This review will help us to understand HEV replication and pathogenesis mechanisms better.
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Affiliation(s)
- Xiaoxuan Li
- Department of Preventive Veterinary Medicine, College of Veterinary Medicine, Northwest Agriculture and Forestry University, Yangling, Shaanxi, China
| | - Xuwen Sun
- Department of Preventive Veterinary Medicine, College of Veterinary Medicine, Northwest Agriculture and Forestry University, Yangling, Shaanxi, China
| | - Ji Pinpin
- Department of Preventive Veterinary Medicine, College of Veterinary Medicine, Northwest Agriculture and Forestry University, Yangling, Shaanxi, China
| | - Qin Zhao
- Department of Preventive Veterinary Medicine, College of Veterinary Medicine, Northwest Agriculture and Forestry University, Yangling, Shaanxi, China
| | - Yani Sun
- Department of Preventive Veterinary Medicine, College of Veterinary Medicine, Northwest Agriculture and Forestry University, Yangling, Shaanxi, China
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Nombot-Yazenguet MPDM, Modiyinji AF, Tricou V, Manirakiza A, Njouom R, Komas NPJ. Investigating animal reservoirs for hepatitis E virus in Bangui, Central African Republic. PLoS One 2024; 19:e0300608. [PMID: 38489313 PMCID: PMC10942039 DOI: 10.1371/journal.pone.0300608] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2023] [Accepted: 02/29/2024] [Indexed: 03/17/2024] Open
Abstract
BACKGROUND Hepatitis E virus (HEV) is a major cause of enterotropic viral hepatitis, a major public health problem in many developing countries. In Central African Republic (CAR), HEV genotypes 1, 2, and 3 have been found to have an impact on human health. However, data on HEV in animal reservoirs are still lacking for CAR. Here, we investigated the presence of HEV in farmed pigs and goats in Bangui, the capital city of CAR, using molecular methods. METHODOLOGY In a prospective study, fecal samples from 61 pigs and 39 goats from farms in five districts (2nd, 4th, 6th, 7th, 8th) of Bangui were collected and tested for HEV RNA by real-time RT-PCR. The samples were further analyzed by nested-PCR and sequenced to determine the genotype and subtype to which the virus belong. RESULTS In total, 22/100 (22.0%) feces samples were successfully amplified for HEV RNA by real time RT-PCR. All positive samples were from pigs (22/61; 36.1%), while all goat samples were negative (0/39). Twelve HEV RNA samples (12/22 or 54.5%) were successfully amplified by nested RT-PCR, and subsequently sequenced. Phylogenetic analysis revealed that the obtained sequences clustered with subtype 3h and were genetically related to the human HEV sequences from CAR. CONCLUSION This study confirms that pigs constitute an HEV reservoir, with genotype 3 being the major circulating strain. Further studies are needed to investigate other local reservoirs and to improve knowledge of the molecular epidemiology of HEV in CAR.
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Affiliation(s)
| | | | - Vianney Tricou
- Viral Hepatitis Laboratory, Institut Pasteur de Bangui, Bangui, Central African Republic
| | - Alexandre Manirakiza
- Epidemiological Service, Institut Pasteur de Bangui, Bangui, Central African Republic
| | - Richard Njouom
- Department of Virology, Centre Pasteur of Cameroon, Yaoundé, Cameroon
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Srivastava M, Bhukya PL, Barman MK, Bhise N, Lole KS. Modulation of cellular autophagy by genotype 1 hepatitis E virus ORF3 protein. J Gen Virol 2023; 104. [PMID: 36809248 DOI: 10.1099/jgv.0.001824] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/23/2023] Open
Abstract
Hepatitis E virus (HEV) egresses from infected hepatocytes as quasienveloped particles containing open reading frame 3 (ORF3) protein. HEV ORF3 (small phosphoprotein) interacts with host proteins to establish a favourable environment for virus replication. It is a functional viroporin that plays an important role during virus release. Our study provides evidence that pORF3 plays a pivotal role in inducing Beclin1-mediated autophagy that helps HEV-1 replication as well as its exit from cells. The ORF3 interacts with host proteins involved in regulation of transcriptional activity, immune response, cellular and molecular processes, and modulation of autophagy, by interacting with proteins, DAPK1, ATG2B, ATG16L2 and also several histone deacetylases (HDACs). For autophagy induction, the ORF3 utilizes non-canonical NF-κB2 pathway and sequesters p52NF-κB and HDAC2 to upregulate DAPK1 expression, leading to enhanced Beclin1 phosphorylation. By sequestering several HDACs, HEV may prevent histone deacetylation to maintain overall cellular transcription intact to promote cell survival. Our findings highlight a novel crosstalk between cell survival pathways participating in ORF3-mediated autophagy.
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Affiliation(s)
| | - Prudhvi Lal Bhukya
- Division of Hepatitis, National Institute of Virology, Pune, India
- ICMR-National Animal Resource Facility for Biomedical Research, Hyderabad, India
| | | | - Neha Bhise
- Division of Hepatitis, National Institute of Virology, Pune, India
| | - Kavita S Lole
- Division of Hepatitis, National Institute of Virology, Pune, India
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Wang Y, Zhao C, Qi Y, Geng Y. Hepatitis E Virus. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2023; 1417:1-13. [PMID: 37223855 DOI: 10.1007/978-981-99-1304-6_1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/25/2023]
Abstract
Since the sequence of hepatitis E virus (HEV) was determined from a patient with enterically transmitted non-A, non-B hepatitis in 1989, similar sequences have been isolated from many different animals, including pigs, wild boars, deer, rabbits, bats, rats, chicken, and trout. All of these sequences have the same genomic organization, which contains open reading frames (ORFs) 1, 2, and 3, although their genomic sequences are variable. Some have proposed that they be classified as new family, Hepeviridae, which would be further divided into different genera and species according to their sequence variability. The size of these virus particles generally ranged from 27 to 34 nm. However, HEV virions produced in cell culture differ in structure from the viruses found in feces. Those from cell culture have a lipid envelope and either lack or have a little ORF3, whereas the viruses isolated from feces lack a lipid envelope but have ORF3 on their surfaces. Surprisingly, most of the secreted ORF2 proteins from both these sources are not associated with HEV RNA.
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Affiliation(s)
- Youchun Wang
- Institute of Medical Biology, Chinese Academy of Medical Science & Peking Union Medical College, Kunming, China.
| | - Chenyan Zhao
- Division of HIV/AIDS and Sex-Transmitted Virus Vaccines, National Institutes for Food and Drug Control, Beijing, China
| | - Ying Qi
- Division of HIV/AIDS and Sex-Transmitted Virus Vaccines, National Institutes for Food and Drug Control, Beijing, China
| | - Yansheng Geng
- Key Laboratory of Public Health Safety of Hebei Province, School of Public Health, Hebei University, Baoding, China
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Mohsen MO, Bachmann MF. Virus-like particle vaccinology, from bench to bedside. Cell Mol Immunol 2022; 19:993-1011. [PMID: 35962190 PMCID: PMC9371956 DOI: 10.1038/s41423-022-00897-8] [Citation(s) in RCA: 123] [Impact Index Per Article: 41.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2022] [Accepted: 06/17/2022] [Indexed: 02/01/2023] Open
Abstract
Virus-like particles (VLPs) have become key tools in biology, medicine and even engineering. After their initial use to resolve viral structures at the atomic level, VLPs were rapidly harnessed to develop antiviral vaccines followed by their use as display platforms to generate any kind of vaccine. Most recently, VLPs have been employed as nanomachines to deliver pharmaceutically active products to specific sites and into specific cells in the body. Here, we focus on the use of VLPs for the development of vaccines with broad fields of indications ranging from classical vaccines against viruses to therapeutic vaccines against chronic inflammation, pain, allergy and cancer. In this review, we take a walk through time, starting with the latest developments in experimental preclinical VLP-based vaccines and ending with marketed vaccines, which earn billions of dollars every year, paving the way for the next wave of prophylactic and therapeutic vaccines already visible on the horizon.
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Affiliation(s)
- Mona O Mohsen
- Department of BioMedical Research, University of Bern, Bern, Switzerland.
- Department of Immunology RIA, University Hospital Bern, Bern, Switzerland.
- Saiba Biotech AG, Bahnhofstr. 13, CH-8808, Pfaeffikon, Switzerland.
| | - Martin F Bachmann
- Department of BioMedical Research, University of Bern, Bern, Switzerland
- Department of Immunology RIA, University Hospital Bern, Bern, Switzerland
- The Jenner Institute, University of Oxford, Oxford, UK
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Wang X, Sun J, Zheng Y, Xie F. Dispersion of synonymous codon usage patterns in hepatitis E virus genomes derived from various hosts. J Basic Microbiol 2022; 62:975-983. [PMID: 35778820 DOI: 10.1002/jobm.202200072] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2022] [Revised: 05/01/2022] [Accepted: 06/11/2022] [Indexed: 11/09/2022]
Abstract
Hepatitis E virus (HEV) is an important zoonotic pathogen infecting a wide range of host species. It has a positive-sense, single-stranded RNA genome encoding three open reading frames (ORFs). Synonymous codon usages of viruses essentially determine their survival and adaptation to susceptible hosts. To better understand the interplay between the ever-expanding host range and synonymous codon usages of HEV, we quantified the dispersion of synonymous codon usages of HEV genomes isolated from different hosts via Vs calculation and information entropy. HEV ORFs show species-specific synonymous codon usage patterns. Ruminant-derived HEV ORFs own the most synonymous codons with stable usage patterns (Vs value <0.1) which leads to the stable overall codon usage patterns (R value being close to zero). Swine-derived HEV ORFs own more concentrated synonymous codons than those from wild boar. Compared with HEV strains isolated from other hosts, the human-derived HEV exhibits a distinct pattern at the overall codon usage (R < 0). Generally, ORF1 contains more synonymous codons with stable usage patterns (Vs < 0.1) than those of ORFs 2 and 3. Moreover, ORF3 contains more synonymous codons with varied patterns (Vs > 1.0) than ORFs 1 and 2. The host factor serving as one of the evolutionary dynamics probably influences synonymous codon usage patterns of the HEV genome. Taken together, synonymous codons with stable usage patterns in ORF1 might help to sustain the infection, while that with varied usage patterns in ORF3 may facilitate cross-species infection and expand the host range.
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Affiliation(s)
- Xin Wang
- School of Stomatology, Lanzhou University, Lanzhou, Gansu, China
| | - Jing Sun
- Department of Endocrine, The Second Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Yueyan Zheng
- School of Stomatology, Lanzhou University, Lanzhou, Gansu, China
| | - Fuqiang Xie
- Department of Stomatology, The Second Hospital of Lanzhou University, Lanzhou, Gansu, China
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El-Kafrawy SA, El-Daly MM. Hepatitis E virus in Saudi Arabia: more surveillance needed. Future Virol 2022. [DOI: 10.2217/fvl-2021-0320] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Hepatitis E virus (HEV) is a small quasi-enveloped ssRNA causing acute hepatitis. HEV is the leading cause of intermittent acute hepatitis and fulminant hepatic failure. Risk factors include drinking contaminated water in developing countries and consumption of infected animal products in developed countries. Previous reports on HEV prevalence in Saudi Arabia had small sample sizes. Nationwide systematic seroprevalence studies are needed to investigate risk factors and annual incidence. Camels play a cultural and economic role in the life of Saudi citizens with frequent human contact and potential role in zoonotic transmission. Future research needs to include larger sample-sizes and nationwide studies. Future studies should also focus on raising awareness of HEV infection and the need for wider population testing and screening.
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Affiliation(s)
- Sherif Aly El-Kafrawy
- Special Infectious Agents Unit-BSL3, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, 21589, Saudi Arabia
- Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, 21589, Saudi Arabia
| | - Mai Mohamed El-Daly
- Special Infectious Agents Unit-BSL3, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, 21589, Saudi Arabia
- Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, 21589, Saudi Arabia
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Cancela F, Noceti O, Arbiza J, Mirazo S. Structural aspects of hepatitis E virus. Arch Virol 2022; 167:2457-2481. [PMID: 36098802 PMCID: PMC9469829 DOI: 10.1007/s00705-022-05575-8] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Accepted: 06/04/2022] [Indexed: 12/14/2022]
Abstract
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.
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Affiliation(s)
- Florencia Cancela
- grid.11630.350000000121657640Sección Virología, Facultad de Ciencias, Universidad de la República, Montevideo, Uruguay
| | - Ofelia Noceti
- grid.414402.70000 0004 0469 0889Programa Nacional de Trasplante Hepático y Unidad Docente Asistencial Centro Nacional de Tratamiento Hepatobiliopancreatico. Hospital Central de las Fuerzas Armadas, Montevideo, Uruguay
| | - Juan Arbiza
- grid.11630.350000000121657640Sección Virología, Facultad de Ciencias, Universidad de la República, Montevideo, Uruguay
| | - Santiago Mirazo
- grid.11630.350000000121657640Sección Virología, Facultad de Ciencias, Universidad de la República, Montevideo, Uruguay ,grid.11630.350000000121657640Departamento de Bacteriología y Virología, Instituto de Higiene, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay ,Av. Alfredo Navarro 3051, PC 11600 Montevideo, Uruguay
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The Capsid (ORF2) Protein of Hepatitis E Virus in Feces Is C-Terminally Truncated. Pathogens 2021; 11:pathogens11010024. [PMID: 35055972 PMCID: PMC8779013 DOI: 10.3390/pathogens11010024] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Revised: 12/21/2021] [Accepted: 12/24/2021] [Indexed: 11/17/2022] Open
Abstract
The hepatitis E virus (HEV) is a causative agent of hepatitis E. HEV virions in circulating blood and culture media are quasi-enveloped, while those in feces are nonenveloped. The capsid (ORF2) protein associated with an enveloped HEV virion is reported to comprise the translation product of leucine 14/methionine 16 to 660 (C-terminal end). However, the nature of the ORF2 protein associated with fecal HEV remains unclear. In the present study, we compared the molecular size of the ORF2 protein among fecal HEV, cell-culture-generated HEV (HEVcc), and detergent-treated protease-digested HEVcc. The ORF2 proteins associated with fecal HEV were C-terminally truncated and showed the same size as those of the detergent-treated protease-digested HEVcc virions (60 kDa), in contrast to those of the HEVcc (68 kDa). The structure prediction of the ORF2 protein (in line with previous studies) demonstrated that the C-terminal region (54 amino acids) of an ORF2 protein is in flux, suggesting that proteases target this region. The nonenveloped nondigested HEV structure prediction indicates that the C-terminal region of the ORF2 protein moves to the surface of the virion and is unnecessary for HEV infection. Our findings clarify the maturation of nonenveloped HEV and will be useful for studies on the HEV lifecycle.
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Yu W, Ji H, Long F, Chen S, He Q, Xia Y, Cong C, Yang C, Wei D, Huang F. Inhibition of hepatitis E virus replication by zinc-finger antiviral Protein synergizes with IFN-β. J Viral Hepat 2021; 28:1219-1229. [PMID: 33894039 DOI: 10.1111/jvh.13522] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Revised: 04/06/2021] [Accepted: 04/08/2021] [Indexed: 01/26/2023]
Abstract
Hepatitis E virus (HEV) infection is the most common cause of acute viral hepatitis worldwide. However, host-HEV interactions have yet to be fully understood. Zinc-finger antiviral protein (ZAP) is a novel interferon (IFN)-stimulated gene product that inhibits a variety of viruses in synergy with IFN-β. To evaluate the role of ZAP in HEV infection, its expressions in HEV-infected patients and in cell cultures were measured. We report a significant inhibition of ZAP expression in patients with HEV genotype four acute infection. The expression of ZAP in the HEV life cycle was monitored in cultures of HEV-infected cells. Results indicated that the ZAP level decreased significantly after HEV infection. ZAP over-expression inhibited HEV replication, whereas its knockdown by RNA interference significantly increased HEV RNA. These suggest that ZAP serves as an antiviral in HEV infection. Moreover, silencing ZAP decreased IFN regulatory factor 3 (IRF3) phosphorylation in HEV-infected cells treated with poly(I:C), indicating that ZAP synergizes with IFN-β. In conclusion, ZAP is an important anti-HEV host factor and in synergy with IFN-β, inhibits HEV replication.
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Affiliation(s)
- Wenhai Yu
- Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming, China
| | - Hanbin Ji
- Medical Faculty, Kunming University of Science and Technology, Kunming, China
| | - Feiyan Long
- Medical Faculty, Kunming University of Science and Technology, Kunming, China
| | - Shuangfeng Chen
- Medical Faculty, Kunming University of Science and Technology, Kunming, China
| | - Qiuxia He
- Medical Faculty, Kunming University of Science and Technology, Kunming, China
| | - Yueping Xia
- Medical Faculty, Kunming University of Science and Technology, Kunming, China
| | - Chao Cong
- Medical Faculty, Kunming University of Science and Technology, Kunming, China
| | - Chenchen Yang
- Medical Faculty, Kunming University of Science and Technology, Kunming, China
| | - Daqiao Wei
- Medical Faculty, Kunming University of Science and Technology, Kunming, China
| | - Fen Huang
- Medical Faculty, Kunming University of Science and Technology, Kunming, China.,Yunnan Provincial Key Laboratory of Clinical Virology, Kunming, China
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Hoa TN, Munshi SU, Ngoc KN, Ngoc CL, Thanh TTT, Akther T, Tabassum S, Parvin N, Baker S, Rahman M. A tightly clustered hepatitis E virus genotype 1a is associated with endemic and outbreak infections in Bangladesh. PLoS One 2021; 16:e0255054. [PMID: 34293039 PMCID: PMC8297744 DOI: 10.1371/journal.pone.0255054] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Accepted: 07/08/2021] [Indexed: 12/27/2022] Open
Abstract
BACKGROUND Hepatitis E virus (HEV) infection is endemic in Bangladesh and there are occasional outbreaks. The molecular characteristics and pathogenesis of endemic and outbreak HEV strains are poorly understood. We compared the genetic relatedness and virulence associated mutations of endemic HEV strains with outbreak strains. METHODS We analyzed systematically collected serum samples from HEV immunoglobulin M (IgM) positive patients attended at Bangabandhu Sheikh Mujib Medical University, Dhaka from August 2013 to June 2015. HEV RNA positive samples were subjected to whole genome sequencing. Genotype and subtype of the strains were determined by phylogenetic analysis. Virulence associated mutations e.g. acute viral hepatitis (AVH), fulminant hepatic failure (FHF), chronic hepatitis, ribavirin treatment failure (RTF), B and T cell neutralization epitopes were determined. RESULTS 92 HEV immunoglobulin M (IgM) antibody positive plasma samples (43 in 2013-2014 and 49 in 2014-2015) were studied. 77.1% (70/92) of the samples were HEV RNA positive. A 279 bp open reading frame (ORF) 2 and ORF 3 sequence was obtained from 54.2% (38/70) of the strains. Of these 38 strains, whole genome sequence (WGS) was obtained from 21 strains. In phylogenetic analysis of 38 (279 bp) sequence all HEV sequences belonged to genotype 1 and subtype 1a. Further phylogenetic analysis of 21 HEV WGS, Bangladeshi HEV sequences clustered with genotype 1a sequences from neighboring countries. Within genotype 1a cluster, Bangladesh HEV strains formed a separate cluster with the 2010 HEV outbreak strains from northern Bangladesh. 80.9 to 100% of the strains had A317T, T735I, L1120I, L1110F, P259S, V1479I, G1634K mutations associates AVH, FHF and RTF. Mutations in T cell recognition epitope T3, T5, T7 was observed in 76.1%, 100% and 100% of the strains respectively. CONCLUSION Strains of HEV genotype 1a are dominant in Bangladesh and are associated with endemic and outbreak of HEV infection. HEV isolates in Bangladesh have high prevalence of virulence associated mutations and mutation which alters antigenicity to B and T cell epitopes.
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Affiliation(s)
- Trang Nguyen Hoa
- Oxford University Clinical Research Unit, Wellcome Asia Programme, The Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam
| | - Saif Ullah Munshi
- Bangabandhu Sheikh Mujib Medical University, Shahbag, Dhaka, Bangladesh
| | - Khanh Nguyen Ngoc
- Oxford University Clinical Research Unit, Wellcome Asia Programme, The Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam
| | - Chau Le Ngoc
- Oxford University Clinical Research Unit, Wellcome Asia Programme, The Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam
| | - Thanh Tran Thi Thanh
- Oxford University Clinical Research Unit, Wellcome Asia Programme, The Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam
| | - Tahmina Akther
- Bangabandhu Sheikh Mujib Medical University, Shahbag, Dhaka, Bangladesh
| | - Shahina Tabassum
- Bangabandhu Sheikh Mujib Medical University, Shahbag, Dhaka, Bangladesh
| | - Nilufa Parvin
- Sir Salimullah Medical College and Hospital (SSMCH), Dhaka, Bangladesh
| | - Stephen Baker
- Cambridge Institute of Therapeutic Immunology & Infectious Disease, Cambridge University, Cambridge, England
| | - Motiur Rahman
- Oxford University Clinical Research Unit, Wellcome Asia Programme, The Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam
- Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, Oxford University, Oxford, United Kingdom
- * E-mail:
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Yang YL, Nan YC. Open reading frame 3 protein of hepatitis E virus: Multi-function protein with endless potential. World J Gastroenterol 2021; 27:2458-2473. [PMID: 34092969 PMCID: PMC8160619 DOI: 10.3748/wjg.v27.i20.2458] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 03/10/2021] [Accepted: 04/12/2021] [Indexed: 02/06/2023] Open
Abstract
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.
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Affiliation(s)
- Yong-Lin Yang
- Department of Infectious Diseases, Taizhou People's Hospital, The Fifth Affiliated Hospital of Nantong University, Taizhou 225300, Jiangsu Province, China
- 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
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14
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Ahmad T, Nasir S, Musa TH, AlRyalat SAS, Khan M, Hui J. Epidemiology, diagnosis, vaccines, and bibliometric analysis of the 100 top-cited studies on Hepatitis E virus. Hum Vaccin Immunother 2021; 17:857-871. [PMID: 32755437 PMCID: PMC7993234 DOI: 10.1080/21645515.2020.1795458] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Revised: 06/27/2020] [Accepted: 07/08/2020] [Indexed: 12/12/2022] Open
Abstract
INTRODUCTION In low-income countries, Hepatitis E infection is a common cause of acute hepatitis. So far, only two recombinant vaccines (rHEV and HEV 239) have been developed against Hepatitis E virus (HEV). Of which HEV 239 is licensed in China, but is not yet available in any other country. OBJECTIVE This study aims to discuss epidemiology, diagnosis, available vaccines for HEV, and provides an overview of 100 top-cited studies on HEV. METHODS A bibliometric analysis was conducted on the topic "HEV" through a systematic search of the Web of Science. The keywords used were "Hepatitis E" and retrieved articles were assessed for number of attributes. RESULTS The search returned a total of 3,235 publications, cited 95,858 times with h-index 129. The main finding for the 100 top-cited articles on HEV showed: number of authors ranging from 1 to 23, cited references range from 4 to 304, global citations score per year range from 6.61 to 175, and global citations score range from 148 to 791. Of the 100 top-cited studies, the authors who published most articles are Purcell (n = 18), Meng (n = 17), and Emerson (n = 15). Most The largest share of articles on HEV was contributed by United States of America (n = 49) with 12,795 citations. The National Institute of Allergy andInfectious Diseases was leading institute with greatest number of publications (n = 16), cited 3,950 times. CONCLUSIONS The studies conducted on HEV have increased over time. The information presented would be very useful in decision making for policy makers providing health care, and for academicians in providing a reference point for future research.
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Affiliation(s)
- Tauseef Ahmad
- Department of Epidemiology and Health Statistics, School of Public Health, Southeast University, Nanjing, China
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, China
| | - Saima Nasir
- Allama Iqbal Open University, Islamabad, Islamic Republic of Pakistan
| | - Taha Hussein Musa
- Department of Epidemiology and Health Statistics, School of Public Health, Southeast University, Nanjing, China
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, China
| | | | - Muhammad Khan
- Department of Genetics, Centre for Human Genetics, Hazara University, Mansehra, Khyber Pakhtunkhwa, Islamic Republic of Pakistan
| | - Jin Hui
- Department of Epidemiology and Health Statistics, School of Public Health, Southeast University, Nanjing, China
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, China
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15
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Shoshan-Barmatz V, Shteinfer-Kuzmine A, Verma A. VDAC1 at the Intersection of Cell Metabolism, Apoptosis, and Diseases. Biomolecules 2020; 10:E1485. [PMID: 33114780 PMCID: PMC7693975 DOI: 10.3390/biom10111485] [Citation(s) in RCA: 133] [Impact Index Per Article: 26.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Revised: 10/02/2020] [Accepted: 10/22/2020] [Indexed: 02/07/2023] Open
Abstract
The voltage-dependent anion channel 1 (VDAC1) protein, is an important regulator of mitochondrial function, and serves as a mitochondrial gatekeeper, with responsibility for cellular fate. In addition to control over energy sources and metabolism, the protein also regulates epigenomic elements and apoptosis via mediating the release of apoptotic proteins from the mitochondria. Apoptotic and pathological conditions, as well as certain viruses, induce cell death by inducing VDAC1 overexpression leading to oligomerization, and the formation of a large channel within the VDAC1 homo-oligomer. This then permits the release of pro-apoptotic proteins from the mitochondria and subsequent apoptosis. Mitochondrial DNA can also be released through this channel, which triggers type-Ι interferon responses. VDAC1 also participates in endoplasmic reticulum (ER)-mitochondria cross-talk, and in the regulation of autophagy, and inflammation. Its location in the outer mitochondrial membrane, makes VDAC1 ideally placed to interact with over 100 proteins, and to orchestrate the interaction of mitochondrial and cellular activities through a number of signaling pathways. Here, we provide insights into the multiple functions of VDAC1 and describe its involvement in several diseases, which demonstrate the potential of this protein as a druggable target in a wide variety of pathologies, including cancer.
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Affiliation(s)
- Varda Shoshan-Barmatz
- Department of Life Sciences and the National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel; (A.S.-K.); (A.V.)
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16
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Aslan AT, Balaban HY. Hepatitis E virus: Epidemiology, diagnosis, clinical manifestations, and treatment. World J Gastroenterol 2020; 26:5543-5560. [PMID: 33071523 PMCID: PMC7545399 DOI: 10.3748/wjg.v26.i37.5543] [Citation(s) in RCA: 110] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2020] [Revised: 08/11/2020] [Accepted: 09/09/2020] [Indexed: 02/06/2023] Open
Abstract
The hepatitis E virus (HEV) is the fifth known form of viral hepatitis and was first recognized as the cause of an epidemic of unexplained acute hepatitis in the early 1980s. Globally, it is one of the most frequent causes of acute viral hepatitis. The majority of HEV infections are asymptomatic and lead to the spontaneous clearance of the virus. Among the eight different genotypes identified to date, HEV genotype 1 (HEV1), HEV2, HEV3, and HEV4 are the most frequent genotypes causing infections in humans. HEV1 and HEV2 are prevalent in developing regions and able to result in large-scale outbreaks originating from contaminated water supplies. They are also responsible for severe hepatitis in pregnant patients and infants. In contrast, HEV3 and HEV4 are zoonotic, and the transmission of these genotypes to humans occurs mainly through the fecal contamination of water and consumption of contaminated meat from infected animals. Their main reservoir is the pig, and they are mostly encountered in developed countries. The major risk groups for HEV infection and its ensuing adverse consequences are pregnant women, infants, older people, immunocompromised individuals, patients with underlying chronic liver diseases, and workers that come into close contact with HEV-infected animals. In the clinical perspective, HEV infections have diverse clinical manifestations including acute and self-limiting hepatitis, acute-on-chronic liver disease, chronic hepatitis, cirrhosis, and liver failure. Although HEV mainly results in acute self-limiting infection, chronic HEV infection may occur among immunocompromised patients (e.g., solid-organ transplant recipients). Additionally, HEV-associated extrahepatic manifestations involving various organs have been reported in the last decade, although the causal link for many of them still needs to be proven. Ribavirin and interferon-alpha are the most widely used agents for the treatment of HEV infections with a certain level of success. However, ribavirin is contraindicated in pregnant patients, and interferon-alpha cannot be used in most transplant recipients. Therefore, there is an urgent need for novel antiviral compounds that are safe and effective particularly for patients having contraindications for ribavirin or interferon-alpha and infected by the ribavirin-resistant HEV. In this review article, a literature search using PubMed and MEDLINE databases was performed, up to March 2020. Only the articles published in English were reviewed.
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Affiliation(s)
| | - Hatice Yasemin Balaban
- Department of Gastroenterology, Hacettepe University Faculty of Medicine, Ankara 06100, Turkey
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Progress in the Production of Virus-Like Particles for Vaccination against Hepatitis E Virus. Viruses 2020; 12:v12080826. [PMID: 32751441 PMCID: PMC7472025 DOI: 10.3390/v12080826] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Revised: 07/16/2020] [Accepted: 07/28/2020] [Indexed: 12/13/2022] Open
Abstract
Hepatitis E virus (HEV), a pathogen that causes acute viral hepatitis, is a small icosahedral, quasi-enveloped, positive ssRNA virus. Its genome has three open reading frames (ORFs), with ORF1 and ORF3 encoding for nonstructural and regulatory proteins, respectively, while ORF2 is translated into the structural, capsid protein. ORF2 is most widely used for vaccine development in viral hepatitis. Hepatitis E virus-like particles (VLPs) are potential vaccine candidates against HEV infection. VLPs are composed of capsid subunits mimicking the natural configuration of the native virus but lack the genetic material needed for replication. As a result, VLPs are unable to replicate and cause disease, constituting safe vaccine platforms. Currently, the recombinant VLP-based vaccine Hecolin® against HEV is only licensed in China. Herein, systematic information about the expression of various HEV ORF2 sequences and their ability to form VLPs in different systems is provided.
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Kar P, Karna R. A Review of the Diagnosis and Management of Hepatitis E. CURRENT TREATMENT OPTIONS IN INFECTIOUS DISEASES 2020; 12:310-320. [PMID: 32837339 PMCID: PMC7366488 DOI: 10.1007/s40506-020-00235-4] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Purpose of review We aim to provide the readers an up-to-date knowledge of the structure, epidemiology, and transmission followed by a detailed discussion on testing, diagnostics and management of hepatitis E virus infection. We have also included a comprehensive review of hepatitis E in pregnancy. Recent findings European Association for the Study of the Liver established clinical practice guidelines for testing and treatment of suspected hepatitis E virus infections in 2018. Evidence suggests chronic hepatitis E may follow a course similar to hepatitis B/C with progression to cirrhosis and possibly hepatocellular carcinoma in immunocompromised patients. Summary Hepatitis E virus is the most common cause of acute viral hepatitis worldwide. A combination of serology and nucleic acid amplification testing is the recommended strategy for suspected patients. Ribavirin therapy for a period of 3 months is the drug of choice for severe acute hepatitis, acute-on chronic liver failure, and chronic infections from hepatitis E virus in immunocompromised patients who are unresponsive to decreased immunosuppression. PEGylated interferon α can be used for ribavirin-resistant liver transplant patients with chronic hepatitis E. Further research in therapeutic options is essential considering the stormy course of hepatitis E infection during pregnancy and teratogenicity of all available options.
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Affiliation(s)
- P. Kar
- Department of Gastroenterology and Hepatology, Max Super Specialty Hospital,Ghaziabad, Delhi, New Delhi 110017 India
| | - R. Karna
- Maulana Azad Medical College & Lok Nayak Hospital, Bahadurshah Zafar Road, New Delhi, India
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Kumar M, Hooda P, Khanna M, Patel U, Sehgal D. Development of BacMam Induced Hepatitis E Virus Replication Model in Hepatoma Cells to Study the Polyprotein Processing. Front Microbiol 2020; 11:1347. [PMID: 32625196 PMCID: PMC7315041 DOI: 10.3389/fmicb.2020.01347] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Accepted: 05/26/2020] [Indexed: 01/10/2023] Open
Abstract
The processing of polyprotein(s) to form structural and non-structural components remains an enigma due to the non-existence of an efficient and robust Hepatitis E Virus (HEV) culture system. We used the BacMam approach to construct an HEV replication model in which the HEV genome was cloned in the BacMam vector under the CMV promoter. The recombinant BacMam was used to infect Huh7 cells to transfer the HEV genome. HEV replication was authenticated by the presence of RNAs of both the polarity (+) and (-) and formation of hybrid RNA, a replication intermediate. The presence of genes for Papain-like Cysteine Protease (PCP), methyltransferase (MeT), RNA dependent RNA polymerase (RdRp), and ORF2 was confirmed by PCR amplification. Further, the infectious nature of the culture system was established as evidenced by the cross-infection of uninfected cells using the cell lysate from the infected cells. The HEV replication model was validated by detection of the ORF1 (Open Reading Frame1) encoded proteins, identified by Western blotting and Immunofluorescence by using epitope-specific antibodies against each protein. Consequently, discrete bands of 18, 35, 37, and 56 kDa corresponding to PCP, MeT, RdRp, and ORF2, respectively, were seen. Besides demonstrating the presence of non-structural enzymes of HEV along with ORF2, activity of a key enzyme, HEV-methyltransferase has also been observed. A 20% decrease in the replicative forms of RNA could be seen in presence of 100 μM Ribavirin after 48 h of treatment. The inhibition gradually increased from 0 to 24 to 48 h post-treatment. Summarily, infectious HEV culture system has been established, which could demonstrate the presence of HEV replicative RNA forms, the structural and non-structural proteins and the methyltransferase in its active form. The system may also be used to study the mechanism of action of Ribavirin in inhibiting HEV replication and develop a therapy.
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Affiliation(s)
- Manjeet Kumar
- Virology Laboratory, Department of Life Sciences, Shiv Nadar University, Greater Noida, India
| | - Preeti Hooda
- Virology Laboratory, Department of Life Sciences, Shiv Nadar University, Greater Noida, India
| | - Madhu Khanna
- Virology Lab, Department of Virology, Vallabhbhai Patel Chest Institute, University of Delhi, New Delhi, India
| | - Utkarsh Patel
- Virology Laboratory, Department of Life Sciences, Shiv Nadar University, Greater Noida, India
| | - Deepak Sehgal
- Virology Laboratory, Department of Life Sciences, Shiv Nadar University, Greater Noida, India
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20
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BK Polyomavirus Hijacks Extracellular Vesicles for En Bloc Transmission. J Virol 2020; 94:JVI.01834-19. [PMID: 31896595 PMCID: PMC7158717 DOI: 10.1128/jvi.01834-19] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2019] [Accepted: 12/17/2019] [Indexed: 12/14/2022] Open
Abstract
Reactivation of BKPyV is responsible for nephropathies in kidney transplant recipients, which frequently lead to graft loss. The mechanisms of persistence and immune evasion used by this virus remain poorly understood, and a therapeutic option for transplant patients is still lacking. Here, we show that BKPyV can be released into EVs, enabling viral particles to infect cells using an alternative entry pathway. This provides a new view of BKPyV pathogenesis. Even though we did not find any decreased sensitivity to neutralizing antibodies when comparing EV-associated particles and naked virions, our study also raises important questions about developing prevention strategies based on the induction or administration of neutralizing antibodies. Deciphering this new release pathway could enable the identification of therapeutic targets to prevent BKPyV nephropathies. It could also lead to a better understanding of the pathophysiology of other polyomaviruses that are associated with human diseases. Most people are asymptomatic carriers of the BK polyomavirus (BKPyV), but the mechanisms of persistence and immune evasion remain poorly understood. Furthermore, BKPyV is responsible for nephropathies in kidney transplant recipients. Unfortunately, the sole therapeutic option is to modulate immunosuppression, which increases the risk of transplant rejection. Using iodixanol density gradients, we observed that Vero and renal proximal tubular epithelial infected cells release two populations of infectious particles, one of which cosediments with extracellular vesicles (EVs). Electron microscopy confirmed that a single vesicle could traffic tens of viral particles. In contrast to naked virions, the EV-associated particles (eBKPyVs) were not able to agglutinate red blood cells and did not use cell surface sialylated glycans as an attachment factor, demonstrating that different entry pathways were involved for each type of infectious particle. However, we also observed that naked BKPyV and eBKPyV were equally sensitive to neutralization by the serum of a seropositive patient or commercially available polyvalent immunoglobulin preparations, which occurred at a postattachment step, after endocytosis. In conclusion, our work shows a new mechanism that likely plays a critical role during the primary infection and in the persistence, but also the reactivation, of BKPyV. IMPORTANCE Reactivation of BKPyV is responsible for nephropathies in kidney transplant recipients, which frequently lead to graft loss. The mechanisms of persistence and immune evasion used by this virus remain poorly understood, and a therapeutic option for transplant patients is still lacking. Here, we show that BKPyV can be released into EVs, enabling viral particles to infect cells using an alternative entry pathway. This provides a new view of BKPyV pathogenesis. Even though we did not find any decreased sensitivity to neutralizing antibodies when comparing EV-associated particles and naked virions, our study also raises important questions about developing prevention strategies based on the induction or administration of neutralizing antibodies. Deciphering this new release pathway could enable the identification of therapeutic targets to prevent BKPyV nephropathies. It could also lead to a better understanding of the pathophysiology of other polyomaviruses that are associated with human diseases.
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Iqbal T, Rashid U, Idrees M, Afroz A, Kamili S, Purdy MA. A novel avian isolate of hepatitis E virus from Pakistan. Virol J 2019; 16:142. [PMID: 31753030 PMCID: PMC6868781 DOI: 10.1186/s12985-019-1247-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2019] [Accepted: 10/30/2019] [Indexed: 01/16/2023] Open
Abstract
Background Avian hepatitis E virus (aHEV) has been associated with hepatitis-splenomegaly syndrome (HSS) in chickens along with asymptomatic subclinical infection in many cases. So far, four genotypes have been described, which cause infection in chickens, specifically in broiler breeders and layer chickens. In the present study, we isolated and identified two novel aHEV strains from the bile of layer chickens in Pakistan evincing clinical symptoms related to HSS. Methodology Histology of liver and spleen tissues was carried out to observe histopathological changes in these tissues. Bile fluid and fecal suspensions were used for viral RNA isolation through MegNA pure and Trizol method which was further used for viral genome detection and characterization by cDNA synthesis and amplification of partial open reading frame (ORF) 1, ORF2 and complete ORF3. The bioinformatics tools; Molecular Evolutionary Genetics Analysis version 6.0 (MEGA 6), Mfold and ProtScale were used for phylogenic analysis, RNA secondary structure prediction and protein hydropathy analysis, respectively. Results Sequencing and phylogenetic analysis on the basis of partial methyltranferase (MeT), helicase (Hel) domain, ORF2 and complete ORF3 sequence suggests these Pakistani aHEV (Pak aHEV) isolates may belong to a Pakistani specific clade. The overall sequence similarity between the Pak aHEV sequences was 98–100%. The ORF1/ORF3 intergenic region contains a conserved cis-reactive element (CRE) and stem-loop structure (SLS). Analysis of the amino acid sequence of ORF3 indicated two hydrophobic domains (HD) and single conserved proline-rich domain (PRD) PREPSAPP (PXXPXXPP) with a single PSAP motif found in C-terminal. Amino acid changes S15 T, A31T, Q35H and G46D unique to the Pak aHEV sequences were found in the N-terminal region of ORF3. Conclusions Our data suggests that Pak aHEV isolates may represent a novel Pakistani clade and high sequence homology to each other support the supposition they may belong to a monophyletic clade circulating in the region around Pakistan. The data presented in this study provide further information for aHEV genetic diversity, genotype mapping, global distribution and epidemiology.
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Affiliation(s)
- Tahir Iqbal
- Department of Biochemistry and Biotechnology, University of Gujrat, Gujrat, 50700, Pakistan.,Division of Viral Hepatitis, Centers for Disease Control and Prevention (CDC), MS-A33, 1600 Clifton Rd NE, Atlanta, GA, 30329, USA
| | - Umer Rashid
- Department of Biochemistry and Biotechnology, University of Gujrat, Gujrat, 50700, Pakistan.
| | - Muhammad Idrees
- Centre for Applied Molecular Biology (CAMB), University of the Punjab, Lahore, 53700, Pakistan.,Hazara University, Mansehra, 21300, Pakistan
| | - Amber Afroz
- Department of Biochemistry and Biotechnology, University of Gujrat, Gujrat, 50700, Pakistan
| | - Saleem Kamili
- Division of Viral Hepatitis, Centers for Disease Control and Prevention (CDC), MS-A33, 1600 Clifton Rd NE, Atlanta, GA, 30329, USA
| | - Michael A Purdy
- Division of Viral Hepatitis, Centers for Disease Control and Prevention (CDC), MS-A33, 1600 Clifton Rd NE, Atlanta, GA, 30329, USA
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Nishiyama T, Kobayashi T, Jirintai S, Nagashima S, Primadharsini PP, Nishizawa T, Okamoto H. Antiviral candidates against the hepatitis E virus (HEV) and their combinations inhibit HEV growth in in vitro. Antiviral Res 2019; 170:104570. [PMID: 31362004 DOI: 10.1016/j.antiviral.2019.104570] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2019] [Revised: 07/24/2019] [Accepted: 07/26/2019] [Indexed: 12/25/2022]
Abstract
Hepatitis E is a global public health problem. Ribavirin (RBV) and pegylated interferon alpha are currently administered to cure hepatitis E. Recently, in combination with RBV, sofosbuvir (SOF), an anti-hepatitis C virus nucleotide analog, is also given to patients with chronic hepatitis E. However, this combinatorial therapy sometimes fails to achieve a sustained virological response. In this study, we used 27 antiviral compounds, including 15 nucleos(t)ide analogs, for in vitro screening against a genotype 3 HEV strain containing a Gaussia luciferase reporter. RBV, SOF, 2'-C-methyladenosine, 2'-C-methylcytidine (2CMC), 2'-C-methylguanosine (2CMG), and two 4'-azido nucleoside analogs (R-1479 and RO-9187) suppressed replication of the reporter genome, while only RBV, SOF, 2CMC and 2CMG inhibited the growth of genotype 3 HEV in cultured cells. Although 2CMG and RBV (2CMG/RBV) exhibited a synergistic effect while SOF/RBV and 2CMC/RBV showed antagonistic effects on the reporter assay, these three nucleos(t)ide analogs acted additively with RBV in inhibiting HEV growth in cultured cells. Furthermore, SOF and 2CMG, with four interferons (IFN-α2b, IFN-λ1, IFN-λ2 and IFN-λ3), inhibited HEV growth efficiently and cleared HEV in cultured cells. These results suggest that, in combination with RBV or interferons, SOF and 2CMG would be promising bases for developing anti-HEV nucleos(t)ide analogs.
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Affiliation(s)
- Takashi Nishiyama
- Division of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, Shimotsuke-Shi, Tochigi, 329-0498, Japan
| | - Tominari Kobayashi
- Division of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, Shimotsuke-Shi, Tochigi, 329-0498, Japan
| | - Suljid Jirintai
- Division of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, Shimotsuke-Shi, Tochigi, 329-0498, Japan; Division of Pathology, Department of Basic Veterinary Medicine, Inner Mongolia Agricultural University College of Veterinary Medicine, Hohhot, Inner Mongolia, China
| | - Shigeo Nagashima
- Division of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, Shimotsuke-Shi, Tochigi, 329-0498, Japan
| | - Putu Prathiwi Primadharsini
- Division of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, Shimotsuke-Shi, Tochigi, 329-0498, Japan
| | - Tsutomu Nishizawa
- Division of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, Shimotsuke-Shi, Tochigi, 329-0498, Japan
| | - Hiroaki Okamoto
- Division of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, Shimotsuke-Shi, Tochigi, 329-0498, Japan.
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Nishiyama T, Kobayashi T, Jirintai S, Kii I, Nagashima S, Prathiwi Primadharsini P, Nishizawa T, Okamoto H. Screening of novel drugs for inhibiting hepatitis E virus replication. J Virol Methods 2019; 270:1-11. [PMID: 31004661 DOI: 10.1016/j.jviromet.2019.04.017] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2018] [Revised: 03/05/2019] [Accepted: 04/16/2019] [Indexed: 12/12/2022]
Abstract
Hepatitis E, which is caused by hepatitis E virus (HEV), is generally a self-limiting, acute, and rarely fatal disease. It is sometimes fulminant and lethal, especially during pregnancy. Indeed, it occasionally takes a chronic course in immunocompromised individuals. To cure hepatitis E patients, the broad-spectrum antivirals (ribavirin and pegylated interferon α) are used. However, this treatment is insufficient and unsafe in some patients due to embryoteratogenic effects, leukopenia, and thrombocytopenia. In this study, we constructed an HEV replication reporter system with Gaussia luciferase for comprehensively screening anti-HEV drug candidates, and developed a cell-culture system using cells robustly producing HEV to validate the efficacy of anti-HEV drug candidates. We screened anti-HEV drug candidates from United States Food and Drug Administration-approved drugs using the established HEV replication reporter system, and investigated the selected candidates and type III interferons (interferon λ1-3) using the cell-culture system. In conclusion, we constructed an HEV replicon system for anti-HEV drug screening and a novel cell-culture system to strictly evaluate the replication-inhibitory activities of the obtained anti-HEV candidates. Our findings suggested that interferon λ1-3 might be effective for treating hepatitis E.
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Affiliation(s)
- Takashi Nishiyama
- Division of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, 3311-1 Yakushiji, Shimotsuke-Shi, Tochigi 329-0498, Japan
| | - Tominari Kobayashi
- Division of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, 3311-1 Yakushiji, Shimotsuke-Shi, Tochigi 329-0498, Japan
| | - Suljid Jirintai
- Division of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, 3311-1 Yakushiji, Shimotsuke-Shi, Tochigi 329-0498, Japan; Division of Pathology, Department of Basic Veterinary Medicine, Inner Mongolia Agricultural University College of Medicine, Hohhot, Inner Mongolia, China
| | - Isao Kii
- Common Facilities Unit, Integrated Research Group, Compass to Healthy Life Research Complex Program, RIKEN Cluster for Science, Technology and Innovation Hub, Kobe, Japan
| | - Shigeo Nagashima
- Division of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, 3311-1 Yakushiji, Shimotsuke-Shi, Tochigi 329-0498, Japan
| | - Putu Prathiwi Primadharsini
- Division of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, 3311-1 Yakushiji, Shimotsuke-Shi, Tochigi 329-0498, Japan
| | - Tsutomu Nishizawa
- Division of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, 3311-1 Yakushiji, Shimotsuke-Shi, Tochigi 329-0498, Japan
| | - Hiroaki Okamoto
- Division of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, 3311-1 Yakushiji, Shimotsuke-Shi, Tochigi 329-0498, Japan.
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Yue N, Wang Q, Zheng M, Wang D, Duan C, Yu X, Zhang X, Bao C, Jin H. Prevalence of hepatitis E virus infection among people and swine in mainland China: A systematic review and meta-analysis. Zoonoses Public Health 2019; 66:265-275. [PMID: 30884147 DOI: 10.1111/zph.12555] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2018] [Revised: 11/19/2018] [Accepted: 11/24/2018] [Indexed: 12/17/2022]
Abstract
Hepatitis E virus (HEV) infection remains an important public health problem, and it is endemic primarily in developing countries. This study aimed to evaluate the seroprevalence of HEV among the general population, occupational population and swine in mainland China and its risk factors based on a systematic review and meta-analysis. Systematic search from EMBASE, PubMed, Web of Science, Cochrane Library and several Chinese databases, such as Wanfang (WF) Data, China National Knowledge Infrastructure (CNKI), Chinese Science and Technology Periodical Database (VIP) and SINOMED, was searched from inception up to 25 April 2018. The overall seroprevalence of HEV and its corresponding 95% confidence interval (CI) as well as the correlation coefficients between different groups were estimated using stata 12.0 and r-3.4.1 software. Potential sources of heterogeneity were explored using subgroup and sensitivity analyses. Twenty-eight studies with 57,274 participants (including human and swine) were included. The seroprevalence of anti-HEV immunoglobulin G (IgG) among the general population, occupational population and swine was 27.3% (95% CI: 22.4-32.2), 47.4% (95% CI: 40.1-54.8) and 66.4% (95% CI: 61.7-71.1), respectively. The overall prevalence of IgM among the general population was 1.8% (95% CI: 0.7-2.9). The odds ratio for the occupational population, as compared to the general population, was 2.63. The highest anti-HEV IgG prevalence (59%) was observed in East China, whereas the lowest (34.8%) was noted in Northeast and North China. In the occupational population, the highest prevalence (77.0%) was observed among swine vendors. Seven studies included 30,392 participants (humans and swine); the correlation coefficient for the prevalence of anti-HEV IgG between the professional population and adult pigs was 0.88. Sensitivity analyses showed that the stability of results was not considered significant. This research found that HEV is common in China, and contact with pork or other pig products may be an important mode of HEV transmission.
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Affiliation(s)
- Na Yue
- Department of Epidemiology and Health Statistics, School of Public Health, Southeast University, Nanjing, China.,Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, China
| | - Qiang Wang
- Department of Epidemiology and Health Statistics, School of Public Health, Southeast University, Nanjing, China.,Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, China
| | - Mengyun Zheng
- Department of Epidemiology and Health Statistics, School of Public Health, Southeast University, Nanjing, China.,Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, China
| | - Donglei Wang
- Department of Epidemiology and Health Statistics, School of Public Health, Southeast University, Nanjing, China.,Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, China
| | - Chunxiao Duan
- Department of Epidemiology and Health Statistics, School of Public Health, Southeast University, Nanjing, China.,Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, China
| | - Xiaoge Yu
- Department of Epidemiology and Health Statistics, School of Public Health, Southeast University, Nanjing, China.,Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, China
| | - Xuefeng Zhang
- Jiangsu Provincial Center for Disease Control and Prevention, Nanjing, China
| | - Changjun Bao
- Jiangsu Provincial Center for Disease Control and Prevention, Nanjing, China
| | - Hui Jin
- Department of Epidemiology and Health Statistics, School of Public Health, Southeast University, Nanjing, China.,Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, China
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25
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The genetic divergences of codon usage shed new lights on transmission of hepatitis E virus from swine to human. INFECTION GENETICS AND EVOLUTION 2019; 68:23-29. [DOI: 10.1016/j.meegid.2018.11.024] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/15/2018] [Revised: 11/22/2018] [Accepted: 11/30/2018] [Indexed: 12/27/2022]
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26
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Norder H, Galli C, Magnil E, Sikora P, Ekvärn E, Nyström K, Magnius LO. Hepatitis E Virus Genotype 3 Genomes from RNA-Positive but Serologically Negative Plasma Donors Have CUG as the Start Codon for ORF3. Intervirology 2018; 61:96-103. [PMID: 30278453 DOI: 10.1159/000491926] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2018] [Accepted: 07/09/2018] [Indexed: 12/20/2022] Open
Abstract
Hepatitis E virus (HEV) is a pathogen that causes hepatitis worldwide. Molecular studies have identified HEV RNA in blood products although its significance is not understood. This study was undertaken to characterize HEV genomes in asymptomatic plasma donors from Sweden and Germany lacking anti-HEV. Complete open reading frames (ORFs) were obtained from HEV strains in 5 out of 18 plasma donors who tested positive for HEV RNA. All strains had CUG as the start codon of ORF3, while 147 GenBank strains all had AUG as the start codon (p < 0.0001). This substitution was found in both interrelated and unrelated strains belonging to different phylogenetic clades. The HEV strains from the seronegative plasma donors had no other substitution in common, which may be why the CUG substitution seems to explain the seronegativity.
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Affiliation(s)
- Heléne Norder
- Department of Infectious Diseases, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Cristina Galli
- Department of Infectious Diseases, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.,Department of Biomedical Sciences for Health, University of Milan, Milan, Italy
| | - Ellen Magnil
- Department of Infectious Diseases, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Per Sikora
- Department of Pathology and Genetics, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.,Clinical Genomics Gothenburg, SciLife Labs, Gothenburg, Sweden
| | | | - Kristina Nyström
- Department of Infectious Diseases, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
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27
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Anang S, Kaushik N, Surjit M. Recent Advances Towards the Development of a Potent Antiviral Against the Hepatitis E Virus. J Clin Transl Hepatol 2018; 6:310-316. [PMID: 30271744 PMCID: PMC6160310 DOI: 10.14218/jcth.2018.00005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2018] [Revised: 02/19/2018] [Accepted: 03/23/2018] [Indexed: 12/18/2022] Open
Abstract
Hepatitis E virus (HEV) is one of the leading causes of acute viral hepatitis. It also causes acute liver failure and acute-on-chronic liver failure in many patients, such as those suffering from other infections/liver injuries or organ transplant/chemotherapy recipients. Despite widespread sporadic and epidemic incidents, there is no specific treatment against HEV, justifying an urgent need for developing a potent antiviral against it. This review summarizes the known antiviral candidates and provides an overview of the potential targets for the development of specific antivirals against HEV.
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Affiliation(s)
- Saumya Anang
- Virology Laboratory, Vaccine and Infectious Disease Research Centre, Translational Health Science and Technology Institute, NCR Biotech Science Cluster, 3rd Milestone, Faridabad-Gurgaon Expressway, Faridabad, Haryana, India
| | - Nidhi Kaushik
- Virology Laboratory, Vaccine and Infectious Disease Research Centre, Translational Health Science and Technology Institute, NCR Biotech Science Cluster, 3rd Milestone, Faridabad-Gurgaon Expressway, Faridabad, Haryana, India
| | - Milan Surjit
- Virology Laboratory, Vaccine and Infectious Disease Research Centre, Translational Health Science and Technology Institute, NCR Biotech Science Cluster, 3rd Milestone, Faridabad-Gurgaon Expressway, Faridabad, Haryana, India
- *Correspondence to: Milan Surjit, Vaccine and Infectious Disease Research Centre, Translational Health Science and Technology Institute, NCR Biotech Science Cluster, 3rd Milestone, Faridabad-Gurgaon Expressway, PO Box No. 04, Faridabad-121001, Haryana, India. Tel: +91-129-2876-318, Fax: +91-129-2876400, E-mail:
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28
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Potent Inhibition of Hepatitis E Virus Release by a Cyclic Peptide Inhibitor of the Interaction between Viral Open Reading Frame 3 Protein and Host Tumor Susceptibility Gene 101. J Virol 2018; 92:JVI.00684-18. [PMID: 30068652 DOI: 10.1128/jvi.00684-18] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2018] [Accepted: 07/25/2018] [Indexed: 12/15/2022] Open
Abstract
Hepatitis E virus (HEV) generally causes self-limiting acute viral hepatitis in normal individuals. It causes a more severe disease in immunocompromised persons and pregnant women. Due to the lack of an efficient cell culture system or animal model, the life cycle of the virus is understudied, few antiviral targets are known, and very few antiviral candidates against HEV infection have been identified. Inhibition of virus release is one possible antiviral development strategy, which limits the spread of the virus. Previous studies have demonstrated the essential role of the interaction between the PSAP motif of the viral open reading frame 3 protein (ORF3-PSAP) and the UEV domain of the host tumor susceptibility gene 101 (TSG101) protein (UEV-TSG101) in mediating the release of genotype 3 HEV. Cyclic peptide (CP) inhibitors of the interaction between the human immunodeficiency virus (HIV) gag-PTAP motif and UEV-TSG101 are known to block the release of HIV. Using a molecular dynamic simulation, we observed that both gag-PTAP and ORF3-PSAP motifs bind to the same site in UEV-TSG101 by hydrogen bonding. HIV-released inhibitory CPs also displayed binding to the same site in UEV-TSG101, indicating that they may compete with ORF3-PSAP or gag-PTAP for binding to UEV-TSG101. Two independent assays confirmed the ability of a cyclic peptide (CP11) to inhibit the ORF3-TSG101 interaction. CP11 treatment also reduced the release of both genotype 1 and genotype 3 HEV by approximately 90%, with a 50% inhibitory concentration (IC50) of 2 μM. Thus, CP11 appears to be an attractive candidate for further validation of its anti-HEV properties.IMPORTANCE There is no specific therapy against hepatitis E virus (HEV)-induced hepatic and nonhepatic health problems. Prevention of the release of the progeny viruses from infected cells is an attractive strategy to limit the spread of the virus. Interactions between the viral open reading frame 3 and the host tumor susceptibility gene 101 proteins have been shown to be essential for the release of genotype 3 HEV from infected cells. In this study, we have identified a cyclic peptide inhibitor of the above-mentioned interaction and demonstrate the efficiency of the inhibitor in preventing virus release from infected cells. Thus, our findings uncover the possibility of developing a specific antiviral agent against HEV by blocking its release from infected cells.
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29
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Phylogenetic analysis of two genotype 3 Hepatitis E viruses from wild boar, Italy. Virus Genes 2018; 54:812-817. [PMID: 30203361 DOI: 10.1007/s11262-018-1597-5] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2018] [Accepted: 08/31/2018] [Indexed: 12/27/2022]
Abstract
The complete and near-complete genome sequences (7206 nt and 7229 nt) of two wild boar HEV strains detected in Southern Italy were obtained by the next generation sequencing. Phylogenetic analysis and p distance comparisons of one of the strains with HEV-3 reference subtype strains confirmed the detection of a subtype 3i (p distance = 0.110) strain in wild boar, never detected in Italy either in wild boar or pigs. The sequence of the second strain was not classifiable in any of the subtypes defined to date, showing a p distance > 0.138 and a low nucleotide identity with all HEV reference strains. The virus may represent a novel subtype, with a low relationship to other strains of genotype 3 detected in wild boar, pigs, or humans in Europe. This result suggests the circulation in Italy of an emerging or uncommon HEV strain. Sequencing followed by phylogenetic analyses of the complete HEV coding regions are important tools for understanding the evolutionary and epidemiological dynamics underlying the wide genetic diversity of HEV strains.
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30
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Parvez MK, Subbarao N. Molecular Analysis and Modeling of Hepatitis E Virus Helicase and Identification of Novel Inhibitors by Virtual Screening. BIOMED RESEARCH INTERNATIONAL 2018; 2018:5753804. [PMID: 30246023 PMCID: PMC6136533 DOI: 10.1155/2018/5753804] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/19/2018] [Accepted: 08/07/2018] [Indexed: 12/20/2022]
Abstract
The hepatitis E virus- (HEV-) helicase as a novel drug-target was evaluated. While cell culture model was used for mutational characterization of helicase, in silico protein modeling and virtual screening were employed to identify helicase inhibitors. None of the saturation mutant replicons significantly affected RNA replication. Notably, mutants encompassing the Walker motifs replicated as wild-type, showing indispensability of nucleotides conservation in viability compared to known criticality of amino acids. A 3D modeling of HEV-helicase and screening of a compound dataset identified ten most promising inhibitors with drug likeness, notably, JFD02650, RDR03130, and HTS11136 that interacted with Walker A residues Gly975, Gly978, Ser979, and Gly980. Our model building and virtual identification of novel helicase inhibitors warrant further studies towards developing anti-HEV drugs.
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Affiliation(s)
- Mohammad K. Parvez
- Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Naidu Subbarao
- School of Computational and Integrative Sciences, Jawaharlal Nehru University, New Delhi, India
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31
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Kaushik N, Anang S, Ganti KP, Surjit M. Zinc: A Potential Antiviral Against Hepatitis E Virus Infection? DNA Cell Biol 2018; 37:593-599. [PMID: 29897788 DOI: 10.1089/dna.2018.4175] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Hepatitis E virus (HEV) is a major cause of viral hepatitis worldwide. Owing to its feco oral transmission route, sporadic as well as epidemic outbreaks recurrently occur. No specific antiviral therapy is available against the disease caused by HEV. Broad spectrum antivirals such as ribavirin and interferon alfa are prescribed in severe and chronic HEV cases. However, the side effects, cost, and limitations of usage render the available treatment unsuitable for several categories of patients. We recently reported the ability of zinc to inhibit viral replication in mammalian cell culture models of HEV infection. Zinc will be a safe and economical antiviral therapy option if it inhibits HEV replication during the natural course of infection. This essay discusses the putative mechanism(s) by which zinc inhibits HEV replication and provides an overview of the possible therapeutic potential of zinc in HEV patients.
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Affiliation(s)
- Nidhi Kaushik
- 1 Virology Laboratory, Vaccine and Infectious Disease Research Centre, Translational Health Science and Technology Institute , NCR Biotech Science Cluster, Faridabad, India
| | - Saumya Anang
- 1 Virology Laboratory, Vaccine and Infectious Disease Research Centre, Translational Health Science and Technology Institute , NCR Biotech Science Cluster, Faridabad, India
| | | | - Milan Surjit
- 1 Virology Laboratory, Vaccine and Infectious Disease Research Centre, Translational Health Science and Technology Institute , NCR Biotech Science Cluster, Faridabad, India
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32
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Lei Q, Li L, Zhang S, Li T, Zhang X, Ding X, Qin B. HEV ORF3 downregulates TLR7 to inhibit the generation of type I interferon via impairment of multiple signaling pathways. Sci Rep 2018; 8:8585. [PMID: 29872132 PMCID: PMC5988675 DOI: 10.1038/s41598-018-26975-4] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2018] [Accepted: 05/22/2018] [Indexed: 12/16/2022] Open
Abstract
Hepatitis E is the most common type of acute hepatitis prevalent worldwide. The open reading frame 3 protein of HEV (HEV ORF3) is proposed to create a favorable environment for viral replication and pathogenesis. However, the mechanisms by which HEV overcomes the effects of host immunity, particularly the role of ORF3, remain to be established. Expression of IFNα and IFNβ in supernatant and cell samples was examined via ELISA and quantitative RT-PCR. The protein levels of specific signaling factors in cells overexpressing HEV ORF3 were examined via western blot. Analyses of cells transfected with vectors expressing ORF3 demonstrated that HEV ORF3 significantly impairs the generation of endogenous type I interferon through downregulating TLR3 and TLR7 as well as their corresponding downstream signaling pathways. Moreover, inhibition of NFκB, JAK/STAT and JNK/MAPK signaling pathways contributed significantly to suppression of increased levels of TLR7. Levels of p-P65, p-STAT1 and p-JNK were markedly impaired in ORF3-expressing cells, even upon treatment with the respective agonists. HEV ORF3 inhibits the production of endogenous type I interferon through downregulation of TLR3 and TLR7. Furthermore, suppression of TLR7 is achieved through impairment of multiple signaling pathways, including NFκB, JAK/STAT and JNK/MAPK.
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Affiliation(s)
- Qingsong Lei
- Chongqing Key Laboratory of Infectious Diseases and Parasitic Diseases,Department of Infectious Diseases, the First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Lin Li
- Department of hepatic diseases, Chongqing Tranditional Chinese Medicine Hospital, Chongqing, 400011, China
| | - Shujun Zhang
- Chongqing Key Laboratory of Infectious Diseases and Parasitic Diseases,Department of Infectious Diseases, the First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Tianju Li
- Chongqing Key Laboratory of Infectious Diseases and Parasitic Diseases,Department of Infectious Diseases, the First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Xiaomei Zhang
- Chongqing Key Laboratory of Infectious Diseases and Parasitic Diseases,Department of Infectious Diseases, the First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Xiaolin Ding
- Chongqing Key Laboratory of Infectious Diseases and Parasitic Diseases,Department of Infectious Diseases, the First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Bo Qin
- Chongqing Key Laboratory of Infectious Diseases and Parasitic Diseases,Department of Infectious Diseases, the First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China.
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33
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Hepatitis E in High-Income Countries: What Do We Know? And What Are the Knowledge Gaps? Viruses 2018; 10:v10060285. [PMID: 29799485 PMCID: PMC6024799 DOI: 10.3390/v10060285] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2018] [Revised: 05/16/2018] [Accepted: 05/23/2018] [Indexed: 12/11/2022] Open
Abstract
Hepatitis E virus (HEV) is a positive-strand RNA virus transmitted by the fecal–oral route. HEV genotypes 1 and 2 infect only humans and cause mainly waterborne outbreaks. HEV genotypes 3 and 4 are widely represented in the animal kingdom, and are mainly transmitted as a zoonosis. For the past 20 years, HEV infection has been considered an imported disease in developed countries, but now there is evidence that HEV is an underrecognized pathogen in high-income countries, and that the incidence of confirmed cases has been steadily increasing over the last decade. In this review, we describe current knowledge about the molecular biology of HEV, its clinical features, its main routes of transmission, and possible therapeutic strategies in developed countries.
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34
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Tanggis, Kobayashi T, Takahashi M, Jirintai S, Nishizawa T, Nagashima S, Nishiyama T, Kunita S, Hayama E, Tanaka T, Mulyanto, Okamoto H. An analysis of two open reading frames (ORF3 and ORF4) of rat hepatitis E virus genome using its infectious cDNA clones with mutations in ORF3 or ORF4. Virus Res 2018; 249:16-30. [DOI: 10.1016/j.virusres.2018.02.014] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2018] [Revised: 02/14/2018] [Accepted: 02/14/2018] [Indexed: 01/13/2023]
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Comparison of hepatitis E virus seroprevalence between HBsAg-positive population and healthy controls in Shandong province, China. BMC Infect Dis 2018; 18:75. [PMID: 29433428 PMCID: PMC5810058 DOI: 10.1186/s12879-018-2974-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2017] [Accepted: 01/23/2018] [Indexed: 02/07/2023] Open
Abstract
Background Persons with chronic hepatitis B (CHB) infection were reported to suffer severe disease after hepatitis E virus (HEV) superinfection, but the studies regarding HEV seroprevalence in this population were limited. A recent study in Vietnam found higher HEV seroprevalence among CHB patients compared with healthy controls. Methods A community-based case-control study was conducted in two counties of Shandong province, China, where hepatitis E incidence was at the highest (Rushan) and lowest (Zhangqiu) in the province based on data from routine public health surveillance. Four townships were selected randomly from each county and all residents in these townships were tested for hepatitis B surface antigen (HBsAg). Those tested positive for HBsAg (CHB group) and the 1:1 age and sex-matched HBsAg-negative residents (control group) were included. Anti-HEV IgM and IgG were tested and positive rates of IgG and IgM were compared between the CHB group and the control group. Results In total, 2048 CHB participants and 2054 controls were included in the study. In the CHB group, HEV IgG seroprevalence was 9.16% (95% CI: 7.47–11.09) in Zhangqiue and 38.06% (95% CI: 35.07–41.19) in Rushan (P < 0.001); the corresponding rates of IgM were 0.1% (95% CI: 0.002–0.54) and 1.57% (95% CI: 0.90–2.53), respectively (P < 0.001). HEV IgG seroprevalence was similar between CHB group and the control group in both counties (P = 0.21, P = 0.47, respectively) and the same results were found for the positive rate of IgM (P = 0.103, P = 0.262, respectively). Multivariable analysis showed the status of HBsAg was not independently associated with the status of anti-HEV IgG in either Zhangqiu or Rushan [P = 0.187, OR = 1.23(95% CI: 0.90, 1.68); P = 0.609, OR = 1.05 (95% CI: 0.87, 1.26)]. Conclusions The seroprevalence of HEV varies greatly in different geographic areas, but the seroprevalence is similar between populations with and without CHB. CHB patients residing in high HEV endemic areas might be at higher risk for HBV-HEV superinfection.
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36
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Al-Ayoubi J, Behrendt P, Bremer B, Suneetha PV, Gisa A, Rinker F, Manns MP, Cornberg M, Wedemeyer H, Kraft ARM. Hepatitis E virus ORF 1 induces proliferative and functional T-cell responses in patients with ongoing and resolved hepatitis E. Liver Int 2018; 38:266-277. [PMID: 28718943 DOI: 10.1111/liv.13521] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2016] [Accepted: 07/08/2017] [Indexed: 12/15/2022]
Abstract
BACKGROUND AND AIMS Hepatitis E virus (HEV) is a major cause of acute viral hepatitis with >3 million symptomatic cases per year accounting for 70 000 HEV-related deaths. HEV-specific T-cell responses have been investigated against structural proteins expressed by open reading frames (ORF) 2 and 3. T-cell responses against non-structural HEV proteins encoded by ORF1 are hardly studied. The aim of this study was to determine HEV ORF1-specific T-cell responses in comparison to ORF2/3 in patients exposed to HEV. METHODS HEV-specific CD4+ and CD8+ T-cell responses against HEV genotype 3 were investigated in patients with acute and chronic hepatitis E as well as in HEV seropositive and seronegative individuals. HEV-specific T-cell responses were determined by proliferation and intracellular cytokine assay upon stimulation of PBMCs with HEV-specific overlapping peptide pools spanning the entire HEV genome. HEV-antigen was measured using an anti-HEV antigen-specific ELISA. RESULTS Broad HEV ORF1-specific T-cell responses were detected in patients with acute, resolved and chronic hepatitis E without distinct dominant regions. The magnitude and frequency in recognition of ORF1-specific T-cell responses were similar compared to responses against HEV ORF2/3. Longitudinal studies of HEV-specific T-cell responses displayed similar behaviour against structural and non-structural proteins. HEV-antigen levels were inversely correlated with HEV-specific T-cell responses. CONCLUSIONS HEV-specific T-cell responses are detectable against the entire HEV genome including the non-structural proteins. HEV-specific T-cell responses are associated with control of HEV infection. These findings have implications for the design of HEV vaccines.
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Affiliation(s)
- Jana Al-Ayoubi
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Patrick Behrendt
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Birgit Bremer
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | | | - Anett Gisa
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Franziska Rinker
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Michael P Manns
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.,German Center for Infection Research (DZIF), Hannover, Germany
| | - Markus Cornberg
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.,German Center for Infection Research (DZIF), Hannover, Germany
| | - Heiner Wedemeyer
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.,German Center for Infection Research (DZIF), Hannover, Germany
| | - Anke R M Kraft
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.,German Center for Infection Research (DZIF), Hannover, Germany
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37
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Gupta N, Sarangi AN, Dadhich S, Dixit VK, Chetri K, Goel A, Aggarwal R. Acute hepatitis E in India appears to be caused exclusively by genotype 1 hepatitis E virus. Indian J Gastroenterol 2018; 37:44-49. [PMID: 29399748 DOI: 10.1007/s12664-018-0819-z] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2017] [Accepted: 01/02/2018] [Indexed: 02/04/2023]
Abstract
BACKGROUND Hepatitis E is caused by infection with hepatitis E virus (HEV), which has four well-known genotypes. Genotypes 1 and 2 HEV have been reported from human cases in areas where the disease is highly endemic. By contrast, genotypes 3 and 4 HEV, which primarily infect several animal species worldwide, have been reported mainly from sporadic human cases in non-endemic areas such as Japan and high-income countries of Europe and North America. To determine whether genotype 3/4 HEV cause sporadic disease in India, a disease-endemic area, we determined HEV genotype in a group of patients with such disease. METHODS A part of the HEV open reading frame (ORF) 1 was amplified and sequenced from sera of 74 patients with sporadic acute viral hepatitis E from four cities in India. The sequences were compared with prototype sequences for various HEV genotypes and subgenotypes and analyzed using phylogenetic tools to determine the genotype of the isolates. For 12 specimens, a part of HEV ORF2 was also similarly analyzed. RESULTS Partial ORF1 sequences of all the 74 isolates belonged to genotype 1 HEV, with 88.2% to 100% nucleotide identity with the prototype genotype 1 isolates. Partial ORF2 sequences for all the 12 isolates also belonged to genotype 1 HEV. On phylogenetic analysis, 71 isolates clustered with prototype genotype 1a HEV; the remaining three isolates were located between subgenotypes 1a and 1c but were closer to the former. CONCLUSION Human sporadic acute hepatitis E in India is caused almost exclusively by genotype 1 HEV.
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Affiliation(s)
- Neha Gupta
- Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Raebareli Road, Lucknow, 226 014, India
| | - Aditya N Sarangi
- Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Raebareli Road, Lucknow, 226 014, India
| | - Sunil Dadhich
- Department of Gastroenterology, Dr. Sampurnanand Medical College, Residency Road, Shastri Nagar, Jodhpur, 342 003, India
| | - V K Dixit
- Department of Gastroenterology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, 221 005, India
| | - Kamal Chetri
- International Hospital, G S Road, Guwahati, 781 005, India
| | - Amit Goel
- Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Raebareli Road, Lucknow, 226 014, India
| | - Rakesh Aggarwal
- Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Raebareli Road, Lucknow, 226 014, India.
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Detection and Characterization of Hepatitis E Virus in Goats at Slaughterhouse in Tai'an Region, China. BIOMED RESEARCH INTERNATIONAL 2017; 2017:3723650. [PMID: 29379797 PMCID: PMC5742876 DOI: 10.1155/2017/3723650] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/07/2017] [Accepted: 11/26/2017] [Indexed: 12/11/2022]
Abstract
Background Hepatitis E virus (HEV) is a significant pathogen of viral hepatitis and can be transmitted through fecal-oral route. Epidemiological data concerning HEV in goats, however, are relatively sparse to date. Here, the prevalence and characteristics of HEV isolated from goats at slaughterhouse were investigated in Tai'an region, China. Methods Anti-HEV immunoglobulin G (IgG) in blood samples and HEV RNA in the liver samples were determined by using an enzyme-linked immunosorbent assay (ELISA) and a nested reverse transcription polymerase chain reaction (RT-PCR), respectively. In addition, partial nucleotide sequences of open reading frame 2 (ORF-2) of HEV isolates were analyzed. Results Fifty goat blood samples (46.7%, 50/120) were masculine for anti-HEV IgG. HEV RNA was detected in 2 liver samples (4.0%, 2/50) and belonged to genotype 4 subtype 4 h, with high identity (91.2-93%) with cow HEV strains detected in the same province, China. Conclusions These findings demonstrated that goats may be an important reservoir for HEV and can become a major source of HEV infection in humans via food chain.
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Farhat R, Ankavay M, Lebsir N, Gouttenoire J, Jackson CL, Wychowski C, Moradpour D, Dubuisson J, Rouillé Y, Cocquerel L. Identification of GBF1 as a cellular factor required for hepatitis E virus RNA replication. Cell Microbiol 2017; 20. [PMID: 29112323 PMCID: PMC7162332 DOI: 10.1111/cmi.12804] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2017] [Revised: 10/30/2017] [Accepted: 10/31/2017] [Indexed: 12/23/2022]
Abstract
The hepatitis E virus (HEV) genome is a single‐stranded, positive‐sense RNA that encodes three proteins including the ORF1 replicase. Mechanisms of HEV replication in host cells are unclear, and only a few cellular factors involved in this step have been identified so far. Here, we used brefeldin A (BFA) that blocks the activity of the cellular Arf guanine nucleotide exchange factors GBF1, BIG1, and BIG2, which play a major role in reshuffling of cellular membranes. We showed that BFA inhibits HEV replication in a dose‐dependent manner. The use of siRNA and Golgicide A identified GBF1 as a host factor critically involved in HEV replication. Experiments using cells expressing a mutation in the catalytic domain of GBF1 and overexpression of wild type GBF1 or a BFA‐resistant GBF1 mutant rescuing HEV replication in BFA‐treated cells, confirmed that GBF1 is the only BFA‐sensitive factor required for HEV replication. We demonstrated that GBF1 is likely required for the activity of HEV replication complexes. However, GBF1 does not colocalise with the ORF1 protein, and its subcellular distribution is unmodified upon infection or overexpression of viral proteins, indicating that GBF1 is likely not recruited to replication sites. Together, our results suggest that HEV replication involves GBF1‐regulated mechanisms.
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Affiliation(s)
- Rayan Farhat
- Pasteur Institute of Lille, U1019-UMR 8204-CIIL- Center for Infection and Immunity of Lille, University of Lille, CNRS, INSERM, CHU Lille, Lille, France
| | - Maliki Ankavay
- Pasteur Institute of Lille, U1019-UMR 8204-CIIL- Center for Infection and Immunity of Lille, University of Lille, CNRS, INSERM, CHU Lille, Lille, France
| | - Nadjet Lebsir
- Pasteur Institute of Lille, U1019-UMR 8204-CIIL- Center for Infection and Immunity of Lille, University of Lille, CNRS, INSERM, CHU Lille, Lille, France
| | - Jérôme Gouttenoire
- Division of Gastroenterology and Hepatology, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland
| | - Catherine L Jackson
- Institut Jacques Monod, CNRS UMR 7592, Université Paris Diderot, Sorbonne Paris Cité, Paris, France
| | - Czeslaw Wychowski
- Pasteur Institute of Lille, U1019-UMR 8204-CIIL- Center for Infection and Immunity of Lille, University of Lille, CNRS, INSERM, CHU Lille, Lille, France
| | - Darius Moradpour
- Division of Gastroenterology and Hepatology, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland
| | - Jean Dubuisson
- Pasteur Institute of Lille, U1019-UMR 8204-CIIL- Center for Infection and Immunity of Lille, University of Lille, CNRS, INSERM, CHU Lille, Lille, France
| | - Yves Rouillé
- Pasteur Institute of Lille, U1019-UMR 8204-CIIL- Center for Infection and Immunity of Lille, University of Lille, CNRS, INSERM, CHU Lille, Lille, France
| | - Laurence Cocquerel
- Pasteur Institute of Lille, U1019-UMR 8204-CIIL- Center for Infection and Immunity of Lille, University of Lille, CNRS, INSERM, CHU Lille, Lille, France
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Long F, Yu W, Yang C, Wang J, Li Y, Li Y, Huang F. High prevalence of hepatitis E virus infection in goats. J Med Virol 2017; 89:1981-1987. [PMID: 28464334 DOI: 10.1002/jmv.24843] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2016] [Accepted: 03/28/2017] [Indexed: 12/27/2022]
Abstract
Hepatitis E virus (HEV) is a major cause of acute hepatitis worldwide, primarily transmitted by fecal-oral route. Zoonotic transmission of HEV from HEV-infected pigs (pork) or cows (milk) to human or non-human primate has been confirmed, but the risk of HEV in goat is still rarely assessed. In the present study, stool, blood, tissues, and milk of goat were collected for HEV infection investigation from Dali City of Yunnan Province in China, where raw mutton and goat milk are traditionally consumed. Surprisingly, a high prevalence of HEV infection in goat was found. Phylogenetic analysis revealed that all HEV isolates from goat belong to genotype 4 and subtype 4h, and shared a high similarity homology (>99.6%) with HEV isolated from human, swine, and cows in the same area. Results suggested that goats are a previously unrecognized HEV host.
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Affiliation(s)
- Feiyan Long
- Medical Faculty, Kunming University of Science and Technology, Kunming, P.R. China
| | - Wenhai Yu
- Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming, P.R. China
| | - Chenchen Yang
- Medical Faculty, Kunming University of Science and Technology, Kunming, P.R. China
| | - Jue Wang
- Medical Faculty, Kunming University of Science and Technology, Kunming, P.R. China
| | - Yunlong Li
- Medical Faculty, Kunming University of Science and Technology, Kunming, P.R. China
| | - Yi Li
- Agriculture and Biotechnology, Shanghai Jiaotong University, Shanghai, P.R. China
| | - Fen Huang
- Medical Faculty, Kunming University of Science and Technology, Kunming, P.R. China
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Parvez MK. The hepatitis E virus nonstructural polyprotein. Future Microbiol 2017; 12:915-924. [PMID: 28686042 DOI: 10.2217/fmb-2017-0016] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2017] [Accepted: 04/24/2017] [Indexed: 12/19/2022] Open
Abstract
Hepatitis E virus (HEV) is a globally important pathogen of acute and chronic hepatitis in humans. The HEV ORF1 gene encodes a nonstructural polyprotein, essential for RNA replication and virus infectivity. Expression and processing of ORF1 polyprotein are shown in prokaryotic and eukaryotic systems, however, its proteolysis into individual proteins is still debated. While molecular or biochemical characterization of methyltransferase, protease, hypervariable region, helicase and RNA polymerase domains in ORF1 has been achieved, the role of the X and Y domains in the HEV life cycle has only been demonstrated very recently. Clinically, detection of a number of ORF1 mutants in infected patients is implicated in disease severity, mortality and drug nonresponse. Moreover, several artificial lethal mutations in ORF1 offer a potential basis for developing live-attenuated vaccines for HEV. This article intends to present the molecular and clinical updates on the HEV ORF1 polyprotein.
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Affiliation(s)
- Mohammad Khalid Parvez
- Department of Pharmacognosy, King Saud University College of Pharmacy, Riyadh 11451, Saudi Arabia
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Donnelly MC, Scobie L, Crossan CL, Dalton H, Hayes PC, Simpson KJ. Review article: hepatitis E-a concise review of virology, epidemiology, clinical presentation and therapy. Aliment Pharmacol Ther 2017; 46:126-141. [PMID: 28449246 DOI: 10.1111/apt.14109] [Citation(s) in RCA: 62] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2016] [Revised: 12/21/2016] [Accepted: 03/30/2017] [Indexed: 12/13/2022]
Abstract
BACKGROUND Hepatitis E virus (HEV) is a leading cause of acute icteric hepatitis and acute liver failure in the developing world. During the last decade, there has been increasing recognition of autochthonous (locally acquired) HEV infection in developed countries. Chronic HEV infection is now recognised, and in transplant recipients this may lead to cirrhosis and organ failure. AIM To detail current understanding of the molecular biology of HEV, diagnostic and therapeutic strategies and propose future directions for basic science and clinical research. METHODS PubMed was searched for English language articles using the key words "hepatitis E", "viral hepatitis", "autochthonous infection", "antiviral therapy", "liver transplantation", "acute", "chronic", "HEV", "genotype", "transmission" "food-borne", "transfusion". Additional relevant publications were identified from article reference lists. RESULTS There has been increasing recognition of autochthonous HEV infection in Western countries, mainly associated with genotype 3. Chronic HEV infection has been recognised since 2008, and in transplant recipients this may lead to cirrhosis and organ failure. Modes of transmission include food-borne transmission, transfusion of blood products and solid organ transplantation. Ribavirin therapy is used to treat patients with chronic HEV infection, but new therapies are required as there have been reports of treatment failure with ribavirin. CONCLUSIONS Autochthonous HEV infection is a clinical issue with increasing burden. Future work should focus on increasing awareness of HEV infection in the developed world, emphasising the need for clinicians to have a low threshold for HEV testing, particularly in immunosuppressed patients. Patients at potential risk of chronic HEV infection must also be educated and given advice regarding prevention of infection.
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Affiliation(s)
- M C Donnelly
- Department of Hepatology and Scottish Liver Transplant Unit, University of Edinburgh, Royal Infirmary of Edinburgh, Edinburgh, UK
| | - L Scobie
- Department of Biological and Biomedical Sciences, Glasgow Caledonian University, Glasgow, UK
| | - C L Crossan
- Department of Biological and Biomedical Sciences, Glasgow Caledonian University, Glasgow, UK
| | - H Dalton
- Royal Cornwall Hospital Trust and European Centre for Environment and Human Health, University of Exeter, Truro, UK
| | - P C Hayes
- Department of Hepatology and Scottish Liver Transplant Unit, University of Edinburgh, Royal Infirmary of Edinburgh, Edinburgh, UK
| | - K J Simpson
- Department of Hepatology and Scottish Liver Transplant Unit, University of Edinburgh, Royal Infirmary of Edinburgh, Edinburgh, UK
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Amanya G, Kizito S, Nabukenya I, Kalyango J, Atuheire C, Nansumba H, Abwoye SA, Opio DN, Kibuuka E, Karamagi C. Risk factors, person, place and time characteristics associated with Hepatitis E Virus outbreak in Napak District, Uganda. BMC Infect Dis 2017; 17:451. [PMID: 28651629 PMCID: PMC5485539 DOI: 10.1186/s12879-017-2542-2] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2017] [Accepted: 06/09/2017] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Hepatitis E is self-limiting, but can cause death in most at risk groups like pregnant women and those with preexisting acute liver disease. In developing countries it presents as epidemic, in 2014 Hepatitis E Virus (HEV) outbreak was reported in Napak district Uganda. The role of factors in this setting that might have propagated this HEV epidemic, including host, agent, and environmental characteristics, were still not clear. This study was therefore conducted to investigate the risk factors, person, place and time characteristics, associated with the hepatitis E virus (HEV) epidemic in Napak district. METHODS Review of line lists data for epidemiological description and matched case control study on neighborhood and age in the ratio of 1:2 were used to assess risk factors for HEV outbreak in Napak. Cluster and random sampling were used to obtain a sample size of 332, (111 cases, 221 controls). Possible interaction and confounding was assessed using conditional logistic regression. RESULTS Over 1359 cases and 30 deaths were reported during 2013/2014 HEV outbreak. The mean age of patients was 29 ± years, 57.9% of cases were females. Overall case Fatality Ratio was 2.2% in general population but 65.2% in pregnant women. More than 94% of the cases were reported in the sub counties of Napak, 5.7% of cases were reported in the outside neighboring districts. The epidemic peaked in January 2014 and gradually subsided by December 2014. Risk factors found to be associated with HEV included drinking untreated water (OR 6.69, 95% CI 3.15-14.16), eating roadside food (OR 6.11, 95% CI 2.85-13.09), reported not cleaning utensils (OR 3.24, 95% CI 1.55-1.76), and being a hunter (OR 1.14, 95% CI 1.03-12.66). CONCLUSION The results of this study suggest that the virus is transmitted by the feco-oral route through contaminated water. They also suggest that active surveillance and appropriate measures targeting community and routine individual health actions are important to prevent transmission and decrease the deaths.
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Affiliation(s)
- Geofrey Amanya
- Clinical Epidemiology Unit, School of Medicine, P.O Box 7072, Kampala, Uganda
| | - Samuel Kizito
- Clinical Epidemiology Unit, School of Medicine, P.O Box 7072, Kampala, Uganda
- Makerere University College of Health Sciences, P.O Box 7072, Kampala, Uganda
| | - Immaculate Nabukenya
- Epidemiology and surveillance Division, Ministry Of Health, P.O Box 7076, Kampala, Uganda
| | - Joan Kalyango
- Clinical Epidemiology Unit, School of Medicine, P.O Box 7072, Kampala, Uganda
- Makerere University College of Health Sciences, P.O Box 7072, Kampala, Uganda
| | - Collins Atuheire
- Clinical Epidemiology Unit, School of Medicine, P.O Box 7072, Kampala, Uganda
| | - Hellen Nansumba
- Clinical Epidemiology Unit, School of Medicine, P.O Box 7072, Kampala, Uganda
| | | | - Denis Nixon Opio
- Clinical Epidemiology Unit, School of Medicine, P.O Box 7072, Kampala, Uganda
| | - Edrisa Kibuuka
- Clinical Epidemiology Unit, School of Medicine, P.O Box 7072, Kampala, Uganda
| | - Charles Karamagi
- Clinical Epidemiology Unit, School of Medicine, P.O Box 7072, Kampala, Uganda
- Makerere University College of Health Sciences, P.O Box 7072, Kampala, Uganda
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Parvez MK. Mutational analysis of hepatitis E virus ORF1 "Y-domain": Effects on RNA replication and virion infectivity. World J Gastroenterol 2017; 23:590-602. [PMID: 28216965 PMCID: PMC5292332 DOI: 10.3748/wjg.v23.i4.590] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2016] [Revised: 12/05/2016] [Accepted: 01/04/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the role of non-structural open reading frame 1 "Y-domain" sequences in the hepatitis E virus (HEV) life cycle. METHODS Sequences of human HEV Y-domain (amino acid sequences 216-442) and closely-related viruses were analyzed in silico. Site-directed mutagenesis of the Y-domain (HEV SAR55) was carried out and studied in the replicon-baculovirus-hepatoma cell model. In vitro transcribed mRNA (pSK-GFP) constructs were transfected into S10-3 cells and viral RNA replicating GFP-positive cells were scored by flow cytometry. Mutant virions' infectivity was assayed on naïve HepG2/C3A cells. RESULTS In silico analysis identified a potential palmitoylation-site (C336C337) and an α-helix segment (L410Y411S412W413L414F415E416) in the HEV Y-domain. Molecular characterization of C336A, C337A and W413A mutants of the three universally conserved residues showed non-viability. Further, of the 10 consecutive saturation mutants covering the entire Y-domain nucleotide sequences (nts 650-1339), three constructs (nts 788-994) severely affected virus replication. This revealed the indispensability of the internal sequences but not of the up- or downstream sequences at the transcriptional level. Interestingly, the three mutated residues corresponded to the downstream codons that tolerated saturation mutation, indicating their post-translational functional/structural essentiality. In addition, RNA secondary structure prediction revealed formation of stable hairpins (nts 788-994) where saturation mutation drastically inhibited virion infectivity. CONCLUSION This is the first demonstration of the critical role of Y-domain sequences in HEV life cycle, which may involve gene regulation and/or membrane binding in intracellular replication complexes.
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Tian Y, Huang W, Yang J, Wen Z, Geng Y, Zhao C, Zhang H, Wang Y. Systematic identification of hepatitis E virus ORF2 interactome reveals that TMEM134 engages in ORF2-mediated NF-κB pathway. Virus Res 2017; 228:102-108. [PMID: 27899274 DOI: 10.1016/j.virusres.2016.11.027] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2016] [Revised: 11/18/2016] [Accepted: 11/18/2016] [Indexed: 01/08/2023]
Abstract
Hepatitis E virus (HEV) is the causative agent of acute hepatitis E. Open reading frame 2 (ORF2) encodes the capsid protein of HEV, which is the main structural protein and may participate, together with the host factors, in viral entry and egress. However, it is still not clear which host proteins are involved in the interaction with ORF2 and what the functions of these ORF2-interacting proteins are. In this study, we have applied a split-ubiquitin yeast two-hybrid screening approach in combination with the pull-down and coimmunoprecipitation assays, identified and validated multiple interacting partners of ORF2 of genotype 1 and 4, which have diverse biological functions. Among these novel candidates that have not been previously reported, we have found that 20 of them are located in endoplasmic reticulum. TMEM134, which interacts and co-localizes with ORF2 in the endoplasmic reticulum, negatively regulates ORF2-mediated inhibition of the NF-κB signaling pathway. Our study for the first time has systematically mapped the ORF2 interactome in two genotypes of HEV, providing a new insight of understanding the virus-host interaction during the pathogenesis of HEV, and may offer potential therapeutic targets to intervene the HEV life cycle.
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Affiliation(s)
- Yabin Tian
- Key Laboratory of the Ministry of Health for Research on Quality and Standardization of Biotech Products, Division of HIV/AIDS and Sexually Transmitted Virus Vaccines, National Institutes for Food and Drug Control, No. 2 Tiantanxili, Beijing 100050, China.
| | - Weijin Huang
- Key Laboratory of the Ministry of Health for Research on Quality and Standardization of Biotech Products, Division of HIV/AIDS and Sexually Transmitted Virus Vaccines, National Institutes for Food and Drug Control, No. 2 Tiantanxili, Beijing 100050, China.
| | - Jun Yang
- Department of Surgery, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38015, USA.
| | - Zhiheng Wen
- Key Laboratory of the Ministry of Health for Research on Quality and Standardization of Biotech Products, Division of HIV/AIDS and Sexually Transmitted Virus Vaccines, National Institutes for Food and Drug Control, No. 2 Tiantanxili, Beijing 100050, China.
| | - Yansheng Geng
- Health Science Center, Hebei University, No. 342 Yuhuadonglu, Baoding 071000, China.
| | - Chenyan Zhao
- Key Laboratory of the Ministry of Health for Research on Quality and Standardization of Biotech Products, Division of HIV/AIDS and Sexually Transmitted Virus Vaccines, National Institutes for Food and Drug Control, No. 2 Tiantanxili, Beijing 100050, China.
| | - Heqiu Zhang
- Department of Bio-diagnosis, Institute of Basic Medical Sciences, 27, Taiping Road, Beijing 100850, China.
| | - Youchun Wang
- Key Laboratory of the Ministry of Health for Research on Quality and Standardization of Biotech Products, Division of HIV/AIDS and Sexually Transmitted Virus Vaccines, National Institutes for Food and Drug Control, No. 2 Tiantanxili, Beijing 100050, China.
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Kodani M, Kamili NA, Tejada-Strop A, Poe A, Denniston MM, Drobeniuc J, Kamili S. Variability in the performance characteristics of IgG anti-HEV assays and its impact on reliability of seroprevalence rates of hepatitis E. J Med Virol 2016; 89:1055-1061. [DOI: 10.1002/jmv.24741] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2016] [Revised: 10/26/2016] [Accepted: 12/02/2016] [Indexed: 12/27/2022]
Affiliation(s)
- Maja Kodani
- Division of Viral Hepatitis, National Center for HIV, Hepatitis, STDs, and TB Prevention; Centers for Disease Control and Prevention; Atlanta Georgia
| | - Nourine A. Kamili
- Division of Viral Hepatitis, National Center for HIV, Hepatitis, STDs, and TB Prevention; Centers for Disease Control and Prevention; Atlanta Georgia
| | - Alexandra Tejada-Strop
- Division of Viral Hepatitis, National Center for HIV, Hepatitis, STDs, and TB Prevention; Centers for Disease Control and Prevention; Atlanta Georgia
| | - Amanda Poe
- Division of Viral Hepatitis, National Center for HIV, Hepatitis, STDs, and TB Prevention; Centers for Disease Control and Prevention; Atlanta Georgia
| | - Maxine M. Denniston
- Division of Viral Hepatitis, National Center for HIV, Hepatitis, STDs, and TB Prevention; Centers for Disease Control and Prevention; Atlanta Georgia
| | - Jan Drobeniuc
- Division of Viral Hepatitis, National Center for HIV, Hepatitis, STDs, and TB Prevention; Centers for Disease Control and Prevention; Atlanta Georgia
| | - Saleem Kamili
- Division of Viral Hepatitis, National Center for HIV, Hepatitis, STDs, and TB Prevention; Centers for Disease Control and Prevention; Atlanta Georgia
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Todt D, Gisa A, Radonic A, Nitsche A, Behrendt P, Suneetha PV, Pischke S, Bremer B, Brown RJP, Manns MP, Cornberg M, Bock CT, Steinmann E, Wedemeyer H. In vivo evidence for ribavirin-induced mutagenesis of the hepatitis E virus genome. Gut 2016; 65:1733-1743. [PMID: 27222534 PMCID: PMC5036239 DOI: 10.1136/gutjnl-2015-311000] [Citation(s) in RCA: 145] [Impact Index Per Article: 16.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2015] [Revised: 03/24/2016] [Accepted: 04/10/2016] [Indexed: 12/12/2022]
Abstract
OBJECTIVE Hepatitis E virus (HEV) infection can take chronic courses in immunocompromised patients potentially leading to liver cirrhosis and liver failure. Ribavirin (RBV) is currently the only treatment option for many patients, but treatment failure can occur which has been associated with the appearance of a distinct HEV polymerase mutant (G1634R). Here, we performed a detailed analysis of HEV viral intrahost evolution during chronic hepatitis E infections. DESIGN Illumina deep sequencing was performed for the detection of intrahost variation in the HEV genome of chronically infected patients. Novel polymerase mutants were investigated in vitro using state-of-the-art HEV cell culture models. RESULTS Together, these data revealed that (1) viral diversity differed markedly between patients but did not show major intraindividual short-term variations in untreated patients with chronic hepatitis E, (2) RBV therapy was associated with an increase in viral heterogeneity which was reversible when treatment was stopped, (3) the G1634R mutant was detectable as a minor population prior to therapy in patients who subsequently failed to achieve a sustained virological response to RBV therapy and (4) in addition to G1634R further dominant variants in the polymerase region emerged, impacting HEV replication efficiency in vitro. CONCLUSIONS In summary, this first investigation of intrahost HEV population evolution indicates that RBV causes HEV mutagenesis in treated patients and that an emergence of distinct mutants within the viral population occurs during RBV therapy. We also suggest that next-generation sequencing could be useful to guide personalised antiviral strategies.
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Affiliation(s)
- Daniel Todt
- Institute of Experimental Virology, Twincore, Centre for Experimental and Clinical Infection Research; a joint venture between the Medical School Hannover (MHH) and the Helmholtz Centre for Infection Research (HZI), Hannover, Germany
| | - Anett Gisa
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Aleksandar Radonic
- Division of Highly Pathogenic Viruses, Robert-Koch-Institut, Centre for Biological Threats and Special Pathogens, Berlin, Germany
| | - Andreas Nitsche
- Division of Highly Pathogenic Viruses, Robert-Koch-Institut, Centre for Biological Threats and Special Pathogens, Berlin, Germany
| | - Patrick Behrendt
- Institute of Experimental Virology, Twincore, Centre for Experimental and Clinical Infection Research; a joint venture between the Medical School Hannover (MHH) and the Helmholtz Centre for Infection Research (HZI), Hannover, Germany
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | | | - Sven Pischke
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
- First Medical Center, University Hospital Hamburg-Eppendorf, Hamburg, Germany
| | - Birgit Bremer
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Richard J P Brown
- Institute of Experimental Virology, Twincore, Centre for Experimental and Clinical Infection Research; a joint venture between the Medical School Hannover (MHH) and the Helmholtz Centre for Infection Research (HZI), Hannover, Germany
| | - Michael P Manns
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
- German Center for Infectious Disease Research (DZIF), Partnersite Hannover-Braunschweig, Germany
| | - Markus Cornberg
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
- German Center for Infectious Disease Research (DZIF), Partnersite Hannover-Braunschweig, Germany
| | - C Thomas Bock
- Division of Viral Gastroenteritis, Hepatitis Pathogens and Enteroviruses, Department of Infectious Diseases,Robert-Koch-Institut, Berlin, Germany
| | - Eike Steinmann
- Institute of Experimental Virology, Twincore, Centre for Experimental and Clinical Infection Research; a joint venture between the Medical School Hannover (MHH) and the Helmholtz Centre for Infection Research (HZI), Hannover, Germany
| | - Heiner Wedemeyer
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
- German Center for Infectious Disease Research (DZIF), Partnersite Hannover-Braunschweig, Germany
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Khuroo MS, Khuroo MS, Khuroo NS. Transmission of Hepatitis E Virus in Developing Countries. Viruses 2016; 8:253. [PMID: 27657112 PMCID: PMC5035967 DOI: 10.3390/v8090253] [Citation(s) in RCA: 110] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2016] [Revised: 09/08/2016] [Accepted: 09/08/2016] [Indexed: 12/11/2022] Open
Abstract
Hepatitis E virus (HEV), an RNA virus of the Hepeviridae family, has marked heterogeneity. While all five HEV genotypes can cause human infections, genotypes HEV-1 and -2 infect humans alone, genotypes HEV-3 and -4 primarily infect pigs, boars and deer, and genotype HEV-7 primarily infects dromedaries. The global distribution of HEV has distinct epidemiological patterns based on ecology and socioeconomic factors. In resource-poor countries, disease presents as large-scale waterborne epidemics, and few epidemics have spread through person-to-person contact; however, endemic diseases within these countries can potentially spread through person-to-person contact or fecally contaminated water and foods. Vertical transmission of HEV from infected mother to fetus causes high fetal and perinatal mortality. Other means of transmission, such as zoonotic transmission, can fluctuate depending upon the region and strain of the virus. For instance, zoonotic transmission can sometimes play an insignificant role in human infections, such as in India, where human and pig HEV infections are unrelated. However, recently China and Southeast Asia have experienced a zoonotic spread of HEV-4 from pigs to humans and this has become the dominant mode of transmission of hepatitis E in eastern China. Zoonotic HEV infections in humans occur by eating undercooked pig flesh, raw liver, and sausages; through vocational contact; or via pig slurry, which leads to environmental contamination of agricultural products and seafood. Lastly, blood transfusion-associated HEV infections occur in many countries and screening of donors for HEV RNA is currently under serious consideration. To summarize, HEV genotypes 1 and 2 cause epidemic and endemic diseases in resource poor countries, primarily spreading through contaminated drinking water. HEV genotypes 3 and 4 on the other hand, cause autochthonous infections in developed, and many developing countries, by means of a unique zoonotic food-borne transmission.
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Affiliation(s)
- Mohammad S Khuroo
- Sher-I-Kashmir Institute of Medical Sciences, Srinagar, Kashmir 190001, India.
- Digestive Diseases Centre, Dr. Khuroo's Medical Clinic, Srinagar, Kashmir 190010, India.
| | - Mehnaaz S Khuroo
- Department of Pathology, Government Medical College, Srinagar, Kashmir 190001, India.
| | - Naira S Khuroo
- Digestive Diseases Centre, Dr. Khuroo's Medical Clinic, Srinagar, Kashmir 190010, India.
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Roth A, Lin J, Magnius L, Karlsson M, Belák S, Widén F, Norder H. Markers for Ongoing or Previous Hepatitis E Virus Infection Are as Common in Wild Ungulates as in Humans in Sweden. Viruses 2016; 8:E259. [PMID: 27657108 PMCID: PMC5035973 DOI: 10.3390/v8090259] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2016] [Revised: 08/30/2016] [Accepted: 09/13/2016] [Indexed: 12/18/2022] Open
Abstract
Hepatitis E virus (HEV) is a human pathogen with zoonotic spread, infecting both domestic and wild animals. About 17% of the Swedish population is immune to HEV, but few cases are reported annually, indicating that most infections are subclinical. However, clinical hepatitis E may also be overlooked. For identified cases, the source of infection is mostly unknown. In order to identify whether HEV may be spread from wild game, the prevalence of markers for past and/or ongoing infection was investigated in sera and stool samples collected from 260 hunted Swedish wild ungulates. HEV markers were found in 43 (17%) of the animals. The most commonly infected animal was moose (Alces alces) with 19 out of 69 animals (28%) showing HEV markers, followed by wild boar (Sus scrofa) with 21 out of 139 animals (15%), roe deer (Capreolus capreolus) with 2 out of 30 animals, red deer (Cervus elaphus) with 1 out of 15 animals, and fallow deer (Dama dama) 0 out of 7 animals. Partial open reading frame 1 (ORF1) of the viral genomes from the animals were sequenced and compared with those from 14 endemic human cases. Phylogenetic analysis revealed that three humans were infected with HEV strains similar to those from wild boar. These results indicate that wild animals may be a source of transmission to humans and could be an unrecognized public health concern.
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Affiliation(s)
- Anette Roth
- Department of Infectious Diseases, Institute of Biomedicine, University of Gothenburg, 413 46 Gothenburg, Sweden.
| | - Jay Lin
- Department of Virology, Microbiology, National Veterinary Institute, 756 51 Uppsala, Sweden.
- Department of Biomedical Science and Veterinary Public Health, Swedish University of Agricultural Sciences (SLU), 756 51 Uppsala, Sweden.
- The OIE (World Organisation for Animal Health) Collaborating Centre for the Biotechnology-Based Diagnosis of Infectious Diseases in Veterinary Medicine, 756 51 Uppsala, Sweden.
| | - Lars Magnius
- Ulf Lundahl Foundation, 116 21 Stockholm, Sweden.
| | - Marie Karlsson
- Department of Infectious Diseases, Institute of Biomedicine, University of Gothenburg, 413 46 Gothenburg, Sweden.
| | - Sándór Belák
- Department of Biomedical Science and Veterinary Public Health, Swedish University of Agricultural Sciences (SLU), 756 51 Uppsala, Sweden.
- The OIE (World Organisation for Animal Health) Collaborating Centre for the Biotechnology-Based Diagnosis of Infectious Diseases in Veterinary Medicine, 756 51 Uppsala, Sweden.
| | - Frederik Widén
- Department of Virology, Microbiology, National Veterinary Institute, 756 51 Uppsala, Sweden.
- Department of Biomedical Science and Veterinary Public Health, Swedish University of Agricultural Sciences (SLU), 756 51 Uppsala, Sweden.
- The OIE (World Organisation for Animal Health) Collaborating Centre for the Biotechnology-Based Diagnosis of Infectious Diseases in Veterinary Medicine, 756 51 Uppsala, Sweden.
| | - Heléne Norder
- Department of Infectious Diseases, Institute of Biomedicine, University of Gothenburg, 413 46 Gothenburg, Sweden.
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50
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Nan Y, Zhang YJ. Molecular Biology and Infection of Hepatitis E Virus. Front Microbiol 2016; 7:1419. [PMID: 27656178 PMCID: PMC5013053 DOI: 10.3389/fmicb.2016.01419] [Citation(s) in RCA: 71] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2016] [Accepted: 08/26/2016] [Indexed: 12/13/2022] Open
Abstract
Hepatitis E virus (HEV) is a viral pathogen transmitted primarily via fecal-oral route. In humans, HEV mainly causes acute hepatitis and is responsible for large outbreaks of hepatitis across the world. The case fatality rate of HEV-induced hepatitis ranges from 0.5 to 3% in young adults and up to 30% in infected pregnant women. HEV strains infecting humans are classified into four genotypes. HEV strains from genotypes 3 and 4 are zoonotic, whereas those from genotypes 1 and 2 have no known animal reservoirs. Recently, notable progress has been accomplished for better understanding of HEV biology and infection, such as chronic HEV infection, in vitro cell culture system, quasi-enveloped HEV virions, functions of the HEV proteins, mechanism of HEV antagonizing host innate immunity, HEV pathogenesis and vaccine development. However, further investigation on the cross-species HEV infection, host tropism, vaccine efficacy, and HEV-specific antiviral strategy is still needed. This review mainly focuses on molecular biology and infection of HEV and offers perspective new insight of this enigmatic virus.
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Affiliation(s)
- Yuchen Nan
- Department of Preventive Veterinary Medicine, College of Veterinary Medicine, Northwest A&F UniversityYangling, China; Molecular Virology Laboratory, VA-MD College of Veterinary Medicine and Maryland Pathogen Research Institute, University of Maryland, College Park, College ParkMD, USA
| | - Yan-Jin Zhang
- Molecular Virology Laboratory, VA-MD College of Veterinary Medicine and Maryland Pathogen Research Institute, University of Maryland, College Park, College Park MD, USA
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