Chapter 30
Structure and Molecular Virology
Xiang-Jin Meng,
Xiang-Jin Meng
Center for Molecular Medicine and Infectious Diseases, Department of Biomedical Sciences and Pathobiology, Virginia Polytechnic Institute and State University (Virginia Tech), Blacksburg, VA, USA
Search for more papers by this authorXiang-Jin Meng,
Xiang-Jin Meng
Center for Molecular Medicine and Infectious Diseases, Department of Biomedical Sciences and Pathobiology, Virginia Polytechnic Institute and State University (Virginia Tech), Blacksburg, VA, USA
Search for more papers by this authorBook Editor(s):Howard C. Thomas BSc, PhD, FRCP, FRCPath, FMedSci,
Anna S.F. Lok MD,
Stephen A. Locarnini MBBS, BSc(Hons), PhD, FRCPath,
Arie J. Zuckerman MD, DSc, FRCP, FRCPath, FMedSci,
Howard C. Thomas BSc, PhD, FRCP, FRCPath, FMedSci
Emeritus Professor of Hepatology, Department of Medicine, Imperial College London, London, UK
Search for more papers by this authorAnna S.F. Lok MD
Alice Lohrman Andrews Research Professor in Hepatology, Director of Clinical Hepatology, Professor of Internal Medicine, Associate Chair for Clinical Research, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI, USA
Search for more papers by this authorStephen A. Locarnini MBBS, BSc(Hons), PhD, FRCPath
Head, Research & Molecular Development, Victorian Infectious Diseases Reference Laboratory, Melbourne, VIC, Australia
Search for more papers by this authorArie J. Zuckerman MD, DSc, FRCP, FRCPath, FMedSci
Emeritus Professor of Medical Microbiology, Formerly Principal and Dean, Royal Free Hospital School of Medicine
Search for more papers by this authorFirst published: 26 July 2013
Summary
Hepatitis E virus (HEV), the causative agent of hepatitis E, belongs to the family Hepeviridae. At least four recognized and two putative genotypes of mammalian HEV have been reported. Besides humans, strains of HEV have also been genetically identified from swine, chickens, sika deer, mongoose, rabbits, and fish. The genome of HEV consists of three open reading frames (ORFs): ORF1 codes for nonstructural proteins involved in virus replication, ORF2 codes for capsid protein that elicits neutralizing antibodies and is the target for vaccine development, and ORF3 codes for a small multifunctional protein involved in virion morphogenesis and viral pathogenesis. ORF2 and ORF3 are translated from a single bicistronic mRNA and overlap each other, but neither overlaps ORF1. Determination of the 3D crystal structure of HEV capsid protein should facilitate the development of vaccines and antivirals. The taxonomy and genomic organization, gene expression and functions, 3D structure of the virions, and life cycle of HEV replication are discussed.
References
- Meng XJ. Hepatitis E virus (hepevirus). In: BWJ van Mahy MHV Regenmortel, editors. Encyclopedia of Virology, 3rd ed. 5 vols. Oxford: Elsevier, 2008; pp. 377–383.
- Emerson SU, Purcell RH. Hepatitis E virus. In: DM Knipe, PM Howley, editors. Fields Virology, 5th ed. Philadelphia: Lippincott Williams & Wilkins, 2007; pp. 3047–3058.
- Meng XJ. Recent advances in hepatitis E virus. J Viral Hepat 2010; 17: 153–161.
- Meng XJ. Hepatitis E virus: animal reservoirs and zoonotic risk. Vet Microbiol 2010; 140: 256–265.
- Meng XJ. Hepatitis E as a zoonosis. In: H Thomas, A Zuckermann, S Lemon, editors. Viral Hepatitis, 3rd ed. Oxford: Blackwell Publishing Ltd, 2006; pp. 611–623.
- Meng XJ, Anderson DA, Arankalle VA, et al. Hepeviridae. In: AMQ King, E. Carstens, M. Adams, E. Lefkowitz, editors. Virus Taxonomy: 9th Report of the International Committee on Taxonomy of Viruses. London: Elsevier/Academic Press, 2012; pp. 1021–1028.
- Ahmad I, Holla RP, Jameel S. Molecular virology of hepatitis E virus. Virus Res 2011; 161: 47–58.
- Mori Y, Matsuura Y. Structure of hepatitis E viral particle. Virus Res 2011; 161: 59–64.
- Haqshenas G, Shivaprasad HL, Woolcock PR, Read DH, Meng XJ. Genetic identification and characterization of a novel virus related to human hepatitis E virus from chickens with hepatitis-splenomegaly syndrome in the United States. J Gen Virol 2001; 82: 2449–2462.
- Meng XJ, Shivaprasad HL, Payne C. Hepatitis E virus infections. In: YM Saif, AM Fadly, JR Glisson, LR McDougald, LK Nolan, DE Swayne, editors. Disease of Poultry, 12th ed. Oxford: Blackwell Publishing Ltd, 2007; pp. 443–452.
- Emerson SU, Arankalle VA, Purcell RH. Thermal stability of hepatitis E virus. J Infect Dis 2005; 192: 930–933.
- Zhao C, Ma Z, Harrison TJ, et al. A novel genotype of hepatitis E virus prevalent among farmed rabbits in China. J Med Virol 2009; 81: 1371–1379.
- Cossaboom CM, Cordoba L, Dryman BA, Meng XJ. 2011. Hepatitis E virus in rabbits, Virginia, USA. Emerg Infect Dis 2011; 17: 2047–2049.
- Johne R, Plenge-Bönig A, Hess M, Ulrich RG, Reetz J, Schielke A. Detection of a novel hepatitis E-like virus in faeces of wild rats using a nested broad-spectrum RT-PCR. J Gen Virol 2010; 91: 750–758.
- Purcell RH, Engle RE, Rood MP, et al. Hepatitis E virus in rats, Los Angeles, California, USA. Emerg Infect Dis 2011; 17: 2216–2222.
- Takahashi M, Nishizawa T, Sato H, et al. Analysis of the full-length genome of a hepatitis E virus isolate obtained from a wild boar in Japan that is classifiable into a novel genotype. J Gen Virol 2011; 92: 902–908.
- Bilic I, Jaskulska B, Basic A, Morrow CJ, Hess M. Sequence analysis and comparison of avian hepatitis E viruses from Australia and Europe indicate the existence of different genotypes. J Gen Virol 2009; 90: 863–873.
- Batts W, Yun S, Hedrick R, Winton J. A novel member of the family Hepeviridae from cutthroat trout (Oncorhynchus clarkii). Virus Res 2011; 158: 116–123.
- van Cuyck H, Fan J, Robertson DL, Roques P. Evidence of recombination between divergent hepatitis E viruses. J Virol 2005; 79: 9306–9314.
- Wang H, Zhang W, Ni B, et al. Recombination analysis reveals a double recombination event in hepatitis E virus. Virol J 2010; 7: 129.
- Fan J. Open reading frame structure analysis as a novel genotyping tool for hepatitis E virus and the subsequent discovery of an inter-genotype recombinant. J Gen Virol 2009; 90: 1353–1358.
- Feagins AR, Córdoba L, Sanford BJ, et al. Intergenotypic chimeric hepatitis E viruses (HEVs) with the genotype 4 human HEV capsid gene in the backbone of genotype 3 swine HEV are infectious in pigs. Virus Res 2011; 156: 141–146.
- Huang YW, Opriessnig T, Halbur PG, Meng XJ. Initiation at the third in-frame AUG codon of open reading frame 3 of the hepatitis E virus is essential for viral infectivity in vivo. J Virol 2007; 81: 3018–3026.
- Emerson SU, Zhang M, Meng XJ, et al. Recombinant hepatitis E virus genomes infectious for primates: importance of capping and discovery of a cis-reactive element. Proc Natl Acad Sci USA 2001; 98: 15270–15275.
- Huang YW, Haqshenas G, Kasorndorkbua C, Halbur PG, Emerson SU, Meng XJ. Capped RNA transcripts of full-length cDNA clones of swine hepatitis E virus are replication competent when transfected into Huh7 cells and infectious when intrahepatically inoculated into pigs. J Virol 2005; 79: 1552–1528.
- Graff J, Nguyen H, Yu C, et al. The open reading frame 3 gene of hepatitis E virus contains a cis-reactive element and encodes a protein required for infection of macaques. J Virol 2005; 79: 6680–6689.
- Cao D, Huang YW, Meng XJ. The nucleotides on the stem-loop RNA structure in the junction region of the hepatitis E virus genome are critical for virus replication. J Virol 2010; 84: 13040–13044.
- Haqshenas G, Huang FF, Fenaux M, et al. The putative capsid protein of the newly identified avian hepatitis E virus shares antigenic epitopes with that of swine and human hepatitis E viruses and chicken big liver and spleen disease virus. J Gen Virol 2002; 83: 2201–2209.
- Karpe YA, Lole KS. NTPase and 5′ to 3′ RNA duplex-unwinding activities of the hepatitis E virus helicase domain. J Virol 2010; 84: 3595–3602.
- Karpe YA, Lole KS. RNA 5′-triphosphatase activity of the hepatitis E virus helicase domain. J Virol 2010; 84: 9637–9641.
- Karpe YA, Lole KS. Deubiquitination activity associated with hepatitis E virus putative papain-like cysteine protease. J Gen Virol 2011; 92: 2088–2092.
- Pudupakam RS, Huang YW, Opriessnig T, Halbur PG, Pierson FW, Meng XJ. Deletions of the hypervariable region (HVR) in open reading frame 1 of hepatitis E virus do not abolish virus infectivity: evidence for attenuation of HVR deletion mutants in vivo. J Virol 2009; 83: 384–395.
- Pudupakam RS, Kenney SP, Córdoba L, et al. Mutational analysis of the hypervariable region of the hepatitis E virus reveals its involvement in the efficiency of viral RNA replication. J Virol 2011; 85: 10031–10040.
- Shukla P, Nguyen HT, Torian U, et al. Cross-species infections of cultured cells by hepatitis E virus and discovery of an infectious virus-host recombinant. Proc Natl Acad Sci USA 2011; 108: 2438–2443.
- Zafrullah M, Ozdener MH, Kumar R, Panda SK, Jameel S. Mutational analysis of glycosylation, membrane translocation, and cell surface expression of the hepatitis E virus ORF2 protein. J Virol 1999; 73: 4074–4082.
- Graff J, Zhou YH, Torian U, et al. Mutations within potential glycosylation sites in the capsid protein of hepatitis E virus prevent the formation of infectious virus particles. J Virol 2008; 82: 1185–1194.
- Córdoba L, Huang YW, Opriessnig T, et al. Three aa mutations (F51L, T59A, and S390L) in the capsid protein of the hepatitis E virus collectively contribute to virus attenuation. J Virol 2011; 85: 5338–5349.
- Schofield DJ, Glamann J, Emerson SU, Purcell RH. Identification by phage display and characterization of two neutralizing chimpanzee monoclonal antibodies to the hepatitis E virus capsid protein. J Virol 2000; 74: 5548–5555.
- Zhang H, Dai X, Shan X, Meng J. The Leu477 and Leu613 of ORF2-encoded protein are critical in forming neutralization antigenic epitope of hepatitis E virus genotype 4. Cell Mol Immunol 2008; 5: 447–456.
- Haqshenas G, Huang FF, Fenaux M, et al. The putative capsid protein of the newly identified avian hepatitis E virus shares antigenic epitopes with that of swine and human hepatitis E viruses and chicken big liver and spleen disease virus. J Gen Virol 2002; 83: 2201–2209.
- Zhu FC, Zhang J, Zhang XF, et al. Efficacy and safety of a recombinant hepatitis E vaccine in healthy adults: a large-scale, randomized, double-blind placebo-controlled, phase 3 trial. Lancet 2010; 376: 895–902.
- Shrestha MP, Scott RM, Joshi DM, et al. Safety and efficacy of a recombinant hepatitis E vaccine. N Engl J Med 2007; 356: 895–903.
- Tyagi S, Surjit M, Roy AK, Jameel S, Lal SK. The ORF3 protein of hepatitis E virus interacts with liver-specific alpha1-microglobulin and its precursor alpha1-microglobulin/bikunin precursor (AMBP) and expedites their export from the hepatocyte. J Biol Chem 2004; 279: 29308–29319.
- Moin SM, Chandra V, Arya R, Jameel S. The hepatitis E virus ORF3 protein stabilizes HIF-1alpha and enhances HIF-1-mediated transcriptional activity through p300/CBP. Cell Microbiol 2009; 11: 1409–1421.
- Williams TP, Kasorndorkbua C, Halbur PG, et al. Evidence of extrahepatic sites of replication of the hepatitis E virus in a swine model. J Clin Microbiol 2001; 39: 3040–3046.
- Kalia M, Chandra V, Rahman SA, Sehgal D, Jameel S. Heparan sulfate proteoglycans are required for cellular binding of the hepatitis E virus ORF2 capsid protein and for viral infection. J Virol 2009; 83: 12714–12724.
- Surjit M, Jameel S, Lal SK. Cytoplasmic localization of the ORF2 protein of hepatitis E virus is dependent on its ability to undergo retrotranslocation from the endoplasmic reticulum. J Virol 2007; 81: 3339–3345.
- Zheng ZZ, Miao J, Zhao M, et al. Role of heat-shock protein 90 in hepatitis E virus capsid trafficking. J Gen Virol 2010; 91: 1728–1736.
- Chandra V, Kalia M, Hajela K, Jameel S. The ORF3 protein of hepatitis E virus delays degradation of activated growth factor receptors by interacting with CIN85 and blocking formation of the Cbl-CIN85 complex. J Virol 2010; 84: 3857–3867.
- Suppiah S, Zhou Y, Frey TK. Lack of processing of the expressed ORF1 gene product of hepatitis E virus. Virol J 2011; 8: 245.
- Rehman S, Kapur N, Durgapal H, Panda SK. Subcellular localization of hepatitis E virus (HEV) replicase. Virology 2008; 370: 77–92.
- Li TC, Takeda N, Miyamura T, et al. Essential elements of the capsid protein for self-assembly into empty virus-like particles of hepatitis E virus. J Virol 2005; 79: 12999–13006.
- Yamada K, Takahashi M, Hoshino Y, et al. ORF3 protein of hepatitis E virus is essential for virion release from infected cells. J Gen Virol 2009; 90: 1880–1891.
- Nagashima S, Takahashi M, Jirintai S, et al. Tumour susceptibility gene 101 and the vacuolar protein sorting pathway are required for release of hepatitis E virions. J Gen Virol 2011; 92: 2838–2848.
- Xing L, Li TC, Mayazaki N, et al. Structure of hepatitis E virion-sized particle reveals an RNA-dependent viral assembly pathway. J Biol Chem 2010; 285: 33175–33183.
- Guu TS, Liu Z, Ye Q, et al. Structure of the hepatitis E virus-like particle suggests mechanisms for virus assembly and receptor binding. Proc Natl Acad Sci USA 2009; 106: 12992–12997.
- Yamashita T, Mori Y, Miyazaki N, et al. Biological and immunological characteristics of hepatitis E virus-like particles based on the crystal structure. Proc Natl Acad Sci USA 2009; 106: 12986–12991.
- Li S, Tang X, Seetharaman J, et al. Dimerization of hepatitis E virus capsid protein E2s domain is essential for virus-host interaction. PLoS Pathog 2009; 5: e1000537.
- Tang X, Yang C, Gu Y, et al. Structural basis for the neutralization and genotype specificity of hepatitis E virus. Proc Natl Acad Sci USA 2011; 108: 10266–10271.
- Xing L, Wang JC, Li TC, et al. Spatial configuration of hepatitis E virus antigenic domain. J Virol 2011; 85: 1117–1124.
