Essential Elements of the Capsid Protein for Self-Assembly into Empty Virus-Like Particles of Hepatitis E Virus

Li, Tiancheng; Takeda, Naokazu; Miyamura, Tatsuo; Matsuura, Yoshiharu; Wang, Joseph Che Yen; Engvall, Helena; Hammar, Lena Marmstål; Li, Xing; Cheng, R. Holland

doi:10.1128/jvi.79.20.12999-13006.2005

Cited by 166 publications

(211 citation statements)

References 26 publications

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“…The 4 structural elements provide a flat interface that is largely hydrophobic in nature. Previous mutagenesis identified a cluster of 6 hydrophobic residues critical for dimeric interactions: A597, V598, A599, L601, and A602 (26). Another study found that the deletion of residues 585-610 led to reduced oligomerization and aberrant folding of the protein (27).…”

Section: Resultsmentioning

confidence: 99%

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Structure of the hepatitis E virus-like particle suggests mechanisms for virus assembly and receptor binding

Guu

Liu

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

220

247

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Hepatitis E virus (HEV), a small, non-enveloped RNA virus in the familyHepeviridae, is associated with endemic and epidemic acute viral hepatitis in developing countries. Our 3.5-Å structure of a HEV-like particle (VLP) shows that each capsid protein contains 3 linear domains that form distinct structural elements: S, the continuous capsid; P1, 3-fold protrusions; and P2, 2-fold spikes. The S domain adopts a jelly-roll fold commonly observed in small RNA viruses. The P1 and P2 domains both adopt ␤-barrel folds. Each domain possesses a potential polysaccharide-binding site that may function in cell-receptor binding. Sugar binding to P1 at the capsid protein interface may lead to capsid disassembly and cell entry. Structural modeling indicates that native T ‫؍‬ 3 capsid contains flat dimers, with less curvature than those of T ‫؍‬ 1 VLP. Our findings significantly advance the understanding of HEV molecular biology and have application to the development of vaccines and antiviral medications.capsid ͉ HEV V iral hepatitis is principally caused by 5 distinct viruses named hepatitis A-E. Despite their similar names, the 5 viruses are unrelated, and they have totally different genome structures with distinct replication mechanisms. Hepatitis E virus (HEV) is responsible for endemic hepatitis as well as sporadic epidemics of acute, enterically transmitted hepatitis in the developing world, including parts of Asia, the Middle East, Africa, and Mexico (1, 2). HEV accounts for more than 50% of acute viral hepatitides in young adults in these regions, with a case fatality of 1-2% in regular patients and up to 20% in pregnant women.Given the lack of a robust cell culture system, and because HEV is not closely related to any other well-characterized virus, little is known about the molecular biology of HEV or its strategy for replication (1). HEV is a small, non-enveloped virus with a 7.2 kb, positive-sense RNA genome. Its genomic RNA is polyadenylated and contains 3 ORFs. Located near the 5Ј-end, ORF1 encodes a non-structural polyprotein with multiple functional domains, including those for methyltransferase, protease, helicase, and polymerase. The viral capsid protein (CP) is encoded by ORF2 near the 3Ј-end. ORF3, which partially overlaps with the other 2 ORFs, codes for an immunogenic protein of unknown function. HEV was originally classified in the Caliciviridae family because of its structural similarity to other caliciviruses; however, it is now the sole member of the Hepeviridae family. The genomic RNA of HEV exhibits several distinct features compared to the genomic RNA of caliciviruses, including a methylated cap at the 5Ј-end and an ORF1 with functional domains arranged in a different order (1, 3).Previous studies of HEV assembly have primarily focused on the overexpression of viral proteins. The ORF2 capsid protein, HEV-CP, contains a total of 660 amino acid residues. At the HEV-CP N terminus is a signal peptide followed by an arginine-rich domain that potentially play a role in viral RNA encapsidation during assem...

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Section: Resultsmentioning

confidence: 99%

“…The P2 domain alone is capable of dimerization (26). Dimerization of the P2 domain is mediated by an extended loop (550-566) and 3 ␤-strands from the central ␤-barrel (␤18, ␤24, and ␤27).…”

Section: Resultsmentioning

confidence: 99%

Structure of the hepatitis E virus-like particle suggests mechanisms for virus assembly and receptor binding

Guu

Liu

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

220

247

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“…The antigen used in the ELISA was HEV-like particles composed of a truncated open reading frame 2 (ORF2) protein of genotype I HEV expressed by a recombinant baculovirus in insect cells and was suspended with 0.5 M carbonate buffer (pH 12.5) at a concentration of 1 µg/ml [3]. The antigen solution (100 µl) was added to duplicate wells of 96-well microplates (Sumiron ELISA plate type H, Sumitomo Bakelite, Tokyo, Japan).…”

Section: Samplesmentioning

confidence: 99%

Prevalence of Hepatitis E Virus (HEV) Infection in Wild Boars (Sus scrofa leucomystax) and Pigs in Gunma Prefecture, Japan

Sakano

Morita

Shiono³

et al. 2009

The Journal of Veterinary Medical Science

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ABSTRACT. The prevalence of hepatitis E virus (HEV) infection in wild boars and pigs in Gunma Prefecture, Japan, was serologically and genetically examined. The positive detection rates of anti-HEV IgG and HEV RNA in the wild boars were 4.5% (4/89) and 1.1% (1/ 89), whereas those in the pigs were 74.6% (126/169) and 1.8% (3/169), respectively. The positive rates of anti-HEV IgG and HEV RNA on the 17 pig farms in the present study ranged from 20% to 100%, respectively. One male wild boar approximately 5 years of age was positive for HEV RNA but was negative for anti-HEV IgG. Three pigs from 2 farms were positive for HEV RNA; 2 of these pigs were negative for HEV IgG, and the other was positive. A phylogenetic analysis revealed that all of the HEV ORF1 genes detected in the present study belonged to genotype III. In Gunma Prefecture, HEV is highly prevalent and widespread, and uncooked wild boar and pig meat may have the potential to transmit HEV to humans. KEY WORDS: hepatitis E virus, Japan, swine, wild boar.J. Vet. Med. Sci. 71(1): 21-25, 2009 Hepatitis E virus (HEV), which belongs to the genus Hepevirus, is the causative agent of hepatitis E. Hepatitis E infection has been found in many developing countries in Asia, Africa and Latin America, where the disease is an important public health concern [15]. HEV is primarily transmitted by the fecal-oral route such as in waterborne epidemics.Recent studies have suggested that HEV is divided into 4 genotypes designated as G I, G II, G III, and G IV [17]. The HEV infections in Asia and Africa are mainly caused by G I, and the majority of the GII infection have been reported in Mexico and Nigeria. On the other hand, only a single case of infection with GIII or GIV has been described in the United States, European counties, Argentina, Taiwan and China [17,21,22]. In Japan, most imported cases with G I have derived from epidemic areas such as Asia and Africa [2]; however, G III or G IV has also been detected in acute hepatitis patients who have never traveled to HEV epidemic areas [6,8,13,14,20,21,24,29]. These patients often have a history of consuming uncooked wild boar (Sus scrofa leucomystax) and sika deer (Cervus nippon) meat and liver [5,27,28]. Also, HEV strains belonging to G I, G III or G IV have been detected in Japanese patients with sporadic acute or fulminate hepatitis E [8, 9, 19-22, 24, 31]. In addition, Yazaki et al. [31] reported that HEV RNA has been detected in 2% (7/363 packages) of sold pig liver on the market by reverse transcription-polymerase chain reaction (RT-PCR).In Japan, it has been suggested that the transmission route of HEV remains unclear in approximately 60% of infected patients [1]; zoonotic food-borne transmissions account for 30%, imported infection accounts for 8% and blood transfusion is responsible for 2%. In Gunma Prefecture, Japan, approximately 3,000 wild boars are annually slaughtered for meat [unpublished data], and the number of breeding pigs in the prefecture was approximately 6 million in 2005. According to the Gunma Pre...

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“…2 ,27 VLPs for Hepatitis E have been assembled using a truncated form of the virus capsid protein. 28 In immunization studies in mice these VLPs were able to induce systemic and mucosal immune responses following oral administration. 28,29 Furthermore, oral administration of the Hepatitis E VLPs to cynomologous monkeys induced IgM, IgA and IgG responses and was sufficient to protect against infection and disease on challenge with virus.…”

Section: Vlps Produced For Structurally Simple Non-enveloped Virusesmentioning

confidence: 99%

“…28 In immunization studies in mice these VLPs were able to induce systemic and mucosal immune responses following oral administration. 28,29 Furthermore, oral administration of the Hepatitis E VLPs to cynomologous monkeys induced IgM, IgA and IgG responses and was sufficient to protect against infection and disease on challenge with virus. 30 Thus there is clear potential for the application of these VLPs as a vaccine for hepatitis E.…”

Section: Vlps Produced For Structurally Simple Non-enveloped Virusesmentioning

confidence: 99%

Virus‑like particles as a vaccine delivery system: Myths and facts

Roy¹,

Noad²

2008

Human Vaccines

150

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Vaccines against viral disease have traditionally relied on attenuated virus strains or inactivation of infectious virus. Subunit vaccines based on viral proteins expressed in heterologous systems have been effective for some pathogens, but have often suffered from poor immunogenicity due to incorrect protein folding or modification. In this review we focus on a specific class of viral subunit vaccine that mimics the overall structure of virus particles and thus preserves the native antigenic conformation of the immunogenic proteins. These virus-like particles (VLPs) have been produced for a wide range of taxonomically and structurally distinct viruses, and have unique advantages in terms of safety and immunogenicity over previous approaches. With new VLP vaccines for papillomavirus beginning to reach the marketplace we argue that this technology has now 'come-of-age' and must be considered a viable vaccine strategy.

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Essential Elements of the Capsid Protein for Self-Assembly into Empty Virus-Like Particles of Hepatitis E Virus

Abstract: Hepatitis E virus (HEV) is a noncultivable virus that causes

Cited by 166 publications

References 26 publications

Structure of the hepatitis E virus-like particle suggests mechanisms for virus assembly and receptor binding

Structure of the hepatitis E virus-like particle suggests mechanisms for virus assembly and receptor binding

Prevalence of Hepatitis E Virus (HEV) Infection in Wild Boars (Sus scrofa leucomystax) and Pigs in Gunma Prefecture, Japan

Virus‑like particles as a vaccine delivery system: Myths and facts

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