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Stephenson-Tsoris S, Liang TJ. Hepatitis Delta Virus-Host Protein Interactions: From Entry to Egress. Viruses 2023; 15:1530. [PMID: 37515216 PMCID: PMC10383234 DOI: 10.3390/v15071530] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2023] [Revised: 07/04/2023] [Accepted: 07/06/2023] [Indexed: 07/30/2023] Open
Abstract
Hepatitis delta virus (HDV) is the smallest known human virus and causes the most severe form of human viral hepatitis, yet it is still not fully understood how the virus replicates and how it interacts with many host proteins during replication. This review aims to provide a systematic review of all the host factors currently known to interact with HDV and their mechanistic involvement in all steps of the HDV replication cycle. Finally, we discuss implications for therapeutic development based on our current knowledge of HDV-host protein interactions.
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Affiliation(s)
- Susannah Stephenson-Tsoris
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health, Bethesda, MD 20892, USA
| | - T Jake Liang
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health, Bethesda, MD 20892, USA
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Lucifora J, Alfaiate D, Pons C, Michelet M, Ramirez R, Fusil F, Amirache F, Rossi A, Legrand AF, Charles E, Vegna S, Farhat R, Rivoire M, Passot G, Gadot N, Testoni B, Bach C, Baumert TF, Hyrina A, Beran RK, Zoulim F, Boonstra A, Büning H, Verrier ER, Cosset FL, Fletcher SP, Salvetti A, Durantel D. Hepatitis D virus interferes with hepatitis B virus RNA production via interferon-dependent and -independent mechanisms. J Hepatol 2023; 78:958-970. [PMID: 36702177 DOI: 10.1016/j.jhep.2023.01.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Revised: 01/10/2023] [Accepted: 01/10/2023] [Indexed: 01/25/2023]
Abstract
BACKGROUND & AIMS Chronic coinfection with HBV and HDV leads to the most aggressive form of chronic viral hepatitis. Herein, we aimed to elucidate the molecular mechanisms underlying the widely reported observation that HDV interferes with HBV in most coinfected patients. METHODS Patient liver tissues, primary human hepatocytes, HepaRG cells and human liver chimeric mice were used to analyze the effect of HDV on HBV using virological and RNA-sequencing analyses, as well as RNA synthesis, stability and association assays. RESULTS Transcriptomic analyses in cell culture and mouse models of coinfection enabled us to define an HDV-induced signature, mainly composed of interferon (IFN)-stimulated genes (ISGs). We also provide evidence that ISGs are upregulated in chronically HDV/HBV-coinfected patients but not in cells that only express HDV antigen (HDAg). Inhibition of the hepatocyte IFN response partially rescued the levels of HBV parameters. We observed less HBV RNA synthesis upon HDV infection or HDV protein expression. Additionally, HDV infection or expression of HDAg alone specifically accelerated the decay of HBV RNA, and HDAg was associated with HBV RNAs. On the contrary, HDAg expression did not affect other viruses such as HCV or SARS-CoV-2. CONCLUSIONS Our data indicate that HDV interferes with HBV through both IFN-dependent and IFN-independent mechanisms. Specifically, we uncover a new viral interference mechanism in which proteins of a satellite virus affect the RNA production of its helper virus. Exploiting these findings could pave the way to the development of new therapeutic strategies against HBV. IMPACT AND IMPLICATIONS Although the molecular mechanisms remained unexplored, it has long been known that despite its dependency, HDV decreases HBV viremia in patients. Herein, using in vitro and in vivo models, we showed that HDV interferes with HBV through both IFN-dependent and IFN-independent mechanisms affecting HBV RNA metabolism, and we defined the HDV-induced modulation signature. The mechanisms we uncovered could pave the way for the development of new therapeutic strategies against HBV by mimicking and/or increasing the effect of HDAg on HBV RNA. Additionally, the HDV-induced modulation signature could potentially be correlated with responsiveness to IFN-α treatment, thereby helping to guide management of HBV/HDV-coinfected patients.
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Affiliation(s)
- Julie Lucifora
- CIRI, Centre International de Recherche en Infectiologie, Univ Lyon, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, F-69007, Lyon, France; INSERM, U1052, Cancer Research Center of Lyon (CRCL), University of Lyon (UCBL1), CNRS UMR_5286, Centre Léon Bérard, Lyon, France.
| | - Dulce Alfaiate
- INSERM, U1052, Cancer Research Center of Lyon (CRCL), University of Lyon (UCBL1), CNRS UMR_5286, Centre Léon Bérard, Lyon, France; Service des Maladies Infectieuses et Tropicales, Hôpital de la Croix-Rousse, Hospices Civils de Lyon, Lyon, France
| | - Caroline Pons
- CIRI, Centre International de Recherche en Infectiologie, Univ Lyon, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, F-69007, Lyon, France; INSERM, U1052, Cancer Research Center of Lyon (CRCL), University of Lyon (UCBL1), CNRS UMR_5286, Centre Léon Bérard, Lyon, France
| | - Maud Michelet
- INSERM, U1052, Cancer Research Center of Lyon (CRCL), University of Lyon (UCBL1), CNRS UMR_5286, Centre Léon Bérard, Lyon, France
| | | | - Floriane Fusil
- CIRI, Centre International de Recherche en Infectiologie, Univ Lyon, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, F-69007, Lyon, France
| | - Fouzia Amirache
- CIRI, Centre International de Recherche en Infectiologie, Univ Lyon, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, F-69007, Lyon, France
| | - Axel Rossi
- Institute of Experimental Hematology, Hannover Medical School, Hannover, Germany
| | - Anne-Flore Legrand
- CIRI, Centre International de Recherche en Infectiologie, Univ Lyon, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, F-69007, Lyon, France
| | - Emilie Charles
- CIRI, Centre International de Recherche en Infectiologie, Univ Lyon, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, F-69007, Lyon, France
| | - Serena Vegna
- INSERM, U1052, Cancer Research Center of Lyon (CRCL), University of Lyon (UCBL1), CNRS UMR_5286, Centre Léon Bérard, Lyon, France
| | - Rayan Farhat
- INSERM, U1052, Cancer Research Center of Lyon (CRCL), University of Lyon (UCBL1), CNRS UMR_5286, Centre Léon Bérard, Lyon, France
| | | | - Guillaume Passot
- Service de chirurgie générale et Oncologique, Hôpital Lyon Sud, Hospices Civils de Lyon Et CICLY, EA3738, Université Lyon 1, France
| | - Nicolas Gadot
- INSERM, U1052, Cancer Research Center of Lyon (CRCL), University of Lyon (UCBL1), CNRS UMR_5286, Centre Léon Bérard, Lyon, France
| | - Barbara Testoni
- INSERM, U1052, Cancer Research Center of Lyon (CRCL), University of Lyon (UCBL1), CNRS UMR_5286, Centre Léon Bérard, Lyon, France
| | - Charlotte Bach
- Université de Strasbourg, Inserm, Institut de Recherche sur les Maladies Virales et Hépatiques UMR_S1110, Strasbourg, France
| | - Thomas F Baumert
- Université de Strasbourg, Inserm, Institut de Recherche sur les Maladies Virales et Hépatiques UMR_S1110, Strasbourg, France; Institut Hospitalo-Universitaire, Pôle Hépato-digestif, Nouvel Hôpital Civil, 67000 Strasbourg, France
| | | | | | - Fabien Zoulim
- INSERM, U1052, Cancer Research Center of Lyon (CRCL), University of Lyon (UCBL1), CNRS UMR_5286, Centre Léon Bérard, Lyon, France; Department of Hepatology, Croix-Rousse Hospital, Hospices Civils de Lyon, Lyon, France
| | - Andre Boonstra
- Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, Gravendijkwal 230, Rotterdam, the Netherlands
| | - Hildegard Büning
- Institute of Experimental Hematology, Hannover Medical School, Hannover, Germany
| | - Eloi R Verrier
- Université de Strasbourg, Inserm, Institut de Recherche sur les Maladies Virales et Hépatiques UMR_S1110, Strasbourg, France
| | - François-Loïc Cosset
- CIRI, Centre International de Recherche en Infectiologie, Univ Lyon, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, F-69007, Lyon, France
| | | | - Anna Salvetti
- CIRI, Centre International de Recherche en Infectiologie, Univ Lyon, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, F-69007, Lyon, France; INSERM, U1052, Cancer Research Center of Lyon (CRCL), University of Lyon (UCBL1), CNRS UMR_5286, Centre Léon Bérard, Lyon, France
| | - David Durantel
- CIRI, Centre International de Recherche en Infectiologie, Univ Lyon, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, F-69007, Lyon, France; INSERM, U1052, Cancer Research Center of Lyon (CRCL), University of Lyon (UCBL1), CNRS UMR_5286, Centre Léon Bérard, Lyon, France
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Medical Advances in Hepatitis D Therapy: Molecular Targets. Int J Mol Sci 2022; 23:ijms231810817. [PMID: 36142728 PMCID: PMC9506394 DOI: 10.3390/ijms231810817] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Revised: 09/08/2022] [Accepted: 09/09/2022] [Indexed: 11/25/2022] Open
Abstract
An approximate number of 250 million people worldwide are chronically infected with hepatitis B virus, making them susceptible to a coinfection with hepatitis D virus. The superinfection causes the most severe form of a viral hepatitis and thus drastically worsens the course of the disease. Until recently, the only available therapy consisted of interferon-α, only eligible for a minority of patients. In July 2020, the EMA granted Hepcludex conditional marketing authorization throughout the European Union. This first-in-class entry inhibitor offers the promise to prevent the spread in order to gain control and eventually participate in curing hepatitis B and D. Hepcludex is an example of how understanding the viral lifecycle can give rise to new therapy options. Sodium taurocholate co-transporting polypeptide, the virus receptor and the target of Hepcludex, and other targets of hepatitis D therapy currently researched are reviewed in this work. Farnesyltransferase inhibitors such as Lonafarnib, targeting another essential molecule in the HDV life cycle, represent a promising target for hepatitis D therapy. Farnesyltransferase attaches a farnesyl (isoprenyl) group to proteins carrying a C-terminal Ca1a2X (C: cysteine, a: aliphatic amino acid, X: C-terminal amino acid) motif like the large hepatitis D virus antigen. This modification enables the interaction of the HBV/HDV particle and the virus envelope proteins. Lonafarnib, which prevents this envelopment, has been tested in clinical trials. Targeting the lifecycle of the hepatitis B virus needs to be considered in hepatitis D therapy in order to cure a patient from both coexisting infections. Nucleic acid polymers target the hepatitis B lifecycle in a manner that is not yet understood. Understanding the possible targets of the hepatitis D virus therapy is inevitable for the improvement and development of a sufficient therapy that HDV patients are desperately in need of.
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Whelan M, Pelchat M. Role of RNA Polymerase II Promoter-Proximal Pausing in Viral Transcription. Viruses 2022; 14:v14092029. [PMID: 36146833 PMCID: PMC9503719 DOI: 10.3390/v14092029] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Revised: 09/09/2022] [Accepted: 09/11/2022] [Indexed: 11/16/2022] Open
Abstract
The promoter-proximal pause induced by the binding of the DRB sensitivity-inducing factor (DSIF) and the negative elongation factor (NELF) to RNAP II is a key step in the regulation of metazoan gene expression. It helps maintain a permissive chromatin landscape and ensures a quick transcriptional response from stimulus-responsive pathways such as the innate immune response. It is also involved in the biology of several RNA viruses such as the human immunodeficiency virus (HIV), the influenza A virus (IAV) and the hepatitis delta virus (HDV). HIV uses the pause as one of its mechanisms to enter and maintain latency, leading to the creation of viral reservoirs resistant to antiretrovirals. IAV, on the other hand, uses the pause to acquire the capped primers necessary to initiate viral transcription through cap-snatching. Finally, the HDV RNA genome is transcribed directly by RNAP II and requires the small hepatitis delta antigen to displace NELF from the polymerase and overcome the transcriptional block caused by RNAP II promoter-proximal pausing. In this review, we will discuss the RNAP II promoter-proximal pause and the roles it plays in the life cycle of RNA viruses such as HIV, IAV and HDV.
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Ma J, Mudiyanselage SDD, Wang Y. Emerging value of the viroid model in molecular biology and beyond. Virus Res 2022; 313:198730. [PMID: 35263622 PMCID: PMC8976779 DOI: 10.1016/j.virusres.2022.198730] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Revised: 02/25/2022] [Accepted: 03/05/2022] [Indexed: 01/21/2023]
Abstract
Viroids are single-stranded circular noncoding RNAs that infect plants. Research in the past five decades has deciphered the viroid genome structures, viroid replication cycles, numerous host factors for viroid infection, viroid motifs for intracellular and intercellular trafficking, interactions with host defense machinery, etc. In this review, we mainly focus on some significant questions that remain to be tackled, centered around (1) how the RNA polymerase II machinery performs transcription on RNA templates of nuclear-replicating viroids, (2) how viroid RNAs coordinate multiple structural elements for diverse functions, and (3) how viroid RNAs activate plant immunity. Research on viroids has led to seminal discoveries in biology, and we expect the research directions outlined in this review to continue providing key knowledge inspiring other areas of biology.
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Affiliation(s)
- Junfei Ma
- Department of Biological Sciences, Mississippi State University, MS 39762, USA
| | | | - Ying Wang
- Department of Biological Sciences, Mississippi State University, MS 39762, USA.
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Flores R, Navarro B, Serra P, Di Serio F. A scenario for the emergence of protoviroids in the RNA world and for their further evolution into viroids and viroid-like RNAs by modular recombinations and mutations. Virus Evol 2022; 8:veab107. [PMID: 35223083 PMCID: PMC8865084 DOI: 10.1093/ve/veab107] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Revised: 12/10/2021] [Accepted: 01/14/2022] [Indexed: 11/14/2022] Open
Abstract
Viroids are tiny, circular, and noncoding RNAs that are able to replicate and systemically infect plants. The smallest known pathogens, viroids have been proposed to represent survivors from the RNA world that likely preceded the cellular world currently dominating life on the earth. Although the small, circular, and compact nature of viroid genomes, some of which are also endowed with catalytic activity mediated by hammerhead ribozymes, support this proposal, the lack of feasible evolutionary routes and the identification of hammerhead ribozymes in a large number of DNA genomes of organisms along the tree of life have led some to question such a proposal. Here, we reassess the origin and subsequent evolution of viroids by complementing phylogenetic reconstructions with molecular data, including the primary and higher-order structure of the genomic RNAs, their replication, and recombination mechanisms and selected biological information. Features of some viroid-like RNAs found in plants, animals, and possibly fungi are also considered. The resulting evolutionary scenario supports the emergence of protoviroids in the RNA world, mainly as replicative modules, followed by a further increase in genome complexity based on module/domain shuffling and combination and mutation. Such a modular evolutionary scenario would have facilitated the inclusion in the protoviroid genomes of complex RNA structures (or coding sequences, as in the case of hepatitis delta virus and delta-like agents), likely needed for their adaptation from the RNA world to a life based on cells, thus generating the ancestors of current infectious viroids and viroid-like RNAs. Other noninfectious viroid-like RNAs, such as retroviroid-like RNA elements and retrozymes, could also be derived from protoviroids if their reverse transcription and integration into viral or eukaryotic DNA, respectively, are considered as a possible key step in their evolution. Comparison of evidence supporting a general and modular evolutionary model for viroids and viroid-like RNAs with that favoring alternative scenarios provides reasonable reasons to keep alive the hypothesis that these small RNA pathogens may be relics of a precellular world.
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Affiliation(s)
- Ricardo Flores
- Instituto de Biología Molecular y Celular de Plantas, Consejo Superior de Investigaciones Científicas–Universidad Politécnica de Valencia, Ingeniero Fausto Elio s/n, Valencia 46022, Spain
| | - Beatriz Navarro
- Istituto per la Protezione Sostenibile delle Piante, Consiglio Nazionale delle Ricerche, Via Amendola 122/D, Bari 70126, Italy
| | - Pedro Serra
- Instituto de Biología Molecular y Celular de Plantas, Consejo Superior de Investigaciones Científicas–Universidad Politécnica de Valencia, Ingeniero Fausto Elio s/n, Valencia 46022, Spain
| | - Francesco Di Serio
- Istituto per la Protezione Sostenibile delle Piante, Consiglio Nazionale delle Ricerche, Via Amendola 122/D, Bari 70126, Italy
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7
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Hepatitis delta virus genome RNA synthesis initiates at position 1646 with a non-templated guanosine. J Virol 2021; 96:e0201721. [PMID: 34878890 DOI: 10.1128/jvi.02017-21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Hepatitis delta virus (HDV) is a significant human pathogen that causes acute and chronic liver disease; there is no licensed therapy. HDV is a circular negative-sense ssRNA virus that produces three RNAs in infected cells: genome, antigenome and mRNA; the latter encodes hepatitis delta antigen, the viral protein. These RNAs are synthesized by host DNA-dependent RNA polymerase acting as an RNA-dependent RNA polymerase. Although HDV genome RNA accumulates to high levels in infected cells, the mechanism by which this process occurs remains poorly understood. For example, the nature of the 5' end of the genome, including the synthesis start site and its chemical composition, are not known. Analysis of this process has been challenging because the initiation site is part of an unstable precursor in the rolling circle mechanism by which HDV genome RNA is synthesized. In this study, circular HDV antigenome RNAs synthesized in vitro were used to directly initiate HDV genome RNA synthesis in transfected cells, thus enabling detection of the 5' end of the genome RNA. The 5' end of this RNA is capped, as expected for a Pol II product. Initiation begins at position 1646 on the genome, which is located near the loop end proximal to the start site for HDAg mRNA synthesis. Unexpectedly, synthesis begins with a guanosine that is not conventionally templated by the HDV RNA. IMPORTANCE Hepatitis delta virus (HDV) is a unique virus that causes severe liver disease. It uses host RNA Polymerase II to copy its circular RNA genome in a unique and poorly understood process. Although the virus RNA accumulates to high levels within infected cells, it is not known how synthesis of the viral RNA begins, nor even where on the genome synthesis starts. Here, we identify the start site for the initiation of HDV genome RNA synthesis as position 1646, which is at one end of the closed hairpin-like structure of the viral RNA. The 5' end of the RNA is capped, as expected for Pol II products. However, RNA synthesis begins with a guanosine that is not present in the genome. Thus, although HDV uses Pol II to synthesize the viral genome, some details of the initiation process are different. These differences could be important for successfully targeting virus replication.
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Pérez-Vargas J, Pereira de Oliveira R, Jacquet S, Pontier D, Cosset FL, Freitas N. HDV-Like Viruses. Viruses 2021; 13:1207. [PMID: 34201626 PMCID: PMC8310214 DOI: 10.3390/v13071207] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Revised: 06/11/2021] [Accepted: 06/16/2021] [Indexed: 02/07/2023] Open
Abstract
Hepatitis delta virus (HDV) is a defective human virus that lacks the ability to produce its own envelope proteins and is thus dependent on the presence of a helper virus, which provides its surface proteins to produce infectious particles. Hepatitis B virus (HBV) was so far thought to be the only helper virus described to be associated with HDV. However, recent studies showed that divergent HDV-like viruses could be detected in fishes, birds, amphibians, and invertebrates, without evidence of any HBV-like agent supporting infection. Another recent study demonstrated that HDV can be transmitted and propagated in experimental infections ex vivo and in vivo by different enveloped viruses unrelated to HBV, including hepatitis C virus (HCV) and flaviviruses such as Dengue and West Nile virus. All this new evidence, in addition to the identification of novel virus species within a large range of hosts in absence of HBV, suggests that deltaviruses may take advantage of a large spectrum of helper viruses and raises questions about HDV origins and evolution.
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Affiliation(s)
- Jimena Pérez-Vargas
- CIRI—Centre International de Recherche en Infectiologie, Université de Lyon, Université Claude Bernard Lyon 1, Inserm, U1111, CNRS, UMR5308, ENS Lyon, 46 allée d’Italie, F-69007 Lyon, France; (J.P.-V.); (R.P.d.O.); (N.F.)
| | - Rémi Pereira de Oliveira
- CIRI—Centre International de Recherche en Infectiologie, Université de Lyon, Université Claude Bernard Lyon 1, Inserm, U1111, CNRS, UMR5308, ENS Lyon, 46 allée d’Italie, F-69007 Lyon, France; (J.P.-V.); (R.P.d.O.); (N.F.)
| | - Stéphanie Jacquet
- LBBE UMR5558 CNRS—Centre National de la Recherche Scientifique, Université de Lyon 1—48 bd du 11 Novembre 1918, 69100 Villeurbanne, France; (S.J.); (D.P.)
| | - Dominique Pontier
- LBBE UMR5558 CNRS—Centre National de la Recherche Scientifique, Université de Lyon 1—48 bd du 11 Novembre 1918, 69100 Villeurbanne, France; (S.J.); (D.P.)
| | - François-Loïc Cosset
- CIRI—Centre International de Recherche en Infectiologie, Université de Lyon, Université Claude Bernard Lyon 1, Inserm, U1111, CNRS, UMR5308, ENS Lyon, 46 allée d’Italie, F-69007 Lyon, France; (J.P.-V.); (R.P.d.O.); (N.F.)
| | - Natalia Freitas
- CIRI—Centre International de Recherche en Infectiologie, Université de Lyon, Université Claude Bernard Lyon 1, Inserm, U1111, CNRS, UMR5308, ENS Lyon, 46 allée d’Italie, F-69007 Lyon, France; (J.P.-V.); (R.P.d.O.); (N.F.)
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Abstract
HDV is a small, defective RNA virus that requires the HBsAg of HBV for its assembly, release, and transmission. Chronic HBV/HDV infection often has a severe clinical outcome and is difficult to treat. The important role of a robust virus-specific T cell response for natural viral control has been established for many other chronic viral infections, but the exact role of the T cell response in the control and progression of chronic HDV infection is far less clear. Several recent studies have characterised HDV-specific CD4+ and CD8+ T cell responses on a peptide level. This review comprehensively summarises all HDV-specific T cell epitopes described to date and describes our current knowledge of the role of T cells in HDV infection. While we now have better tools to study the adaptive anti-HDV-specific T cell response, further efforts are needed to define the HLA restriction of additional HDV-specific T cell epitopes, establish additional HDV-specific MHC tetramers, understand the degree of cross HDV genotype reactivity of individual epitopes and understand the correlation of the HBV- and HDV-specific T cell response, as well as the breadth and specificity of the intrahepatic HDV-specific T cell response.
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Key Words
- ADAR1, adenosine deaminases acting on RNA
- ALT, alanine aminotransferase
- AST, aspartate aminotransferase
- CD4+
- CD8+
- ELISpot, enzyme-linked immune spot assay
- HBV
- HDAg, hepatitis delta antigen
- HDV
- Hepatitis Delta
- ICS, intracellular cytokine staining
- IFN-, interferon-
- L-HDAg, large hepatitis delta antigen
- MAIT, mucosa-associated invariant T cells
- NK cells, natural killer cells
- NTCP, sodium taurocholate co-transporting polypeptide
- PBMCs, peripheral blood mononuclear cells
- PD-1, programmed cell death protein 1
- PTM, post-translational modification
- Peg-IFN-α, pegylated interferon alpha
- S-HDAg, small hepatitis delta antigen
- T cell
- TCF, T cell-specific transcription factor
- TNFα, tumour necrosis factor-α
- Th1, T helper 1
- aa, amino acid(s)
- cccDNA, covalently closed circular DNA
- epitope
- viral escape
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Fearns R. Negative‐strand RNA Viruses. Virology 2021. [DOI: 10.1002/9781119818526.ch3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
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Lucifora J, Delphin M. Current knowledge on Hepatitis Delta Virus replication. Antiviral Res 2020; 179:104812. [PMID: 32360949 DOI: 10.1016/j.antiviral.2020.104812] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Revised: 04/20/2020] [Accepted: 04/25/2020] [Indexed: 12/14/2022]
Abstract
Hepatitis B Virus (HBV) that infects liver parenchymal cells is responsible for severe liver diseases and co-infection with Hepatitis Delta Virus (HDV) leads to the most aggressive form of viral hepatitis. Even tough being different for their viral genome (relaxed circular partially double stranded DNA for HBV and circular RNA for HDV), HBV and HDV are both maintained as episomes in the nucleus of infected cells and use the cellular machinery for the transcription of their viral RNAs. We propose here an update on the current knowledge on HDV replication cycle that may eventually help to identify new antiviral targets.
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Affiliation(s)
- Julie Lucifora
- INSERM, U1052, Cancer Research Center of Lyon (CRCL), Université de Lyon (UCBL1), CNRS UMR_5286, France.
| | - Marion Delphin
- INSERM, U1052, Cancer Research Center of Lyon (CRCL), Université de Lyon (UCBL1), CNRS UMR_5286, France
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12
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Hsu CW, Juang HH, Kuo CY, Li HP, Iang SB, Lin SH, Yeh CT, Chao M. Structural Pattern Differences in Unbranched Rod-like RNA of Hepatitis Delta Virus affect RNA Editing. Viruses 2019; 11:v11100934. [PMID: 31614652 PMCID: PMC6832723 DOI: 10.3390/v11100934] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2019] [Revised: 10/08/2019] [Accepted: 10/08/2019] [Indexed: 12/18/2022] Open
Abstract
Hepatitis delta virus (HDV) RNA forms an unbranched rod-like structure and complexes with the delta antigen (HDAg). Host ADAR1-catalyzed RNA editing at the amber/W site of the small HDAg leads to the production of the large HDAg, which inhibits replication and is required for virion assembly. For HDV genotype 1, amber/W editing is controlled by HDAg and the RNA structure immediate vicinity and downstream of the editing site. Here, the effects of 20 mutants carrying an increased length of consecutive base-pairing at various sites in HDV RNA on amber/W site editing were examined. All nine mutants carrying genomic regions that formed up to 15 consecutive base pairs, which is also the maximum length observed in 41 naturally occurring HDV genomes, showed normal editing rate. However, mutants carrying a 16 or 17 consecutive base-paired antigenomic segment located as far as 114 nt upstream could increase editing efficiency, possibly by interfering with HDAg binding. These data show for the first time that extended base-pairing upstream of the amber/W site could increase HDV RNA editing efficiency. Furthermore, it appears that the naturally occurring HDV RNA structures have been selected for suboptimal amber/W RNA editing, which favors the HDV replication cycle.
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Affiliation(s)
- Chao-Wei Hsu
- Liver Research Center, Department of Hepato-Gastroenterology, Chang Gung Memorial Hospital, Guishan, Taoyang 33302, Taiwan; (C.-W.H.); (C.-T.Y.)
| | - Horng-Heng Juang
- Department of Anatomy, Chang Gung University, Guishan, Taoyang 33302, Taiwan;
| | - Chien-Yi Kuo
- Department of Microbiology and Immunology, Chang Gung University, Guishan, Taoyang 33302, Taiwan; (C.-Y.K.); (H.-P.L.); (S.-B.I.); (S.-H.L.)
| | - Hsin-Pai Li
- Department of Microbiology and Immunology, Chang Gung University, Guishan, Taoyang 33302, Taiwan; (C.-Y.K.); (H.-P.L.); (S.-B.I.); (S.-H.L.)
- Division of Microbiology, Graduate Institute of Biomedical Sciences, Chang Gung University, Guishan, Taoyang 33302, Taiwan
| | - Shan-Bei Iang
- Department of Microbiology and Immunology, Chang Gung University, Guishan, Taoyang 33302, Taiwan; (C.-Y.K.); (H.-P.L.); (S.-B.I.); (S.-H.L.)
| | - Siao-Han Lin
- Department of Microbiology and Immunology, Chang Gung University, Guishan, Taoyang 33302, Taiwan; (C.-Y.K.); (H.-P.L.); (S.-B.I.); (S.-H.L.)
| | - Chau-Ting Yeh
- Liver Research Center, Department of Hepato-Gastroenterology, Chang Gung Memorial Hospital, Guishan, Taoyang 33302, Taiwan; (C.-W.H.); (C.-T.Y.)
| | - Mei Chao
- Liver Research Center, Department of Hepato-Gastroenterology, Chang Gung Memorial Hospital, Guishan, Taoyang 33302, Taiwan; (C.-W.H.); (C.-T.Y.)
- Department of Microbiology and Immunology, Chang Gung University, Guishan, Taoyang 33302, Taiwan; (C.-Y.K.); (H.-P.L.); (S.-B.I.); (S.-H.L.)
- Division of Microbiology, Graduate Institute of Biomedical Sciences, Chang Gung University, Guishan, Taoyang 33302, Taiwan
- Correspondence:
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13
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Mentha N, Clément S, Negro F, Alfaiate D. A review on hepatitis D: From virology to new therapies. J Adv Res 2019; 17:3-15. [PMID: 31193285 PMCID: PMC6526199 DOI: 10.1016/j.jare.2019.03.009] [Citation(s) in RCA: 65] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2019] [Revised: 03/21/2019] [Accepted: 03/22/2019] [Indexed: 02/06/2023] Open
Abstract
Hepatitis delta virus (HDV) is a defective virus that requires the hepatitis B virus (HBV) to complete its life cycle in human hepatocytes. HDV virions contain an envelope incorporating HBV surface antigen protein and a ribonucleoprotein containing the viral circular single-stranded RNA genome associated with both forms of hepatitis delta antigen, the only viral encoded protein. Replication is mediated by the host cell DNA-dependent RNA polymerases. HDV infects up to72 million people worldwide and is associated with an increased risk of severe and rapidly progressive liver disease. Pegylated interferon-alpha is still the only available treatment for chronic hepatitis D, with poor tolerance and dismal success rate. Although the development of antivirals inhibiting the viral replication is challenging, as HDV does not possess its own polymerase, several antiviral molecules targeting other steps of the viral life cycle are currently under clinical development: Myrcludex B, which blocks HDV entry into hepatocytes, lonafarnib, a prenylation inhibitor that prevents virion assembly, and finally REP 2139, which is thought to inhibit HBsAg release from hepatocytes and interact with hepatitis delta antigen. This review updates the epidemiology, virology and management of HDV infection.
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Affiliation(s)
- Nathalie Mentha
- Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland
| | - Sophie Clément
- Division of Clinical Pathology, Geneva University Hospitals, 1211 Geneva, Switzerland
| | - Francesco Negro
- Division of Clinical Pathology, Geneva University Hospitals, 1211 Geneva, Switzerland
- Division of Gastroenterology and Hepatology, Geneva University Hospitals, 1205 Geneva, Switzerland
| | - Dulce Alfaiate
- Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland
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14
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Hepatitis Delta Antigen Regulates mRNA and Antigenome RNA Levels during Hepatitis Delta Virus Replication. J Virol 2019; 93:JVI.01989-18. [PMID: 30728256 DOI: 10.1128/jvi.01989-18] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2018] [Accepted: 01/18/2019] [Indexed: 01/17/2023] Open
Abstract
Hepatitis delta virus (HDV) is a satellite of hepatitis B virus that increases the severity of acute and chronic liver disease. HDV produces three processed RNAs that accumulate in infected cells: the circular genome; the circular antigenome, which serves as a replication intermediate; and lesser amounts of the mRNA, which encodes the sole viral protein, hepatitis delta antigen (HDAg). The HDV genome and antigenome RNAs form ribonucleoprotein complexes with HDAg. Although HDAg is required for HDV replication, it is not known how the relative amounts of HDAg and HDV RNA affect replication, or whether HDAg synthesis is regulated by the virus. Using a novel transfection system in which HDV replication is initiated using in vitro-synthesized circular HDV RNAs, HDV replication was found to depend strongly on the relative amounts of HDV RNA and HDAg. HDV controls these relative amounts via differential effects of HDAg on the production of HDV mRNA and antigenome RNA, both of which are synthesized from the genome RNA template. mRNA synthesis is favored at low HDAg levels but becomes saturated at high HDAg concentrations. Antigenome RNA accumulation increases linearly with HDAg and dominates at high HDAg levels. These results provide a conceptual model for how HDV antigenome RNA production and mRNA transcription are controlled from the earliest stage of infection onward and also demonstrate that, in this control, HDV behaves similarly to other negative-strand RNA viruses, even though there is no genetic similarity between them.IMPORTANCE Hepatitis delta virus (HDV) is a satellite of hepatitis B virus that increases the severity of liver disease; approximately 15 million people are chronically infected worldwide. There are no licensed therapies available. HDV is not related to any known virus, and few details regarding its replication cycle are known. One key question is whether and how HDV regulates the relative amounts of viral RNA and protein in infected cells. Such regulation might be important because the HDV RNA and protein form complexes that are essential for HDV replication, and the proper stoichiometry of these complexes could be critical for their function. Our results show that the relative amounts of HDV RNA and protein in cells are indeed important for HDV replication and that the virus does control them. These observations indicate that further study of these regulatory mechanisms is required to better understand replication of this serious human pathogen.
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15
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Goodrum G, Pelchat M. Insight into the Contribution and Disruption of Host Processes during HDV Replication. Viruses 2018; 11:v11010021. [PMID: 30602655 PMCID: PMC6356607 DOI: 10.3390/v11010021] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2018] [Revised: 12/18/2018] [Accepted: 12/30/2018] [Indexed: 02/07/2023] Open
Abstract
Hepatitis delta virus (HDV) is unique among animal viruses. HDV is a satellite virus of the hepatitis B virus (HBV), however it shares no sequence similarity with its helper virus and replicates independently in infected cells. HDV is the smallest human pathogenic RNA virus and shares numerous characteristics with viroids. Like viroids, HDV has a circular RNA genome which adopts a rod-like secondary structure, possesses ribozyme domains, replicates in the nucleus of infected cells by redirecting host DNA-dependent RNA polymerases (RNAP), and relies heavily on host proteins for its replication due to its small size and limited protein coding capacity. These similarities suggest an evolutionary relationship between HDV and viroids, and information on HDV could allow a better understanding of viroids and might globally help understanding the pathogenesis and molecular biology of these subviral RNAs. In this review, we discuss the host involvement in HDV replication and its implication for HDV pathogenesis.
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Affiliation(s)
- Gabrielle Goodrum
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada.
| | - Martin Pelchat
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada.
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16
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Abeywickrama-Samarakoon N, Cortay JC, Sureau C, Alfaiate D, Levrero M, Dény P. [Hepatitis delta virus replication and the role of the small hepatitis delta protein S-HDAg]. Med Sci (Paris) 2018; 34:833-841. [PMID: 30451678 DOI: 10.1051/medsci/2018209] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Hepatitis delta virus (HDV) is a mammalian defective virus. Its genome is a small single-stranded circular RNA of approximately 1,680 nucleotides. To spread, HDV relies on hepatitis B virus envelope proteins that are needed for viral particle assembly and egress. Severe clinical features of HBV-HDV infection include acute fulminant hepatitis and chronic liver fibrosis leading to cirrhosis and hepatocellular carcinoma. One uniqueness of HDV relies on its genome similarity to viroids, small plant infectious uncoated RNAs. Devoid of viral replicase activity, HDV has to use host DNA-dependant RNA Pol II to replicate its genomic RNA. Thus, one can ask how does this replication occur? We describe first here the major steps of the viral RNA transcription and replication and then we detail the role of the Small HD protein in these processes, especially with regard to the Pol II recruitment.
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Affiliation(s)
| | - Jean-Claude Cortay
- Inserm, U1052 - UMR CNRS 5286, Centre de recherche en cancérologie de Lyon, Lyon, France
| | - Camille Sureau
- Laboratoire de virologie moléculaire, Inserm UMR S_1134, Institut National de Transfusion Sanguine, Paris, France
| | - Dulce Alfaiate
- Département de pathologie et immunologie, université de Genève, Suisse
| | - Massimo Levrero
- Inserm, U1052 - UMR CNRS 5286, Centre de recherche en cancérologie de Lyon, Lyon, France - Service d'hépato-gastroentérologie, Hôpital de la Croix Rousse, université Lyon-I, France
| | - Paul Dény
- Inserm, U1052 - UMR CNRS 5286, Centre de recherche en cancérologie de Lyon, Lyon, France - Laboratoire de microbiologie clinique, groupe des Hôpitaux universitaires de Paris-Seine Saint Denis, UFR santé médecine, biologie humaine, université Paris 13, Bobigny, France
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17
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The Hepatitis Delta Virus accumulation requires paraspeckle components and affects NEAT1 level and PSP1 localization. Sci Rep 2018; 8:6031. [PMID: 29662142 PMCID: PMC5902443 DOI: 10.1038/s41598-018-24500-1] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2017] [Accepted: 04/03/2018] [Indexed: 12/12/2022] Open
Abstract
The Hepatitis Delta Virus (HDV) relies mainly on host proteins for its replication. We previously identified that PSF and p54nrb associate with the HDV RNA genome during viral replication. Together with PSP1, these proteins are part of paraspeckles, which are subnuclear bodies nucleated by the long non-coding RNA NEAT1. In this work, we established the requirement for PSF, p54nrb and PSP1 in HDV replication using RNAi-mediated knockdown in HEK-293 cells replicating the HDV RNA genome. We determined that HDV replication induces the delocalization of PSP1 to cytoplasmic foci containing PABP and increases NEAT1 level causing an enlargement of NEAT1 foci. Overall, our data support a role for the main paraspeckles proteins in HDV life cycle and indicate that HDV replication causes a cellular stress and induces both a delocalization of the PSP1 to the cytoplasm and a disruption of paraspeckles.
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18
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Heller T, Koh C, Glenn JS. Hepatitis D. ZAKIM AND BOYER'S HEPATOLOGY 2018:501-511.e4. [DOI: 10.1016/b978-0-323-37591-7.00034-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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19
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Lempp FA, Urban S. Hepatitis Delta Virus: Replication Strategy and Upcoming Therapeutic Options for a Neglected Human Pathogen. Viruses 2017; 9:E172. [PMID: 28677645 PMCID: PMC5537664 DOI: 10.3390/v9070172] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2017] [Revised: 06/28/2017] [Accepted: 06/29/2017] [Indexed: 12/15/2022] Open
Abstract
The human Hepatitis Delta Virus (HDV) is unique among all viral pathogens. Encoding only one protein (Hepatitis Delta Antigen; HDAg) within its viroid-like self-complementary RNA, HDV constitutes the smallest known virus in the animal kingdom. To disseminate in its host, HDV depends on a helper virus, the human Hepatitis B virus (HBV), which provides the envelope proteins required for HDV assembly. HDV affects an estimated 15-20 million out of the 240 million chronic HBV-carriers and disperses unequally in disparate geographical regions of the world. The disease it causes (chronic Hepatitis D) presents as the most severe form of viral hepatitis, leading to accelerated progression of liver dysfunction including cirrhosis and hepatocellular carcinoma and a high mortality rate. The lack of approved drugs interfering with specific steps of HDV replication poses a high burden for gaining insights into the molecular biology of the virus and, consequently, the development of specific novel medications that resiliently control HDV replication or, in the best case, functionally cure HDV infection or HBV/HDV co-infection. This review summarizes our current knowledge of HBV molecular biology, presents an update on novel cell culture and animal models to study the virus and provides updates on the clinical development of the three developmental drugs Lonafarnib, REP2139-Ca and Myrcludex B.
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Affiliation(s)
- Florian A Lempp
- Department of Infectious Diseases, Molecular Virology, Heidelberg University, Im Neuenheimer Feld 345, 69120 Heidelberg, Germany.
- German Centre for Infection Research (DZIF), Partner Site Heidelberg, 69120 Heidelberg, Germany.
| | - Stephan Urban
- Department of Infectious Diseases, Molecular Virology, Heidelberg University, Im Neuenheimer Feld 345, 69120 Heidelberg, Germany.
- German Centre for Infection Research (DZIF), Partner Site Heidelberg, 69120 Heidelberg, Germany.
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20
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Lempp FA, Ni Y, Urban S. Hepatitis delta virus: insights into a peculiar pathogen and novel treatment options. Nat Rev Gastroenterol Hepatol 2016; 13:580-9. [PMID: 27534692 DOI: 10.1038/nrgastro.2016.126] [Citation(s) in RCA: 107] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Chronic hepatitis D is the most severe form of viral hepatitis, affecting ∼20 million HBV-infected people worldwide. The causative agent, hepatitis delta virus (HDV), is a unique human pathogen: it is the smallest known virus; it depends on HBV to disseminate its viroid-like RNA; it encodes only one protein (HDAg), which has both structural and regulatory functions; and it replicates using predominantly host proteins. The failure of HBV-specific nucleoside analogues to suppress the HBV helper function, and the limitations of experimental systems to study the HDV life cycle, have impeded the development of HDV-specific drugs. Thus, the only clinical regimen for HDV is IFNα, which shows some efficacy but long-term virological responses are rare. Insights into the receptor-mediated entry of HDV, and the observation that HDV assembly requires farnesyltransferase, have enabled novel therapeutic strategies to be developed. Interference with entry, for example through blockade of the HBV-HDV-specific receptor sodium/taurocholate cotransporting polypeptide NTCP by Myrcludex B, and inhibition of assembly by blockade of farnesyltransferase using lonafarnib or nucleic acid polymers such as REP 2139-Ca, have shown promising results in phase II studies. In this Review, we summarize our knowledge of HDV epidemiology, pathogenesis and molecular biology, with a particular emphasis on possible future developments.
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Affiliation(s)
- Florian A Lempp
- Department of Infectious Diseases, Molecular Virology, University Hospital Heidelberg, Im Neuenheimer Feld 345, 69120 Heidelberg, Germany
| | - Yi Ni
- Department of Infectious Diseases, Molecular Virology, University Hospital Heidelberg, Im Neuenheimer Feld 345, 69120 Heidelberg, Germany.,German Center for Infection Research (DZIF), Heidelberg Partner Site, Im Neuenheimer Feld 324, 69120 Heidelberg, Germany
| | - Stephan Urban
- Department of Infectious Diseases, Molecular Virology, University Hospital Heidelberg, Im Neuenheimer Feld 345, 69120 Heidelberg, Germany.,German Center for Infection Research (DZIF), Heidelberg Partner Site, Im Neuenheimer Feld 324, 69120 Heidelberg, Germany
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21
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Sureau C, Negro F. The hepatitis delta virus: Replication and pathogenesis. J Hepatol 2016; 64:S102-S116. [PMID: 27084031 DOI: 10.1016/j.jhep.2016.02.013] [Citation(s) in RCA: 186] [Impact Index Per Article: 20.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2015] [Revised: 02/01/2016] [Accepted: 02/10/2016] [Indexed: 02/06/2023]
Abstract
Hepatitis delta virus (HDV) is a defective virus and a satellite of the hepatitis B virus (HBV). Its RNA genome is unique among animal viruses, but it shares common features with some plant viroids, including a replication mechanism that uses a host RNA polymerase. In infected cells, HDV genome replication and formation of a nucleocapsid-like ribonucleoprotein (RNP) are independent of HBV. But the RNP cannot exit, and therefore propagate, in the absence of HBV, as the latter supplies the propagation mechanism, from coating the HDV RNP with the HBV envelope proteins for cell egress to delivery of the HDV virions to the human hepatocyte target. HDV is therefore an obligate satellite of HBV; it infects humans either concomitantly with HBV or after HBV infection. HDV affects an estimated 15 to 20 million individuals worldwide, and the clinical significance of HDV infection is more severe forms of viral hepatitis--acute or chronic--, and a higher risk of developing cirrhosis and hepatocellular carcinoma in comparison to HBV monoinfection. This review covers molecular aspects of HDV replication cycle, including its interaction with the helper HBV and the pathogenesis of infection in humans.
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Affiliation(s)
- Camille Sureau
- Molecular Virology laboratory, Institut National de la Transfusion Sanguine (INTS), CNRS INSERM U1134, Paris, France.
| | - Francesco Negro
- Division of Gastroenterology and Hepatology, University Hospitals, Geneva, Switzerland; Division of Clinical Pathology, University Hospitals, Geneva, Switzerland.
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22
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Cunha C, Tavanez JP, Gudima S. Hepatitis delta virus: A fascinating and neglected pathogen. World J Virol 2015; 4:313-322. [PMID: 26568914 PMCID: PMC4641224 DOI: 10.5501/wjv.v4.i4.313] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2015] [Revised: 08/21/2015] [Accepted: 10/27/2015] [Indexed: 02/05/2023] Open
Abstract
Hepatitis delta virus (HDV) is the etiologic agent of the most severe form of virus hepatitis in humans. Sharing some structural and functional properties with plant viroids, the HDV RNA contains a single open reading frame coding for the only virus protein, the Delta antigen. A number of unique features, including ribozyme activity, RNA editing, rolling-circle RNA replication, and redirection for a RNA template of host DNA-dependent RNA polymerase II, make this small pathogen an excellent model to study virus-cell interactions and RNA biology. Treatment options for chronic hepatitis Delta are scarce and ineffective. The disease burden is perhaps largely underestimated making the search for new, specific drugs, targets, and treatment strategies an important public health challenge. In this review we address the main features of virus structure, replication, and interaction with the host. Virus pathogenicity and current treatment options are discussed in the light of recent developments.
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23
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Abstract
This work reviews specific related aspects of hepatitis delta virus (HDV) reproduction, including virion structure, the RNA genome, the mode of genome replication, the delta antigens, and the assembly of HDV using the envelope proteins of its helper virus, hepatitis B virus (HBV). These topics are considered with perspectives ranging from a history of discovery through to still-unsolved problems. HDV evolution, virus entry, and associated pathogenic potential and treatment of infections are considered in other articles in this collection.
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Affiliation(s)
- John M Taylor
- Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111
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24
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Alfaiate D, Dény P, Durantel D. Hepatitis delta virus: From biological and medical aspects to current and investigational therapeutic options. Antiviral Res 2015; 122:112-29. [PMID: 26275800 DOI: 10.1016/j.antiviral.2015.08.009] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2015] [Revised: 08/10/2015] [Accepted: 08/11/2015] [Indexed: 12/14/2022]
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25
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Abstract
Because RNA can be a carrier of genetic information and a biocatalyst, there is a consensus that it emerged before DNA and proteins, which eventually assumed these roles and relegated RNA to intermediate functions. If such a scenario--the so-called RNA world--existed, we might hope to find its relics in our present world. The properties of viroids that make them candidates for being survivors of the RNA world include those expected for primitive RNA replicons: (a) small size imposed by error-prone replication, (b) high G + C content to increase replication fidelity, (c) circular structure for assuring complete replication without genomic tags, (d) structural periodicity for modular assembly into enlarged genomes, (e) lack of protein-coding ability consistent with a ribosome-free habitat, and (f) replication mediated in some by ribozymes, the fingerprint of the RNA world. With the advent of DNA and proteins, those protoviroids lost some abilities and became the plant parasites we now know.
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Affiliation(s)
- Ricardo Flores
- Instituto de Biología Molecular y Celular de Plantas (UPV-CSIC), 46022 València, Spain;
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26
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The unexpected roles of eukaryotic translation elongation factors in RNA virus replication and pathogenesis. Microbiol Mol Biol Rev 2014; 77:253-66. [PMID: 23699257 DOI: 10.1128/mmbr.00059-12] [Citation(s) in RCA: 90] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
The prokaryotic translation elongation factors were identified as essential cofactors for RNA-dependent RNA polymerase activity of the bacteriophage Qβ more than 40 years ago. A growing body of evidence now shows that eukaryotic translation elongation factors (eEFs), predominantly eEF1A, acting in partially characterized complexes sometimes involving additional eEFs, facilitate virus replication. The functions of eEF1A as a protein chaperone and an RNA- and actin-binding protein enable its "moonlighting" roles as a virus replication cofactor. A diverse group of viruses, from human immunodeficiency type 1 and West Nile virus to tomato bushy stunt virus, have adapted to use eEFs as cofactors for viral transcription, translation, assembly, and pathogenesis. Here we review the mechanisms used by viral pathogens to usurp these abundant cellular proteins for their replication.
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27
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Taylor JM. Host RNA circles and the origin of hepatitis delta virus. World J Gastroenterol 2014; 20:2971-2978. [PMID: 24659888 PMCID: PMC3961984 DOI: 10.3748/wjg.v20.i11.2971] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2013] [Revised: 12/20/2013] [Accepted: 02/20/2014] [Indexed: 02/06/2023] Open
Abstract
Recent reports show that many cellular RNAs are processed to form circular species that are relatively abundant and resistant to host nucleases. In some cases, such circles actually bind host microRNAs. Such depletion of available microRNAs appears to have biological roles; for instance, in homeostasis and disease. These findings regarding host RNA circles support a speculative reappraisal of the origin and mode of replication of hepatitis delta virus, hepatitis delta virus (HDV), an agent with a small circular RNA genome; specifically, it is proposed that in hepatocytes infected with hepatitis B virus (HBV), some viral RNA species are processed to circular forms, which by a series of chance events lead to an RNA that can be both replicated by host enzymes and assembled, using HBV envelope proteins, to form particles some of which are infectious. Such a model also may provide some new insights into the potential pathogenic potential of HDV infections. In return, new insights into HDV might provide information leading to a better understanding of the roles of the host RNA circles.
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28
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Beeharry Y, Rocheleau L, Pelchat M. Conserved features of an RNA promoter for RNA polymerase II determined from sequence heterogeneity of a hepatitis delta virus population. Virology 2014; 450-451:165-73. [DOI: 10.1016/j.virol.2013.12.017] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2013] [Revised: 12/11/2013] [Accepted: 12/15/2013] [Indexed: 01/08/2023]
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29
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Hepatitis delta virus: a peculiar virus. Adv Virol 2013; 2013:560105. [PMID: 24198831 PMCID: PMC3807834 DOI: 10.1155/2013/560105] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2013] [Revised: 08/29/2013] [Accepted: 08/29/2013] [Indexed: 02/07/2023] Open
Abstract
The hepatitis delta virus (HDV) is distributed worldwide and related to the most severe form of viral hepatitis. HDV is a satellite RNA virus dependent on hepatitis B surface antigens to assemble its envelope and thus form new virions and propagate infection. HDV has a small 1.7 Kb genome making it the smallest known human virus. This deceivingly simple virus has unique biological features and many aspects of its life cycle remain elusive. The present review endeavors to gather the available information on HDV epidemiology and clinical features as well as HDV biology.
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30
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Sikora D, Zhang D, Bojic T, Beeharry Y, Tanara A, Pelchat M. Identification of a binding site for ASF/SF2 on an RNA fragment derived from the hepatitis delta virus genome. PLoS One 2013; 8:e54832. [PMID: 23349975 PMCID: PMC3548785 DOI: 10.1371/journal.pone.0054832] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2012] [Accepted: 12/19/2012] [Indexed: 02/07/2023] Open
Abstract
The hepatitis delta virus (HDV) is a small (∼1700 nucleotides) RNA pathogen which encodes only one open reading frame. Consequently, HDV is dependent on host proteins to replicate its RNA genome. Recently, we reported that ASF/SF2 binds directly and specifically to an HDV-derived RNA fragment which has RNA polymerase II promoter activity. Here, we localized the binding site of ASF/SF2 on the HDV RNA fragment by performing binding experiments using purified recombinant ASF/SF2 combined with deletion analysis and site-directed mutagenesis. In addition, we investigated the requirement of ASF/SF2 for HDV RNA replication using RNAi-mediated knock-down of ASF/SF2 in 293 cells replicating HDV RNA. Overall, our results indicate that ASF/SF2 binds to a purine-rich region distant from both the previously published initiation site of HDV mRNA transcription and binding site of RNAP II, and suggest that this protein is not involved in HDV replication in the cellular system used.
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Affiliation(s)
- Dorota Sikora
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, Canada
| | - Dajiang Zhang
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, Canada
| | - Teodora Bojic
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, Canada
| | - Yasnee Beeharry
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, Canada
| | - Ali Tanara
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, Canada
| | - Martin Pelchat
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, Canada
- * E-mail:
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31
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Liao FT, Hsu LS, Ko JL, Lin CC, Sheu GT. Multiple genomic sequences of hepatitis delta virus are associated with cDNA promoter activity and RNA double rolling-circle replication. J Gen Virol 2012; 93:577-587. [DOI: 10.1099/vir.0.037507-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
To understand how DNA-dependent RNA polymerase II (pol II) recognizes hepatitis delta virus (HDV) RNA as a template, it is first necessary to identify the HDV sequence that acts as a promoter of pol II-initiated RNA synthesis. Therefore, we isolated the pol II-response element from HDV cDNA and examined the regulation by hepatitis delta antigens (HDAgs). Two HDV cDNA fragments containing bidirectional promoter activity were identified. One was located at nt 1582–1683 (transcription-promoter region 1, TR-P1) and the other at nt 1223–1363 (transcription-internal region 5, TR-I5). The promoter activities of these two regions were enhanced by HDAgs to differing degrees. Next, the role of these sequences in an HDV cDNA-free RNA replication system was characterized by site-directed mutagenesis. Our data showed that: (i) the AUG codon at the HDAg ORF of HDV RNA (nt 1599–1601) that mutates to UAG (amber stop codon) results in loss of dimeric but not monomeric HDV RNA synthesis. (ii) A 5 nt mutation of TR-P1 (P1-m5, nt 1670–1674) abolishes RNA replication completely. Two-nucleotide-mutated RNA (P1-m2, nt 1662–1663) is able to synthesize short RNAs but not monomeric HDV RNA. (iii) A mutation in 5 nt at the TR-I5 region (I5-m5, nt 1351–1355) also abolishes HDV replication. Mutants with 2 nt mutations (I5-m2, nt 1351–1352) or 3 nt mutations (I5-m3, nt 1353–1355) inhibit HDV dimeric but not monomeric RNA synthesis. Furthermore, large HDAg is expressed in cells transfected with I5-m3 and I5-m2 RNAs and that demonstrate the RNA-editing event in the monomeric HDV RNA. These results provide further understanding of the double rolling-circle mechanism in HDV RNA replication.
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Affiliation(s)
- Fu-Tien Liao
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan, ROC
| | - Li-Sung Hsu
- Institute of Biochemistry and Biotechnology, Chung Shan Medical University, Taichung, Taiwan, ROC
| | - Jiunn-Liang Ko
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan, ROC
| | - Chun-Che Lin
- Department of Internal Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan, ROC
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan, ROC
| | - Gwo-Tarng Sheu
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan, ROC
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Abstract
This article addresses some of the questions relating to how hepatitis delta virus (HDV), an agent so far unique in the animal world, might have arisen. HDV was discovered in patients infected with hepatitis B virus (HBV). It generally makes HBV infections more damaging to the liver. It is a subviral satellite agent that depends upon HBV envelope proteins for its assembly and ability to infect new cells. In other aspects of replication, HDV is both independent of and very different from HBV. In addition, the small single-stranded circular RNA genome of HDV, and its mechanism of replication, demonstrate an increasing number of similarities to the viroids - a large family of helper-independent subviral agents that cause pathogenesis in plants.
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Affiliation(s)
- John Taylor
- Chase Cancer Center, PA 19111, USA, Tel.: +1 215 728 2436, Fax: +1 215 728 2412,
| | - Martin Pelchat
- Department of Biochemistry, Microbiology & Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada, Tel.: +1 613 562 5800 ext. 8846, Fax: +1 613 562 5452,
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33
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Interaction of host cellular proteins with components of the hepatitis delta virus. Viruses 2010; 2:189-212. [PMID: 21994607 PMCID: PMC3185554 DOI: 10.3390/v2010189] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2009] [Revised: 01/13/2010] [Accepted: 01/14/2010] [Indexed: 12/18/2022] Open
Abstract
The hepatitis delta virus (HDV) is the smallest known RNA pathogen capable of propagation in the human host and causes substantial global morbidity and mortality. Due to its small size and limited protein coding capacity, HDV is exquisitely reliant upon host cellular proteins to facilitate its transcription and replication. Remarkably, HDV does not encode an RNA-dependent RNA polymerase which is traditionally required to catalyze RNA-templated RNA synthesis. Furthermore, HDV lacks enzymes responsible for post-transcriptional and -translational modification, processes which are integral to the HDV life cycle. This review summarizes the known HDV-interacting proteins and discusses their significance in HDV biology.
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34
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Phosphorylation of serine 177 of the small hepatitis delta antigen regulates viral antigenomic RNA replication by interacting with the processive RNA polymerase II. J Virol 2009; 84:1430-8. [PMID: 19923176 DOI: 10.1128/jvi.02083-09] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Recent studies revealed that posttranslational modifications (e.g., phosphorylation and methylation) of the small hepatitis delta antigen (SHDAg) are required for hepatitis delta virus (HDV) replication from antigenomic to genomic RNA. The phosphorylation of SHDAg at serine 177 (Ser(177)) is involved in this step, and this residue is crucial for interaction with RNA polymerase II (RNAP II), the enzyme assumed to be responsible for antigenomic RNA replication. This study demonstrated that SHDAg dephosphorylated at Ser(177) interacted preferentially with hypophosphorylated RNAP II (RNAP IIA), which generally binds at the transcription initiation sites. In contrast, the Ser(177)-phosphorylated counterpart (pSer(177)-SHDAg) exhibited preferential binding to hyperphosphorylated RNAP II (RNAP IIO). In addition, RNAP IIO associated with pSer(177)-SHDAg was hyperphosphorylated at both the Ser(2) and Ser(5) residues of its carboxyl-terminal domain (CTD), which is a hallmark of the transcription elongation isoform. Moreover, the RNAP II CTD kinase inhibitor 5,6-dichloro-1-beta-D-ribofuranosyl-benzimidazole (DRB) not only blocked the interaction between pSer(177)-SHDAg and RNAP IIO but also inhibited HDV antigenomic RNA replication. Our results suggest that the phosphorylation of SHDAg at Ser177 shifted its affinitytoward the RNAP IIO isoform [corrected] and thus is a switch for HDV antigenomic RNA replication from the initiation to the elongation stage.
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35
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Hepatitis delta virus RNA replication. Viruses 2009; 1:818-31. [PMID: 21994571 PMCID: PMC3185533 DOI: 10.3390/v1030818] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2009] [Revised: 11/03/2009] [Accepted: 11/03/2009] [Indexed: 12/12/2022] Open
Abstract
Hepatitis delta virus (HDV) is a distant relative of plant viroids in the animal world. Similar to plant viroids, HDV replicates its circular RNA genome using a double rolling-circle mechanism. Nevertheless, the production of hepatitis delta antigen (HDAg), which is indispensible for HDV replication, is a unique feature distinct from plant viroids, which do not encode any protein. Here the HDV RNA replication cycle is reviewed, with emphasis on the function of HDAg in modulating RNA replication and the nature of the enzyme involved.
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36
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Abstract
Regulation of protein synthesis by viruses occurs at all levels of translation. Even prior to protein synthesis itself, the accessibility of the various open reading frames contained in the viral genome is precisely controlled. Eukaryotic viruses resort to a vast array of strategies to divert the translation machinery in their favor, in particular, at initiation of translation. These strategies are not only designed to circumvent strategies common to cell protein synthesis in eukaryotes, but as revealed more recently, they also aim at modifying or damaging cell factors, the virus having the capacity to multiply in the absence of these factors. In addition to unraveling mechanisms that may constitute new targets in view of controlling virus diseases, viruses constitute incomparably useful tools to gain in-depth knowledge on a multitude of cell pathways.
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Abstract
Hepatitis delta virus (HDV) is a subviral agent dependent upon hepatitis B virus (HBV). HDV uses the envelope proteins of HBV to achieve assembly and infection of target cells. Otherwise, the replication of the RNA genome of HDV is totally different from that of its helper virus, and involves redirection of host polymerase activity. This chapter is concerned with recent developments in our understanding of the genome replication process.
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Affiliation(s)
- John M Taylor
- Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA
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38
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Sikora D, Greco-Stewart VS, Miron P, Pelchat M. The hepatitis delta virus RNA genome interacts with eEF1A1, p54(nrb), hnRNP-L, GAPDH and ASF/SF2. Virology 2009; 390:71-8. [PMID: 19464723 DOI: 10.1016/j.virol.2009.04.022] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2009] [Revised: 03/26/2009] [Accepted: 04/29/2009] [Indexed: 02/08/2023]
Abstract
Because of its extremely limited coding capacity, the hepatitis delta virus (HDV) takes over cellular machineries for its replication and propagation. Despite the functional importance of host factors in both HDV biology and pathogenicity, little is known about proteins that associate with its RNA genome. Here, we report the identification of several host proteins interacting with an RNA corresponding to the right terminal stem-loop domain of HDV genomic RNA, using mass spectrometry on a UV crosslinked ribonucleoprotein complex, RNA affinity chromatography, and screening of a library of purified RNA-binding proteins. Co-immunoprecipitation was used to confirm the interactions of eEF1A1, p54(nrb), hnRNP-L, GAPDH and ASF/SF2 with the right terminal stem-loop domain of HDV genomic RNA in vitro, and with both polarities of HDV RNA within HeLa cells. Our discovery that HDV RNA associates with RNA-processing pathways and translation machinery during its replication provides new insights into HDV biology and its pathogenicity.
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Affiliation(s)
- Dorota Sikora
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Room 4111A, Ottawa, Ontario, Canada, K1H 8M5
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Abrahem A, Pelchat M. Formation of an RNA polymerase II preinitiation complex on an RNA promoter derived from the hepatitis delta virus RNA genome. Nucleic Acids Res 2008; 36:5201-11. [PMID: 18682525 PMCID: PMC2532721 DOI: 10.1093/nar/gkn501] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023] Open
Abstract
Although RNA polymerases (RNAPs) are able to use RNA as template, it is unknown how they recognize RNA promoters. In this study, we used an RNA fragment derived from the hepatitis delta virus (HDV) genome as a model to investigate the recognition of RNA promoters by RNAP II. Inhibition of the transcription reaction using an antibody specific to the largest subunit of RNAP II and the direct binding of purified RNAP II to the RNA promoter confirmed the involvement of RNAP II in the reaction. RNA affinity chromatography established that an active RNAP II preinitiation complex forms on the RNA promoter and indicated that this complex contains the core RNAP II subunit and the general transcription factors TFIIA, TFIIB, TFIID, TFIIE, TFIIF, TFIIH and TFIIS. Binding assays demonstrated the direct binding of the TATA-binding protein and suggested that this protein is required to nucleate the RNAP II complex on the RNA promoter. Our findings provide a better understanding of the events leading to RNA promoter recognition by RNAP II.
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Affiliation(s)
- Abrahem Abrahem
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, K1H 8M5, Canada
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40
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Transcription of subgenomic mRNA of hepatitis delta virus requires a modified hepatitis delta antigen that is distinct from antigenomic RNA synthesis. J Virol 2008; 82:9409-16. [PMID: 18653455 DOI: 10.1128/jvi.00428-08] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Hepatitis delta virus (HDV) contains a viroid-like, 1.7-kb circular RNA genome, which replicates via a double-rolling-circle model. However, the exact mechanism involved in HDV genome RNA replication and subgenomic mRNA transcription is still unclear. Our previous studies have shown that the replications of genomic and antigenomic HDV RNA strands have different sensitivities to alpha-amanitin and are associated with different nuclear bodies, suggesting that these two strands are synthesized in different transcription machineries in the cells. In this study, we developed a unique quantitative reverse transcription-PCR (qRT-PCR) procedure for detection of various HDV RNA species from an RNA transfection system. Using this qRT-PCR procedure and a series of HDV mutants, we demonstrated that Arg-13 methylation, Lys-72 acetylation, and Ser-177 phosphorylation of small hepatitis delta antigen (S-HDAg) are important for HDV mRNA transcription. In addition, these three S-HDAg modifications are dispensable for antigenomic RNA synthesis but are required for genomic RNA synthesis. Furthermore, the three RNA species had different sensitivities to acetylation and deacetylation inhibitors, showing that the metabolic requirements for the synthesis of HDV antigenomic RNA are different from those for the synthesis of genomic RNA and mRNA. In sum, our data support the hypothesis that the cellular machinery involved in the synthesis of HDV antigenomic RNA is different from that of genomic RNA synthesis and mRNA transcription, even though the antigenomic RNA and the mRNA are made from the same RNA template. We propose that acetylation and deacetylation of HDAg may provide a molecular switch for the synthesis of the different HDV RNA species.
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41
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Transcription factor YY1 and its associated acetyltransferases CBP and p300 interact with hepatitis delta antigens and modulate hepatitis delta virus RNA replication. J Virol 2008; 82:7313-24. [PMID: 18480431 DOI: 10.1128/jvi.02581-07] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Hepatitis delta virus (HDV) is a pathogenic RNA virus with a plant viroid-like genome structure. HDV encodes two isoforms of delta antigen (HDAg), the small and large forms of HDAg (SHDAg and LHDAg), which are essential for HDV RNA replication and virion assembly, respectively. Replication of HDV RNA depends on host cellular transcription machinery, and the exact molecular mechanism for HDV RNA replication is still unclear. In this study, we demonstrated that both isoforms of HDAg interact with transcription factor YY1 (Yin Yang 1) in vivo and in vitro. Their interaction domains were identified as the middle region encompassing the RNA binding domain of HDAg and the middle GA/GK-rich region and the C-terminal zinc-finger region of YY1. Results of sucrose gradient centrifugation analysis indicated the cosedimentation of the majority of SHDAg and a portion of the LHDAg with YY1 and its associated acetyltransferases CBP (CREB-binding protein) and p300 as a large nuclear complex in vivo. Furthermore, exogenous expression of YY1 or CBP/p300 in HDV RNA replication system showed an enhancement of HDV RNA replication. Interestingly, the acetyltransferase activity of p300 is important for this enhancement. Moreover, SHDAg could be acetylated in vivo, and treatment with cellular deacetylase inhibitor elevated the replication of HDV RNA and acetylation of SHDAg. All together, our results reveal that HDAg interacts with cellular transcription factor YY1 and its associated acetyltransferases CBP and p300 in a large nuclear complex, which in turn modulates the replication of HDV RNA.
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42
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Chang J, Nie X, Chang HE, Han Z, Taylor J. Transcription of hepatitis delta virus RNA by RNA polymerase II. J Virol 2008; 82:1118-27. [PMID: 18032511 PMCID: PMC2224410 DOI: 10.1128/jvi.01758-07] [Citation(s) in RCA: 78] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2007] [Accepted: 11/06/2007] [Indexed: 12/11/2022] Open
Abstract
Previous studies have indicated that the replication of the RNA genome of hepatitis delta virus (HDV) involves redirection of RNA polymerase II (Pol II), a host enzyme that normally uses DNA as a template. However, there has been some controversy about whether in one part of this HDV RNA transcription, a polymerase other than Pol II is involved. The present study applied a recently described cell system (293-HDV) of tetracycline-inducible HDV RNA replication to provide new data regarding the involvement of host polymerases in HDV transcription. The data generated with a nuclear run-on assay demonstrated that synthesis not only of genomic RNA but also of its complement, the antigenome, could be inhibited by low concentrations of amanitin specific for Pol II transcription. Subsequent studies used immunoprecipitation and rate-zonal sedimentation of nuclear extracts together with double immunostaining of 293-HDV cells, in order to examine the associations between Pol II and HDV RNAs, as well as the small delta antigen, an HDV-encoded protein known to be essential for replication. Findings include evidence that HDV replication is somehow able to direct the available delta antigen to sites in the nucleoplasm, almost exclusively colocalized with Pol II in what others have described as transcription factories.
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Affiliation(s)
- Jinhong Chang
- Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111-2497, USA
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43
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Greco-Stewart VS, Miron P, Abrahem A, Pelchat M. The human RNA polymerase II interacts with the terminal stem-loop regions of the hepatitis delta virus RNA genome. Virology 2006; 357:68-78. [PMID: 16959288 DOI: 10.1016/j.virol.2006.08.010] [Citation(s) in RCA: 53] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2006] [Revised: 06/02/2006] [Accepted: 08/07/2006] [Indexed: 12/28/2022]
Abstract
The hepatitis delta virus (HDV) is an RNA virus that depends on DNA-dependent RNA polymerase (RNAP) for its transcription and replication. While it is generally accepted that RNAP II is involved in HDV replication, its interaction with HDV RNA requires confirmation. A monoclonal antibody specific to the carboxy terminal domain of the largest subunit of RNAP II was used to establish the association of RNAP II with both polarities of HDV RNA in HeLa cells. Co-immunoprecipitations using HeLa nuclear extract revealed that RNAP II interacts with HDV-derived RNAs at sites located within the terminal stem-loop domains of both polarities of HDV RNA. Analysis of these regions revealed a strong selection to maintain a rod-like conformation and demonstrated several conserved features. These results provide the first direct evidence of an association between human RNAP II and HDV RNA and suggest two transcription start sites on both polarities of HDV RNA.
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Affiliation(s)
- Valerie S Greco-Stewart
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada K1H 8M5
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44
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Abstract
While this volume covers many different aspects of hepatitis delta virus (HDV) replication, the focus in this chapter is on studies of the structure and replication of the HDV RNA genome. An evaluation of such studies is not only an integral part of our understanding of HDV infections but it also sheds new light on some important aspects of cell biology, such as the fidelity of RNA transcription by a host RNA polymerase and on various forms of post-transcriptional RNA processing. Representations of the replication of the RNA genome are frequently simplified to a form of rolling-circle model, analogous to what have been described for plant viroids. One theme of this review is that such models, even after some revision, deceptively simplify the complexity of HDV replication and can fail to make clear major questions yet to be solved.
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Affiliation(s)
- J M Taylor
- Fox Chase Cancer Center, Philadelphia, PA 19111-2497, USA.
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45
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Abstract
HDV replicates its circular RNA genome using a double rolling-circle mechanism and transcribes a hepatitis delta antigen-encodeing mRNA from the same RNA template during its life cycle. Both processes are carried out by RNA-dependent RNA synthesis despite the fact that HDV does not encode an RNA-dependent RNA polymerase (RdRP). Cellular RNA polymerase II has long been implicated in these processes. Recent findings, however, have shown that the syntheses of genomic and antigenomic RNA strands have different metabolic requirements, including sensitives to alpha-amanitin and the site of synthesis. Evidence is summarized here for the involvement of other cellular polymerases, probably pol I, in the synthesis of antigenomic RNA strand. The ability of mammalian cells to replicate HDV RNA implies that RNA-dependent RNA synthesis was preserved throughout evolution.
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Affiliation(s)
- T B Macnaughton
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles 90033, USA
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46
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Greco-Stewart VS, Thibault CSL, Pelchat M. Binding of the polypyrimidine tract-binding protein-associated splicing factor (PSF) to the hepatitis delta virus RNA. Virology 2006; 356:35-44. [PMID: 16938326 DOI: 10.1016/j.virol.2006.06.040] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2006] [Revised: 04/04/2006] [Accepted: 06/09/2006] [Indexed: 12/17/2022]
Abstract
The hepatitis delta virus (HDV) has a very limited protein coding capacity and must rely on host proteins for its replication. A ribonucleoprotein complex was detected following UV cross-linking between HeLa nuclear proteins and an RNA corresponding to the right terminal stem-loop domain of HDV genomic RNA. Mass spectrometric analysis of the complex revealed the polypyrimidine tract-binding protein-associated splicing factor (PSF) as a novel HDV RNA-interacting protein. Co-immunoprecipitation demonstrated the interaction between HDV RNA and PSF both in vitro in HeLa nuclear extract and in vivo within HeLa cells containing both polarities of the HDV genome. Analysis of the binding of various HDV-derived RNAs to purified, recombinant PSF further confirmed the specificity of the interaction and revealed that PSF directly binds to the terminal stem-loop domains of both polarities of HDV RNA. Our findings provide evidence of the involvement of a host mRNA processing protein in the HDV life cycle.
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Affiliation(s)
- Valerie S Greco-Stewart
- Department of Biochemistry, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Room 4223A, Ottawa, ON, Canada K1H 8M5
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47
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Gudima SO, Chang J, Taylor JM. Restoration in vivo of defective hepatitis delta virus RNA genomes. RNA (NEW YORK, N.Y.) 2006; 12:1061-73. [PMID: 16618966 PMCID: PMC1464851 DOI: 10.1261/rna.2328806] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/08/2023]
Abstract
The 1679-nt single-stranded RNA genome of hepatitis delta virus (HDV) is circular in conformation. It is able to fold into an unbranched rodlike structure via intramolecular base-pairing. This RNA is replicated by host RNA polymerase II (Pol II). Such transcription is unique, because Pol II is known only for its ability to act on DNA templates. The present study addressed the ability of the HDV RNA replication to tolerate insertions of up to 1000 nt of non-HDV sequence either at an end of the rodlike RNA structure or at a site embedded within the rod. The insertions did not interfere with the ability of primary transcripts to be processed in vivo by ribozyme cleavage and ligation. The insertions greatly reduced the ability of genomes to replicate. However, when total RNA from such transfected cells was used to transfect new recipient cells, replicating HDV RNAs could be detected by Northern analyses. The size of the emerged RNAs was consistent with loss of the inserted sequences. RT-PCR, cloning, and sequencing showed that recovery involved removal of inserted sequences with or without small deletions of adjacent RNA sequences. Such restoration of the RNA genome is consistent with a model requiring intramolecular template-switching (RNA recombination) during RNA-directed transcription, in combination with biological selection for maintenance of the rodlike structure of the template.
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48
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Abstract
Hepatitis delta virus (HDV) is a sub-viral agent that is dependent for its life cycle on hepatitis B virus (HBV). The help it obtains from HBV is limited to the sharing of envelope proteins. These proteins are needed to facilitate the assembly of the HDV genome into new virus particles, and in turn, to allow the attachment and entry of HDV into new host cells. In other respects, the replication of the small single-stranded circular RNA genome of HDV is independent of HBV. HDV genome replication produces two forms of a RNA-binding protein known as the long and small delta antigens (Ag). All other proteins needed for HDV genome replication, especially the RNA-directed RNA polymerase activity, are provided by the host cell. This mini-review article is a mixture of personal perspective and speculations about the future of HDV research. It starts with a brief overview of HDV and its replication, notes some of the major unresolved questions, and directs the interested reader to more detailed reviews.
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Affiliation(s)
- John M Taylor
- Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111-2497, USA.
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49
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Chang J, Gudima SO, Taylor JM. Evolution of hepatitis delta virus RNA genome following long-term replication in cell culture. J Virol 2005; 79:13310-6. [PMID: 16227253 PMCID: PMC1262577 DOI: 10.1128/jvi.79.21.13310-13316.2005] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Previous studies have defined a novel cell culture system in which a modified RNA genome of hepatitis delta virus (HDV) is able to maintain a low level of continuous replication for at least 1 year, using a separate and limited DNA-directed source of mRNA for the essential small delta protein. This mode of replication is analogous to that used by plant viroids. An examination was made of the nucleotide changes that accumulated on the HDV RNA during 1 year of replication. The length of the RNA genome was maintained, except for some single-nucleotide deletions and insertions. There was an abundance of single-nucleotide substitutions, with a 22-fold excess of these being base transitions rather than transversions. Of the detected transitions, at least 70% were consistent with being the consequences of posttranscriptional RNA editing by an adenosine deaminase acting on RNA. The remainder of the changes, including the single-nucleotide insertions and deletions, are likely to be the consequence of misincorporation during transcription. In addition, an intermolecular competition assay was used to show that the majority of the genomes present after 1 year of replication were essentially as competent in replication as the original single HDV RNA sequence that was used to initiate the genome replication. A model is provided to explain how, in this experimental system, the observed single-nucleotide changes were essentially neutral in terms of their effect on the ability of the HDV genome to carry out continued rounds of replication.
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Affiliation(s)
- Jinhong Chang
- Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, Pennsylvania 19111-2497.
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50
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Gudima SO, Chang J, Taylor JM. Reconstitution in cultured cells of replicating HDV RNA from pairs of less than full-length RNAs. RNA (NEW YORK, N.Y.) 2005; 11:90-8. [PMID: 15574517 PMCID: PMC1370694 DOI: 10.1261/rna.7164905] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/20/2004] [Accepted: 10/11/2004] [Indexed: 05/24/2023]
Abstract
The genome of hepatitis delta virus (HDV) is a small single-stranded circular RNA that is replicated via RNA-directed RNA synthesis. This makes use of a host RNA polymerase, probably pol II, that normally transcribes DNA templates. In vivo, the host polymerase can initiate replication from transfected linear RNAs using intramolecular template-switching. The present studies report that the polymerase could also achieve intermolecular switching leading to "reconstitution" of full-length HDV RNAs following transfection with two linear RNAs that were less than full length and yet lacking different regions of the genome. These two RNAs were synthesized in vitro, gel purified, pre-annealed, and then transfected into delta293, a cell line conditionally expressing the small delta antigen that is essential for HDV replication. Northern analyses of total RNA harvested from transfected cells detected the accumulation of full-length HDV genomic and antigenomic RNAs. Such reconstitution of full-length replicating HDV RNA was also achieved using nine other pairs of antigenomic RNAs and three pairs of genomic RNAs. Annealing of the RNAs prior to transfection was required for detectable HDV reconstitution. A second cell line, Huh7, also supported reconstitution when a pair of RNAs was cotransfected together with mRNA for the small delta protein. Taken together, these results support a model that observed genome reconstitution is a special form of recombination involving intermolecular template switches and they provide insights into the mechanism of RNA-directed RNA transcription catalyzed by a host RNA polymerase.
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Affiliation(s)
- Severin O Gudima
- Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111-2497, USA
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