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Blaney H, Khalid M, Heller T, Koh C. Epidemiology, presentation, and therapeutic approaches for hepatitis D infections. Expert Rev Anti Infect Ther 2023; 21:127-142. [PMID: 36519386 PMCID: PMC9905306 DOI: 10.1080/14787210.2023.2159379] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Accepted: 12/13/2022] [Indexed: 12/23/2022]
Abstract
INTRODUCTION Chronic Hepatitis D virus (HDV) infection remains an important global public health problem, with a changing epidemiological landscape over the past decade along with widespread implementation of hepatitis B vaccination and human migration. The landscape of HDV treatments has been changing, with therapies that have been under development for the last decade now in late stage clinical trials. The anticipated availability of these new therapies will hopefully replace the current therapies which are minimally effective. AREAS COVERED This narrative review discusses the clinical course, screening and diagnosis, transmission risk factors, epidemiology, current and investigational therapies, and liver transplantation in HDV. Literature review was performed using PubMed and ClinicalTrials.gov and includes relevant articles from 1977 to 2022. EXPERT OPINION HDV infection is an important global public health issue with a true prevalence that is still unknown. The distribution of HDV infection has changed globally with the availability of HBV vaccination and patterns of human migration. As HDV infection is associated with accelerated disease courses and poor outcomes, the global community needs to agree upon a uniform HDV screening strategy to understand the truth of global prevalence such that new therapies can target appropriate individuals as they become available in the future.
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Affiliation(s)
- Hanna Blaney
- Digestive Diseases Branch, National Institute of Diabetes & Digestive & Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Mian Khalid
- Digestive Diseases Branch, National Institute of Diabetes & Digestive & Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Theo Heller
- Liver Diseases Branch, National Institute of Diabetes & Digestive & Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Christopher Koh
- Liver Diseases Branch, National Institute of Diabetes & Digestive & Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
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2
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Caviglia GP, Ciancio A, Rizzetto M. A Review of HDV Infection. Viruses 2022; 14:1749. [PMID: 36016371 PMCID: PMC9414459 DOI: 10.3390/v14081749] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Revised: 08/06/2022] [Accepted: 08/09/2022] [Indexed: 01/04/2023] Open
Abstract
Hepatitis D is the most severe viral hepatitis. Hepatitis D virus (HDV) has a very small RNA genome with unique biological properties. It requires for infection the presence of hepatitis B virus (HBV) and is transmitted parenterally, mainly by superinfection of HBsAg carriers who then develop chronic hepatitis D. HDV has been brought under control in high-income countries by the implementation of HBV vaccination, and the clinical pattern has changed to a chronic hepatitis D seen in ageing patients with advanced fibrotic disease; the disease remains a major health concern in developing countries of Africa and Asia. Every HBsAg-positive subject should be tested for HDV serum markers by reflex testing, independently of clinical status. Vaccination against HBV provides the best prophylaxis against hepatitis D. The only therapy available so far has been the poorly performing Interferon alfa; however, several new and promising therapeutic approaches are under study.
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Affiliation(s)
| | - Alessia Ciancio
- Department of Medical Sciences, University of Turin, 10126 Turin, Italy
- Unit of Gastroenterology, “Città della Salute e della Scienza di Torino” Molinette Hospital, 10126 Turin, Italy
| | - Mario Rizzetto
- Department of Medical Sciences, University of Turin, 10126 Turin, Italy
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3
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Yardeni D, Heller T, Koh C. Chronic hepatitis D-What is changing? J Viral Hepat 2022; 29:240-251. [PMID: 35122369 DOI: 10.1111/jvh.13651] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Accepted: 01/03/2022] [Indexed: 01/04/2023]
Abstract
Hepatitis D virus (HDV) infection is a chronic viral disease of the liver that is still largely considered to be incurable due to lack of effective treatment options. Without treatment, the risk for the development of advanced liver disease, cirrhosis and hepatocellular carcinoma is significantly high. Currently, new therapeutic options are emerging out of ongoing phase 3 clinical trials, promising a new hope of cure for this devastating liver infection. Recently, bulevirtide, a first in its class HDV entry inhibitor, has received conditional authorization of use from the European Medicines Agency (EMA) and was also submitted for approval in the United States. Other novel therapeutic options in clincal trials include interferon lambda, the prenylation inhibitor lonafarnib and nucleic acidic polymers (NAPs). This review describes all recent advances and ongoing changes to the field of HDV therpaeutics.
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Affiliation(s)
- David Yardeni
- Liver Diseases Branch, National Institute of Diabetes & Digestive & Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Theo Heller
- Liver Diseases Branch, National Institute of Diabetes & Digestive & Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Christopher Koh
- Liver Diseases Branch, National Institute of Diabetes & Digestive & Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
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4
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de la Peña M, Gago-Zachert S. A life of research on circular RNAs and ribozymes: towards the origin of viroids, deltaviruses and life. Virus Res 2022; 314:198757. [PMID: 35346751 DOI: 10.1016/j.virusres.2022.198757] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Revised: 03/14/2022] [Accepted: 03/24/2022] [Indexed: 12/31/2022]
Abstract
The first examples of circular RNAs (circRNAs) were reported in the '70s as a family of minimal infectious agents of flowering plants; the viroids and viral satellites of circRNA. In some cases, these small circular genomes encode self-cleaving RNA motifs or ribozymes, including an exceptional circRNA infecting not plants but humans: the Hepatitis Delta Virus. Autocatalytic ribozymes not only allowed to propose a common rolling-circle replication mechanism for all these subviral agents, but also a tentative link with the origin of life as molecular fossils of the so-called RNA world. Despite the weak biologic connection between angiosperm plants and the human liver, diverse scientists, and most notably Ricardo Flores, firmly supported an evolutionary relationship between plant viroids and human deltavirus agents. The tireless and inspiring work done by Ricardo's lab in the field of infectious circRNAs fuelled multiple hypotheses for the origin of these entities, allowing advances in other fields, from eukaryotic circRNAs to small ribozymes in genomes from all life kingdoms. The recent discovery of a plethora of viral-like circRNAs with ribozymes in disparate biological samples may finally allow us to connect plant and animal subviral agents, confirming again that Ricardo's eye for science was always a keen eye.
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Affiliation(s)
- Marcos de la Peña
- Instituto de Biología Molecular y Celular de Plantas (CSIC-UPV). C/ Ingeniero Fausto Elio s/n, 46022, Valencia, Spain.
| | - Selma Gago-Zachert
- Institute of Biochemistry and Biotechnology, Martin Luther University Halle-Wittenberg, Section Microbial Biotechnology, Halle/Saale D-06120, Germany
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5
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Rolling-circle and strand-displacement mechanisms for non-enzymatic RNA replication at the time of the origin of life. J Theor Biol 2021; 527:110822. [PMID: 34214567 DOI: 10.1016/j.jtbi.2021.110822] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Revised: 06/11/2021] [Accepted: 06/26/2021] [Indexed: 11/21/2022]
Abstract
It is likely that RNA replication began non-enzymatically, and that polymerases were later selected to speed up the process. We consider replication mechanisms in modern viruses and ask which of these is possible non-enzymatically, using mathematical models and experimental data found in the literature to estimate rates of RNA synthesis and replication. Replication via alternating plus and minus strands is found in some single-stranded RNA viruses. However, if this occurred non-enzymatically it would lead to double-stranded RNA that would not separate. With some form of environmental cycling, such as temperature, salinity, or pH cycling, double-stranded RNA can be melted to form single-stranded RNA, although re-annealing of existing strands would then occur much faster than synthesis of new strands. We show that re-annealing blocks this form of replication at a very low concentration of strands. Other kinds of viruses synthesize linear double strands from single strands and then make new single strands from double strands via strand-displacement. This does not require environmental cycling and is not blocked by re-annealing. However, under non-enzymatic conditions, if strand-displacement occurs from a linear template, we expect the incomplete new strand to be almost always displaced by the tail end of the old strand through toehold-mediated displacement. A third kind of replication in viruses and viroids is rolling-circle replication which occurs via strand-displacement on a circular template. Rolling-circle replication does not require environmental cycling and is not prevented by toehold-mediated displacement. Rolling-circle replication is therefore expected to occur non-enzymatically and is a likely starting point for the evolution of polymerase-catalysed replication.
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6
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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: 21] [Impact Index Per Article: 5.3] [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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7
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Moelling K, Broecker F. Viroids and the Origin of Life. Int J Mol Sci 2021; 22:ijms22073476. [PMID: 33800543 PMCID: PMC8036462 DOI: 10.3390/ijms22073476] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2021] [Revised: 03/24/2021] [Accepted: 03/24/2021] [Indexed: 11/16/2022] Open
Abstract
Viroids are non-coding circular RNA molecules with rod-like or branched structures. They are often ribozymes, characterized by catalytic RNA. They can perform many basic functions of life and may have played a role in evolution since the beginning of life on Earth. They can cleave, join, replicate, and undergo Darwinian evolution. Furthermore, ribozymes are the essential elements for protein synthesis of cellular organisms as parts of ribosomes. Thus, they must have preceded DNA and proteins during evolution. Here, we discuss the current evidence for viroids or viroid-like RNAs as a likely origin of life on Earth. As such, they may also be considered as models for life on other planets or moons in the solar system as well as on exoplanets.
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Affiliation(s)
- Karin Moelling
- Institute of Medical Microbiology, University of Zurich, Gloriastr 30, 8006 Zurich, Switzerland
- Max Planck Institute for molecular Genetics, Ihnestr. 63-73, 14195 Berlin, Germany
- Correspondence: ; Tel.: +49-(172)-3274306
| | - Felix Broecker
- Vaxxilon Deutschland GmbH, Magnusstr. 11, 12489 Berlin, Germany;
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Flores R, Navarro B, Delgado S, Serra P, Di Serio F. Viroid pathogenesis: a critical appraisal of the role of RNA silencing in triggering the initial molecular lesion. FEMS Microbiol Rev 2021; 44:386-398. [PMID: 32379313 DOI: 10.1093/femsre/fuaa011] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2019] [Accepted: 05/06/2020] [Indexed: 12/15/2022] Open
Abstract
The initial molecular lesions through which viroids, satellite RNAs and viruses trigger signal cascades resulting in plant diseases are hotly debated. Since viroids are circular non-protein-coding RNAs of ∼250-430 nucleotides, they appear very convenient to address this issue. Viroids are targeted by their host RNA silencing defense, generating viroid-derived small RNAs (vd-sRNAs) that are presumed to direct Argonaute (AGO) proteins to inactivate messenger RNAs, thus initiating disease. Here, we review the existing evidence. Viroid-induced symptoms reveal a distinction. Those attributed to vd-sRNAs from potato spindle tuber viroid and members of the family Pospiviroidae (replicating in the nucleus) are late, non-specific and systemic. In contrast, those attributed to vd-sRNAs from peach latent mosaic viroid (PLMVd) and other members of the family Avsunviroidae (replicating in plastids) are early, specific and local. Remarkably, leaf sectors expressing different PLMVd-induced chloroses accumulate viroid variants with specific pathogenic determinants. Some vd-sRNAs containing such determinant guide AGO1-mediated cleavage of mRNAs that code for proteins regulating chloroplast biogenesis/development. Therefore, the initial lesions and the expected phenotypes are connected by short signal cascades, hence supporting a cause-effect relationship. Intriguingly, one virus satellite RNA initiates disease through a similar mechanism, whereas in the Pospiviroidae and in plant viruses the situation remains uncertain.
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Affiliation(s)
- Ricardo Flores
- Instituto de Biología Molecular y Celular de Plantas (CSIC-UPV), Avenida de los Naranjos s/n 46010, Valencia, Spain
| | - Beatriz Navarro
- Istituto per la Protezione Sostenibile delle Piante, Via Amendola 122/D, 70126 Bari, Italy
| | - Sonia Delgado
- Instituto de Biología Molecular y Celular de Plantas (CSIC-UPV), Avenida de los Naranjos s/n 46010, Valencia, Spain
| | - Pedro Serra
- Instituto de Biología Molecular y Celular de Plantas (CSIC-UPV), Avenida de los Naranjos s/n 46010, Valencia, Spain
| | - Francesco Di Serio
- Istituto per la Protezione Sostenibile delle Piante, Via Amendola 122/D, 70126 Bari, Italy
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de la Peña M, Ceprián R, Casey JL, Cervera A. Hepatitis delta virus-like circular RNAs from diverse metazoans encode conserved hammerhead ribozymes. Virus Evol 2021; 7:veab016. [PMID: 33708415 PMCID: PMC7936874 DOI: 10.1093/ve/veab016] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Human hepatitis delta virus (HDV) is a unique infectious agent whose genome is composed of a small circular RNA. Recent data, however, have reported the existence of highly divergent HDV-like circRNAs in the transcriptomes of diverse vertebrate and invertebrate species. The HDV-like genomes described in amniotes such as birds and reptiles encode self-cleaving RNA motifs or ribozymes similar to the ones present in the human HDV, whereas no catalytic RNA domains have been reported for the HDV-like genomes detected in metagenomic data from some amphibians, fish, and invertebrates. Herein, we describe the self-cleaving motifs of the HDV-like genomes reported in newts and fish, which belong to the characteristic class of HDV ribozymes. Surprisingly, HDV-like genomes from a toad and a termite show conserved type III hammerhead ribozymes, which belong to an unrelated class of catalytic RNAs characteristic of plant genomes and plant subviral circRNAs, such as some viral satellites and viroids. Sequence analyses revealed the presence of similar HDV-like hammerhead ribozymes encoded in two termite genomes, but also in the genomes of several dipteran species. In vitro transcriptions confirmed the cleaving activity for these motifs, with moderate rates of self-cleavage. These data indicate that all described HDV-like agents contain self-cleaving motifs from either the HDV or the hammerhead class. Autocatalytic ribozymes in HDV-like genomes could be regarded as interchangeable domains and may have arisen from cellular transcriptomes, although we still cannot rule out some other evolutionary explanations.
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Affiliation(s)
- Marcos de la Peña
- IBMCP (CSIC-UPV), C/Ingeniero Fausto Elio s/n, Valencia 46022, Spain
| | - Raquel Ceprián
- IBMCP (CSIC-UPV), C/Ingeniero Fausto Elio s/n, Valencia 46022, Spain
| | - John L Casey
- Department of Microbiology and Immunology, Georgetown University Medical Center, Washington, DC, USA
| | - Amelia Cervera
- IBMCP (CSIC-UPV), C/Ingeniero Fausto Elio s/n, Valencia 46022, Spain
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10
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Mammalian deltavirus without hepadnavirus coinfection in the neotropical rodent Proechimys semispinosus. Proc Natl Acad Sci U S A 2020; 117:17977-17983. [PMID: 32651267 PMCID: PMC7395443 DOI: 10.1073/pnas.2006750117] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Hepatitis delta virus (HDV) is a human hepatitis-causing RNA virus, unrelated to any other taxonomic group of RNA viruses. Its occurrence as a satellite virus of hepatitis B virus (HBV) is a singular case in animal virology for which no consensus evolutionary explanation exists. Here we present a mammalian deltavirus that does not occur in humans, identified in the neotropical rodent species Proechimys semispinosus The rodent deltavirus is highly distinct, showing a common ancestor with a recently described deltavirus in snakes. Reverse genetics based on a tandem minus-strand complementary DNA genome copy under the control of a cytomegalovirus (CMV) promoter confirms autonomous genome replication in transfected cells, with initiation of replication from the upstream genome copy. In contrast to HDV, a large delta antigen is not expressed and the farnesylation motif critical for HBV interaction is absent from a genome region that might correspond to a hypothetical rodent large delta antigen. Correspondingly, there is no evidence for coinfection with an HBV-related hepadnavirus based on virus detection and serology in any deltavirus-positive animal. No other coinfecting viruses were detected by RNA sequencing studies of 120 wild-caught animals that could serve as a potential helper virus. The presence of virus in blood and pronounced detection in reproductively active males suggest horizontal transmission linked to competitive behavior. Our study establishes a nonhuman, mammalian deltavirus that occurs as a horizontally transmitted infection, is potentially cleared by immune response, is not focused in the liver, and possibly does not require helper virus coinfection.
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11
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Abstract
Satellite viruses, most commonly found in plants, rely on helper viruses to complete their replication cycle. The only known example of a human satellite virus is the hepatitis D virus (HDV), and it is generally thought to require hepatitis B virus (HBV) to form infectious particles. Until 2018, HDV was the sole representative of the genus Deltavirus and was thought to have evolved in humans, the only known HDV host. The subsequent identification of HDV-like agents in birds, snakes, fish, amphibians, and invertebrates indicated that the evolutionary history of deltaviruses is likely much longer than previously hypothesized. Interestingly, none of the HDV-like agents were found in coinfection with an HBV-like agent, suggesting that these viruses use different helper virus(es). Here we show, using snake deltavirus (SDeV), that HBV and hepadnaviruses represent only one example of helper viruses for deltaviruses. We cloned the SDeV genome into a mammalian expression plasmid, and by transfection could initiate SDeV replication in cultured snake and mammalian cell lines. By superinfecting persistently SDeV-infected cells with reptarenaviruses and hartmaniviruses, or by transfecting their surface proteins, we could induce production of infectious SDeV particles. Our findings indicate that deltaviruses can likely use a multitude of helper viruses or even viral glycoproteins to form infectious particles. This suggests that persistent infections, such as those caused by arenaviruses and orthohantaviruses used in this study, and recurrent infections would be beneficial for the spread of deltaviruses. It seems plausible that further human or animal disease associations with deltavirus infections will be identified in the future.IMPORTANCE Deltaviruses need a coinfecting enveloped virus to produce infectious particles necessary for transmission to a new host. Hepatitis D virus (HDV), the only known deltavirus until 2018, has been found only in humans, and its coinfection with hepatitis B virus (HBV) is linked with fulminant hepatitis. The recent discovery of deltaviruses without a coinfecting HBV-like agent in several different taxa suggested that deltaviruses could employ coinfection by other enveloped viruses to complete their life cycle. In this report, we show that snake deltavirus (SDeV) efficiently utilizes coinfecting reptarena- and hartmaniviruses to form infectious particles. Furthermore, we demonstrate that cells expressing the envelope proteins of arenaviruses and orthohantaviruses produce infectious SDeV particles. As the envelope proteins are responsible for binding and infecting new host cells, our findings indicate that deltaviruses are likely not restricted in their tissue tropism, implying that they could be linked to animal or human diseases other than hepatitis.
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12
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Gasmi A, Guenifi W, Ouyahia A, Rais M, Boukhrissa H, Hachani A, Mechakra S, Laouamri S, Touabti A, Lacheheb A. First study of hepatitis delta virus in Algeria: Seroprevalence and risk factors in Setif region (east of Algeria). S Afr J Infect Dis 2019; 34:110. [PMID: 34485451 PMCID: PMC8378082 DOI: 10.4102/sajid.v34i1.110] [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: 08/16/2017] [Accepted: 07/12/2019] [Indexed: 11/14/2022] Open
Abstract
Background No recent data are available on hepatitis delta virus (HDV) prevalence in Algeria. For this reason we conducted an epidemiological study, cross-sectional seroprevalence of HDV in the region of Setif. Methods Between 2011 and 2014, sera samples of 500 patients (carrying HBsAg) admitted to the Division of Infectious Diseases Teaching Hospital, Setif (east of Algeria), were tested for anti-HDV-IgG ab (ETI-AB-DeltaK-2). Results The prevalence of HDV obtained is estimated at 2.4%. The prevalence ranges from 1% in chronic hepatitis to 11.1% in cirrhotic hepatitis (low endemic area). Seropositivity rate is closely correlated with age (Odds ratio [OR] = 9.98, p = 0.000) and gender (OR = 0.24, p = 0.025); it reaches 58.3% in the age group of 51–60 years and 0% in children (age group 1–15 years); it represents 75% in females and 25% in males. The presence of familial cases of HBsAg positive (OR = 4.54, p = 0.006), the endoscopic procedure (OR = 6.54, p = 0.000) and tattooing (OR = 20, p = 0.000) were found to be the transmission risk factors. A statistically significant relationship was found between the positivity of anti-HDV and advanced liver disease, cirrhosis (OR = 9. 16, p = 0.000). A significant correlation was found between the positivity of anti-HDV with diabetes (OR = 6.83, p = 0.000), obesity (OR = 4.19, p = 0.009) and viral suppression B (OR = 5.69, p = 0.003). Conclusion Our results show that HDV infection is low in Algeria. Research for total anti-HDV should be part of the initial assessment of patient care with viral hepatitis B as well as the prevalence of other viruses (hepatitis C [HCV] and HIV). A multicentre study should be carried out to know the importance of HDV infection and identify the risk groups.
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Affiliation(s)
- Abdelkader Gasmi
- Division of Infectious Diseases Teaching Hospital, Faculty of Medicine, University Ferhat Abbes Setif, Setif, Algeria
| | - Wahiba Guenifi
- Division of Infectious Diseases Teaching Hospital, Faculty of Medicine, University Ferhat Abbes Setif, Setif, Algeria
| | - Amel Ouyahia
- Division of Infectious Diseases Teaching Hospital, Faculty of Medicine, University Ferhat Abbes Setif, Setif, Algeria
| | - Mounira Rais
- Division of Infectious Diseases Teaching Hospital, Faculty of Medicine, University Ferhat Abbes Setif, Setif, Algeria
| | - Houda Boukhrissa
- Division of Infectious Diseases Teaching Hospital, Faculty of Medicine, University Ferhat Abbes Setif, Setif, Algeria
| | - Abderahmen Hachani
- Division of Infectious Diseases Teaching Hospital, Faculty of Medicine, University Ferhat Abbes Setif, Setif, Algeria
| | - Salah Mechakra
- Division of Infectious Diseases Teaching Hospital, Faculty of Medicine, University Ferhat Abbes Setif, Setif, Algeria
| | - Slimen Laouamri
- Division of Epidemiology Teaching Hospital, Faculty of Medicine, University Ferhat Abbes Setif, Setif, Algeria
| | - Abderezak Touabti
- Division of Microbiology Teaching Hospital, Faculty of Medicine, University Ferhat Abbes Setif, Setif, Algeria
| | - Abdelmadjid Lacheheb
- Division of Infectious Diseases Teaching Hospital, Faculty of Medicine, University Ferhat Abbes Setif, Setif, Algeria
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13
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Maurel MC, Leclerc F, Vergne J, Zaccai G. RNA Back and Forth: Looking through Ribozyme and Viroid Motifs. Viruses 2019; 11:E283. [PMID: 30901893 PMCID: PMC6466107 DOI: 10.3390/v11030283] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2019] [Revised: 03/14/2019] [Accepted: 03/18/2019] [Indexed: 12/28/2022] Open
Abstract
Current cellular facts allow us to follow the link from chemical to biochemical metabolites, from the ancient to the modern world. In this context, the "RNA world" hypothesis proposes that early in the evolution of life, the ribozyme was responsible for the storage and transfer of genetic information and for the catalysis of biochemical reactions. Accordingly, the hammerhead ribozyme (HHR) and the hairpin ribozyme belong to a family of endonucleolytic RNAs performing self-cleavage that might occur during replication. Furthermore, regarding the widespread occurrence of HHRs in several genomes of modern organisms (from mammals to small parasites and elsewhere), these small ribozymes have been regarded as living fossils of a primitive RNA world. They fold into 3D structures that generally require long-range intramolecular interactions to adopt the catalytically active conformation under specific physicochemical conditions. By studying viroids as plausible remains of ancient RNA, we recently demonstrated that they replicate in non-specific hosts, emphasizing their adaptability to different environments, which enhanced their survival probability over the ages. All these results exemplify ubiquitous features of life. Those are the structural and functional versatility of small RNAs, ribozymes, and viroids, as well as their diversity and adaptability to various extreme conditions. All these traits must have originated in early life to generate novel RNA populations.
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Affiliation(s)
- Marie-Christine Maurel
- Sorbonne Université, Museum National d'Histoire Naturelle, CNRS MNHN UMR 7205, Institut de Systématique, Evolution, Biodiversité, ISYEB, F-75005 Paris, France.
| | - Fabrice Leclerc
- Institute for Integrative Biology of the Cell (I2BC), CNRS, CEA, Université Paris Sud, F-91198 Gif-sur-Yvette, France.
| | - Jacques Vergne
- Sorbonne Université, Museum National d'Histoire Naturelle, CNRS MNHN UMR 7205, Institut de Systématique, Evolution, Biodiversité, ISYEB, F-75005 Paris, France.
| | - Giuseppe Zaccai
- Institut de Biologie Structurale CNRS-CEA-UGA, F-380447 Grenoble, France, and Institut Laue Langevin, 71 Avenue des Martyrs, F-38042 Grenoble, France.
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Abstract
Hepatitis delta virus (HDV) is a defective RNA virus that depends on the presence of hepatitis B virus (HBV) for the creation of new virions and propagation of the infection to hepatocytes. Chronic infection with HDV is usually associated with a worsening of HBV infection, leading more frequently to cirrhosis, increased risk of liver decompensation and hepatocellular carcinoma (HCC) occurrence. In spite of a progressive declining prevalence of both acute and chronic HDV infection observed over several years, mainly due to increased global health policies and mass vaccination against HBV, several European countries have more recently observed stable HDV prevalence mainly due to migrants from non-European countries. Persistent HDV replication has been widely demonstrated as associated with cirrhosis development and, as a consequence, development of liver decompensation and occurrence of HCC. Several treatment options have been attempted with poor results in terms of HDV eradication and improvement of long-term prognosis. A global effort is deemed urgent to enhance the models already existing as well as to learn more about HDV infection and correlated tumourigenesis mechanisms.
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Soriano V, Aguilera A. Hepatitis Delta Enters a New Therapeutic Era. J Infect Dis 2018; 217:1173-1176. [DOI: 10.1093/infdis/jix658] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2017] [Accepted: 12/15/2017] [Indexed: 12/18/2022] Open
Affiliation(s)
- Vincent Soriano
- Infectious Diseases Unit, La Paz University Hospital, Madrid
| | - Antonio Aguilera
- Microbiology Department, Complexo Hospitalario Universitario Santiago and University of Santiago, Santiago de Compostela, Spain
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16
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Suárez-Amarán L, Usai C, Di Scala M, Godoy C, Ni Y, Hommel M, Palomo L, Segura V, Olagüe C, Vales A, Ruiz-Ripa A, Buti M, Salido E, Prieto J, Urban S, Rodríguez-Frias F, Aldabe R, González-Aseguinolaza G. A new HDV mouse model identifies mitochondrial antiviral signaling protein (MAVS) as a key player in IFN-β induction. J Hepatol 2017; 67:669-679. [PMID: 28527664 DOI: 10.1016/j.jhep.2017.05.010] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2016] [Revised: 04/28/2017] [Accepted: 05/06/2017] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS Studying hepatitis delta virus (HDV) and developing new treatments is hampered by the limited availability of small animal models. Herein, a description of a robust mouse model of HDV infection that mimics several important characteristics of the human disease is presented. METHODS HDV and hepatitis B virus (HBV) replication competent genomes were delivered to the mouse liver using adeno-associated viruses (AAV; AAV-HDV and AAV-HBV). Viral load, antigen expression and genomes were quantified at different time points after AAV injection. Furthermore, liver pathology, genome editing, and the activation of the innate immune response were evaluated. RESULTS AAV-HDV infection initiated HDV replication in mouse hepatocytes. Genome editing was confirmed by the presence of small and large HDV antigens and sequencing. Viral replication was detected for 45days, even after the AAV-HDV vector had almost disappeared. In the presence of HBV, HDV infectious particles were detected in serum. Furthermore, as observed in patients, co-infection was associated with the reduction of HBV antigen expression and the onset of liver damage that included the alteration of genes involved in the development of liver pathologies. HDV replication induced a sustained type I interferon response, which was significantly reduced in immunodeficient mice and almost absent in mitochondrial antiviral signaling protein (MAVS)-deficient mice. CONCLUSION The animal model described here reproduces important characteristics of human HDV infection and provides a valuable tool for characterizing the viral infection and for developing new treatments. Furthermore, MAVS was identified as a main player in HDV detection and adaptive immunity was found to be involved in the amplification of the innate immune response. Lay summary: Co-infection with hepatitis B and D virus (HBV and HDV, respectively) often causes a more severe disease condition than HBV alone. Gaining more insight into HDV and developing new treatments is hampered by limited availability of adequate immune competent small animal models and new ones are needed. Here, a mouse model of HDV infection is described, which mimics several important characteristics of the human disease, such as the initiation and maintenance of replication in murine hepatocytes, genome editing and, in the presence of HBV, generation of infectious particles. Lastly, the involvement of an adaptive immunity and the intracellular signaling molecule MAVS in mounting a strong and lasting innate response was shown. Thus, our model serves as a useful tool for the investigation of HDV biology and new treatments.
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MESH Headings
- Adaptive Immunity
- Adaptor Proteins, Signal Transducing/deficiency
- Adaptor Proteins, Signal Transducing/genetics
- Adaptor Proteins, Signal Transducing/immunology
- Animals
- Cell Line
- Coinfection/immunology
- Coinfection/pathology
- Coinfection/virology
- Dependovirus/genetics
- Disease Models, Animal
- Genome, Viral
- Hepatitis B/complications
- Hepatitis B/immunology
- Hepatitis B/virology
- Hepatitis B Antigens/metabolism
- Hepatitis B virus/genetics
- Hepatitis B virus/immunology
- Hepatitis D/complications
- Hepatitis D/immunology
- Hepatitis D/virology
- Hepatitis Delta Virus/genetics
- Hepatitis Delta Virus/immunology
- Hepatitis Delta Virus/physiology
- Hepatitis delta Antigens/metabolism
- Humans
- Immunity, Innate
- Interferon-beta/biosynthesis
- Liver/pathology
- Male
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Mice, Transgenic
- Models, Immunological
- Signal Transduction/immunology
- Virus Replication
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Affiliation(s)
- Lester Suárez-Amarán
- Gene Therapy and Regulation of Gene Expression Program, Center for Applied Medical Research (CIMA), Pamplona, Spain; Instituto de Investigación Sanitaria de Navarra (IdiSNA), Calle Irunlarrea 3, Pamplona 31008, Spain
| | - Carla Usai
- Gene Therapy and Regulation of Gene Expression Program, Center for Applied Medical Research (CIMA), Pamplona, Spain; Instituto de Investigación Sanitaria de Navarra (IdiSNA), Calle Irunlarrea 3, Pamplona 31008, Spain
| | - Marianna Di Scala
- Gene Therapy and Regulation of Gene Expression Program, Center for Applied Medical Research (CIMA), Pamplona, Spain; Instituto de Investigación Sanitaria de Navarra (IdiSNA), Calle Irunlarrea 3, Pamplona 31008, Spain
| | - Cristina Godoy
- Centro de Investigación Biomédica en red: Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Barcelona, Spain; Liver Pathology Unit, Departments of Biochemistry and Microbiology, Hospital Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain; Virology Unit, Department of Microbiology, Hospital Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Yi Ni
- Department of Infectious Diseases, Molecular Virology, University Hospital Heidelberg, Heidelberg, Germany
| | - Mirja Hommel
- Gene Therapy and Regulation of Gene Expression Program, Center for Applied Medical Research (CIMA), Pamplona, Spain; Instituto de Investigación Sanitaria de Navarra (IdiSNA), Calle Irunlarrea 3, Pamplona 31008, Spain
| | - Laura Palomo
- Gene Therapy and Regulation of Gene Expression Program, Center for Applied Medical Research (CIMA), Pamplona, Spain; Instituto de Investigación Sanitaria de Navarra (IdiSNA), Calle Irunlarrea 3, Pamplona 31008, Spain
| | - Víctor Segura
- Instituto de Investigación Sanitaria de Navarra (IdiSNA), Calle Irunlarrea 3, Pamplona 31008, Spain; Bioinformatics Unit, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain
| | - Cristina Olagüe
- Gene Therapy and Regulation of Gene Expression Program, Center for Applied Medical Research (CIMA), Pamplona, Spain; Instituto de Investigación Sanitaria de Navarra (IdiSNA), Calle Irunlarrea 3, Pamplona 31008, Spain
| | - Africa Vales
- Gene Therapy and Regulation of Gene Expression Program, Center for Applied Medical Research (CIMA), Pamplona, Spain; Instituto de Investigación Sanitaria de Navarra (IdiSNA), Calle Irunlarrea 3, Pamplona 31008, Spain
| | - Alicia Ruiz-Ripa
- Centro de Investigación Biomédica en red: Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Barcelona, Spain; Liver Pathology Unit, Departments of Biochemistry and Microbiology, Hospital Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain; Virology Unit, Department of Microbiology, Hospital Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Maria Buti
- Centro de Investigación Biomédica en red: Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Barcelona, Spain; Liver Pathology Unit, Departments of Biochemistry and Microbiology, Hospital Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain; Virology Unit, Department of Microbiology, Hospital Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Eduardo Salido
- Department of Pathology, Centre for Biomedical Research on Rare Diseases (CIBERER), La Laguna, S/C Tenerife, Spain
| | - Jesús Prieto
- Gene Therapy and Regulation of Gene Expression Program, Center for Applied Medical Research (CIMA), Pamplona, Spain; Instituto de Investigación Sanitaria de Navarra (IdiSNA), Calle Irunlarrea 3, Pamplona 31008, Spain; Centro de Investigación Biomédica en red: Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Pamplona, Spain
| | - Stephan Urban
- Department of Infectious Diseases, Molecular Virology, University Hospital Heidelberg, Heidelberg, Germany
| | - Francisco Rodríguez-Frias
- Centro de Investigación Biomédica en red: Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Barcelona, Spain; Liver Pathology Unit, Departments of Biochemistry and Microbiology, Hospital Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain; Virology Unit, Department of Microbiology, Hospital Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Rafael Aldabe
- Gene Therapy and Regulation of Gene Expression Program, Center for Applied Medical Research (CIMA), Pamplona, Spain; Instituto de Investigación Sanitaria de Navarra (IdiSNA), Calle Irunlarrea 3, Pamplona 31008, Spain
| | - Gloria González-Aseguinolaza
- Gene Therapy and Regulation of Gene Expression Program, Center for Applied Medical Research (CIMA), Pamplona, Spain; Instituto de Investigación Sanitaria de Navarra (IdiSNA), Calle Irunlarrea 3, Pamplona 31008, Spain.
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Glouzon JPS, Perreault JP, Wang S. The super-n-motifs model: a novel alignment-free approach for representing and comparing RNA secondary structures. Bioinformatics 2017; 33:1169-1178. [PMID: 28088762 DOI: 10.1093/bioinformatics/btw773] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2015] [Indexed: 12/13/2022] Open
Abstract
Motivation Comparing ribonucleic acid (RNA) secondary structures of arbitrary size uncovers structural patterns that can provide a better understanding of RNA functions. However, performing fast and accurate secondary structure comparisons is challenging when we take into account the RNA configuration (i.e. linear or circular), the presence of pseudoknot and G-quadruplex (G4) motifs and the increasing number of secondary structures generated by high-throughput probing techniques. To address this challenge, we propose the super-n-motifs model based on a latent analysis of enhanced motifs comprising not only basic motifs but also adjacency relations. The super-n-motifs model computes a vector representation of secondary structures as linear combinations of these motifs. Results We demonstrate the accuracy of our model for comparison of secondary structures from linear and circular RNA while also considering pseudoknot and G4 motifs. We show that the super-n-motifs representation effectively captures the most important structural features of secondary structures, as compared to other representations such as ordered tree, arc-annotated and string representations. Finally, we demonstrate the time efficiency of our model, which is alignment free and capable of performing large-scale comparisons of 10 000 secondary structures with an efficiency up to 4 orders of magnitude faster than existing approaches. Availability and Implementation The super-n-motifs model was implemented in C ++. Source code and Linux binary are freely available at http://jpsglouzon.github.io/supernmotifs/ . Contact Shengrui.Wang@Usherbrooke.ca. Supplementary information Supplementary data are available at Bioinformatics o nline.
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Affiliation(s)
- Jean-Pierre Séhi Glouzon
- Department of Computer Science, Faculty of Science, Université de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada.,RNA Group, Department of Biochemistry, Faculty of Medicine and Health Sciences, Applied Cancer Research Pavilion, Université de Sherbrooke, Sherbrooke, QC J1E 4K8, Canada
| | - Jean-Pierre Perreault
- RNA Group, Department of Biochemistry, Faculty of Medicine and Health Sciences, Applied Cancer Research Pavilion, Université de Sherbrooke, Sherbrooke, QC J1E 4K8, Canada
| | - Shengrui Wang
- Department of Computer Science, Faculty of Science, Université de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada
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18
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Abstract
Viral liver diseases are frequent comorbidities and major contributors to death in HIV-positive individuals on antiretroviral therapy. Although cure of hepatitis C and control of hepatitis B with antivirals avert liver disease progression in most HIV-coinfected patients, the lack of satisfactory treatment for hepatitis delta virus (HDV) infection remains a major threat for developing cirrhosis and liver cancer in this population. In the European Union (EU) and North America, sexual contact has replaced injection drug use that has been the major transmission route for HDV in HIV-positive persons. PegIFNα is the only approved HDV therapy; however, sustained HDV-RNA clearance is achieved by less than 25%. The recent discovery of sodium taurocholate cotransporting polypeptide as the key hepatitis B virus (HBV) and HDV cell entry receptor has opened the door to a new therapeutic era. Indeed, promising results have been released using Myrcludex-B, a sodium taurocholate cotransporting polypeptide inhibitor. More encouraging are data with new classes of HDV blockers, such as prenylation inhibitors (i.e. lonafarnib) and nucleic acid polymers. At this time, sustained suppression of HDV replication is the primary goal of HDV therapy, as it is associated with normalization of liver enzymes and histological improvement. Of note, the use of specific antivirals for HDV must be given along with anti-HBV agents to prevent HBV rebounds following removal of viral interference. The lack of persistent forms of HDV-RNA could provide a unique opportunity for curing hepatitis delta, even without eliminating HBV circular covalently closed DNA. Ultimately, suppression of HDV replication along with hepatitis B surface antigen clearance once drugs are off would be the best reflect of hepatitis delta cure.
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19
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Liu J, Goicochea P, Block T, Brosgart CL, Donaldson EF, Lenz O, Gee Lim S, Marins EG, Mishra P, Peters MG, Miller V. Advancing the regulatory path on hepatitis B virus treatment and curative research: a stakeholders consultation. J Virus Erad 2017. [DOI: 10.1016/s2055-6640(20)30302-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
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20
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Aguilera A, Trastoy R, Barreiro P, Costa JJ, de Mendoza C, Peña JM, Soriano V. Decline and changing profile of hepatitis delta among injection drug users in Spain. Antivir Ther 2017; 23:87-90. [PMID: 28353446 DOI: 10.3851/imp3161] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/27/2017] [Indexed: 10/19/2022]
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21
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Homs M, Rodriguez-Frias F, Gregori J, Ruiz A, Reimundo P, Casillas R, Tabernero D, Godoy C, Barakat S, Quer J, Riveiro-Barciela M, Roggendorf M, Esteban R, Buti M. Evidence of an Exponential Decay Pattern of the Hepatitis Delta Virus Evolution Rate and Fluctuations in Quasispecies Complexity in Long-Term Studies of Chronic Delta Infection. PLoS One 2016; 11:e0158557. [PMID: 27362848 PMCID: PMC4928832 DOI: 10.1371/journal.pone.0158557] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2016] [Accepted: 06/19/2016] [Indexed: 02/07/2023] Open
Abstract
Chronic HDV infection can cause a severe form of viral hepatitis for which there is no specific treatment. Characterization of the hepatitis B or C viral quasispecies has provided insight into treatment failure and disease recurrence following liver transplantation, has proven useful to understand hepatitis B e antigen seroconversion, and has helped to predict whether hepatitis C infection will resolve or become chronic. It is likely that characterization of the hepatitis delta virus (HDV) quasispecies will ultimately have similar value for the management of this infection. This study sought to determine the RNA evolution rates in serum of chronic hepatitis delta (CHD) treatment-naïve patients, using next-generation sequencing methods. The region selected for study encompassed nucleotide positions 910 to 1270 of the genome and included the amber/W codon. Amber/W is a substrate of the editing process by the ADAR1 host enzyme and is essential for encoding the 2 delta antigens (HDAg). The amber codon encodes the small (unedited) HDAg form and the W codon the large (edited) HDAg form. The evolution rate was analyzed taking into account the time elapsed between samples, the percentage of unedited and edited genomes, and the complexity of the viral population. The longitudinal studies included 29 sequential samples from CHD patients followed up for a mean of 11.5 years. In total, 121,116 sequences were analyzed. The HDV evolution rate ranged from 9.5x10-3 to 1.2x10-3 substitutions/site/year and showed a negative correlation with the time elapsed between samples (p<0.05). An accumulation of transition-type changes was found to be responsible for higher evolution rates. The percentages of unedited and edited genomes and the quasispecies complexity showed no relationships with the evolution rate, but the fluctuations in the percentages of genomes and in complexity suggest continuous adaptation of HDV to the host conditions.
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Affiliation(s)
- Maria Homs
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Barcelona, Spain
- Liver Pathology Unit, Departments of Biochemistry and Microbiology, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona (UAB), Barcelona, Spain
| | - Francisco Rodriguez-Frias
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Barcelona, Spain
- Liver Pathology Unit, Departments of Biochemistry and Microbiology, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona (UAB), Barcelona, Spain
| | - Josep Gregori
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Barcelona, Spain
- Liver Diseases Unit, Vall d’Hebron Research Institute, Barcelona, Spain
- Roche Diagnostics SL, Sant Cugat del Vallès, Spain
| | - Alicia Ruiz
- Liver Pathology Unit, Departments of Biochemistry and Microbiology, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona (UAB), Barcelona, Spain
| | - Pilar Reimundo
- Liver Pathology Unit, Departments of Biochemistry and Microbiology, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona (UAB), Barcelona, Spain
| | - Rosario Casillas
- Liver Pathology Unit, Departments of Biochemistry and Microbiology, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona (UAB), Barcelona, Spain
- Liver Diseases Unit, Vall d’Hebron Research Institute, Barcelona, Spain
| | - David Tabernero
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Barcelona, Spain
- Liver Pathology Unit, Departments of Biochemistry and Microbiology, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona (UAB), Barcelona, Spain
| | - Cristina Godoy
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Barcelona, Spain
- Liver Pathology Unit, Departments of Biochemistry and Microbiology, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona (UAB), Barcelona, Spain
| | - Salma Barakat
- Gastroenterology Department, National Centre for Gastrointestinal and Liver disease, Khartoum, Sudan
| | - Josep Quer
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Barcelona, Spain
- Liver Diseases Unit, Vall d’Hebron Research Institute, Barcelona, Spain
| | - Mar Riveiro-Barciela
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Barcelona, Spain
- Liver Unit, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona (UAB), Barcelona, Spain
| | - Michael Roggendorf
- Institut of Virology, Technische Universität München/Helmholtz Zentrum München, Munich, Germany
| | - Rafael Esteban
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Barcelona, Spain
- Liver Unit, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona (UAB), Barcelona, Spain
| | - Maria Buti
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Barcelona, Spain
- Liver Unit, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona (UAB), Barcelona, Spain
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Abstract
The discovery of the viroid in 1971, which initiated the third major expansion of the biosphere towards smaller living entities-after discovery of the "subvisual" microorganisms in 1675 and that of the "submicroscopic" viruses in 1892-has been officially endorsed by the International Committee on Virus Taxonomy as a new order called subviral agents.In 1989, I proposed that, based on their respective molecular properties, viroids are more plausible "living fossils" of the hypothetical RNA World (widely assumed to have existed prior to the evolution of DNA or proteins) than are intron-derived RNAs, which were, at that time, suggested as putative survivors. There were few citations of my proposal-and virtually none of viroids-beyond plant virology unil 1994, when Cheles-Flores critically examined the hypothesis and pointed out a serious difficulty, as well as a process by which this difficulty could be overcome. In 2013, when investigations by Koonin and Dolja revealed that of extant RNAs, viroids "strikingly" display some of the molecular properties posited for the earliest evolving, selfish RNAs (primordial RNAs), but, because extant organisms, aside from higher plants, appear not to harbor viroids, they cannot be regarded as primordial fossils, but appear to have evolved post LUCA (the Last Universal Common Ancestor). Here, I review whether some evidence nevertheless is compatible with the original postulate of the 1989 hypothesis. My analysis reveals no unequivocal evidence for an ancient origin of viroids, but suggests, alternatively, that viroids may have evolved de novo more recently, probably by novel processes similar to those suggested by each reviewer.These results are important, because they help illuminate a little understood period of abiogenesis--after the abiotic synthesis of life's chemical building blocks, which is, in principle, understood, and before the evolution of DNA and proteins in the late RNA World.
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Affiliation(s)
- Theodor O Diener
- Department of Cell Biology and Molecular Genetics, University of Maryland, 6141 Plant Sciences Building, College Park, MD, 20742, USA.
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23
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Rizzetto M, Smedile A, Ciancio A. Hepatitis D. CLINICAL VIROLOGY 2016:1409-1423. [DOI: 10.1128/9781555819439.ch58] [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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Soriano V, Labarga P, de Mendoza C, Fernández-Montero JV, Treviño A, Benítez-Gutiérrez L, Peña JM, Barreiro P. Delta hepatitis: new approaches to therapy. Future Virol 2016. [DOI: 10.2217/fvl-2015-0009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Hepatitis delta virus (HDV) infection is a neglected disease despite causing the most severe form of viral hepatitis. Over 15 million people are infected worldwide. IFN-α is largely inefficient and poorly tolerated. The discovery of sodium taurocholate cotransporting polypeptide as the cell receptor for HBV (and consequently for HDV) has allowed development of viral entry inhibitors (i.e., myrcludex-B). More recently, prenylation inhibitors (i.e., lonafarnib) that disrupt virion assembly are being tested. At this time, sustained suppression of HDV replication is the primary goal of hepatitis delta treatment, being associated with normalization of liver enzymes and histological improvement. The lack of persistent forms of HDV-RNA could provide unique opportunities for hepatitis delta cure using specific antivirals, even in the face of persistent HBV cccDNA.
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Affiliation(s)
- Vincent Soriano
- Infectious Diseases Unit, La Paz University Hospital, Madrid, Spain
| | - Pablo Labarga
- Department of Internal Medicine, La Luz Clinic, Madrid, Spain
| | - Carmen de Mendoza
- Department of Internal Medicine, Puerta de Hierro Research Institute & University Hospital, Majadahonda, Spain
| | | | - Ana Treviño
- Infectious Diseases Unit, La Paz University Hospital, Madrid, Spain
| | - Laura Benítez-Gutiérrez
- Department of Internal Medicine, Puerta de Hierro Research Institute & University Hospital, Majadahonda, Spain
| | - José M Peña
- Infectious Diseases Unit, La Paz University Hospital, Madrid, Spain
| | - Pablo Barreiro
- Infectious Diseases Unit, La Paz University Hospital, Madrid, Spain
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Flores R, Owens RA, Taylor J. Pathogenesis by subviral agents: viroids and hepatitis delta virus. Curr Opin Virol 2016; 17:87-94. [PMID: 26897654 DOI: 10.1016/j.coviro.2016.01.022] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2015] [Revised: 01/21/2016] [Accepted: 01/29/2016] [Indexed: 12/18/2022]
Abstract
The viroids of plants are the simplest known infectious genetic elements. They have RNA genomes of up to 400 nucleotides in length and no protein encoding capacity. Hepatitis delta virus (HDV), an infectious agent found only in humans co-infected with hepatitis B virus (HBV), is just slightly more complex, with an RNA genome of about 1700 nucleotides, and the ability to express just one small protein. Viroid and HDV RNAs share several features that include circular structure, compact folding, and replication via a rolling-circle mechanism. Both agents were detected because of their obvious pathogenic effects. Their simplicity demands a greater need than conventional RNA or DNA viruses to redirect host components for facilitating their infectious cycle, a need that directly and indirectly incites pathogenic effects. The mechanisms by which these pathogenic effects are produced are the topic of this review. In this context, RNA silencing mediates certain aspects of viroid pathogenesis.
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Affiliation(s)
- Ricardo Flores
- Instituto de Biología Molecular y Celular de Plantas (UPV-CSIC), Universidad Politécnica de Valencia, Valencia 46022, Spain.
| | - Robert A Owens
- Molecular Plant Pathology Laboratory, USDA-ARS, Beltsville, MD 20705, USA.
| | - John Taylor
- Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
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Abstract
The hepatitis D virus (HDV) is unique in animal virology. It has a circular RNA genome that is the smallest of human viruses, requires the HBsAg capsid of the hepatitis B virus to assembly into infectious virions, parasitizes the transcriptional machinery of the host by hijacking cellular RNA polymerases to replicate its RNA genome and is replicated by a rolling circle mechanism unknown to mammalian cells. Hepatitis D is ubiquitous but prevalence varies throughout the world. It is the most severe form of chronic viral liver disorder; carriers of HBsAg superinfected by the HDV are the major victims and the reservoir of the infection. In the last 20 years vaccination against the hepatitis B virus (HBV) has decreased the circulation of HDV in industrialized countries; nevertheless hepatitis D is returning to Western Europe through immigration from HDV endemic areas. Hepatitis D is being rediscovered in the developing world. It has a significant medical impact on areas of Africa, Asia and South America where the partner HBV is not controlled; Pakistan and Mongolia appear to be worldwide the areas with the highest prevalence of the disease. A major obstacle in treatment is that the virus has no replicative function of its own to be targeted by antivirals. Peg-Interferon remains the mainstay of treatment. New strategies are explored to prevent entry of the virion into hepatocytes by blocking the cellular HBsAg receptor or preventing the prenylation process of the large-delta antigen necessary for the assembly of the HDV particle.
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Affiliation(s)
- Mario Rizzetto
- Department of Medical Sciences, University of Torino, Torino, 10126, Italy
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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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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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29
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Durzyńska J, Goździcka-Józefiak A. Viruses and cells intertwined since the dawn of evolution. Virol J 2015; 12:169. [PMID: 26475454 PMCID: PMC4609113 DOI: 10.1186/s12985-015-0400-7] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2014] [Accepted: 10/07/2015] [Indexed: 12/24/2022] Open
Abstract
Many attempts have been made to define nature of viruses and to uncover their origin. Our aim within this work was to show that there are different perceptions of viruses and many concepts to explain their emergence: the virus-first concept (also called co-evolution), the escape and the reduction theories. Moreover, a relatively new concept of polyphyletic virus origin called “three RNA cells, three DNA viruses” proposed by Forterre is described herein. In this paper, not only is each thesis supported by a body of evidence but also counter-argued in the light of various findings to give more insightful considerations to the readers. As the origin of viruses and that of living cells are most probably interdependent, we decided to reveal ideas concerning nature of cellular last universal common ancestor (LUCA). Furthermore, we discuss monophyletic ancestry of cellular domains and their relationships at the molecular level of membrane lipids and replication strategies of these three types of cells. In this review, we also present the emergence of DNA viruses requiring an evolutionary transition from RNA to DNA and recently discovered giant DNA viruses possibly involved in eukaryogenesis. In the course of evolution viruses emerged many times. They have always played a key role through horizontal gene transfer in evolutionary events and in formation of the tree of life or netlike routes of evolution providing a great deal of genetic diversity. In our opinion, future findings are crucial to better understand past relations between viruses and cells and the origin of both.
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Affiliation(s)
- Julia Durzyńska
- Department of Molecular Virology, Institute of Experimental Biology, Faculty of Biology, A. Mickiewicz University, ul. Umultowska 89, 61-614, Poznań, Poland.
| | - Anna Goździcka-Józefiak
- Department of Molecular Virology, Institute of Experimental Biology, Faculty of Biology, A. Mickiewicz University, ul. Umultowska 89, 61-614, Poznań, Poland
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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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Abbas Z, Abbas M. Management of hepatitis delta: Need for novel therapeutic options. World J Gastroenterol 2015; 21:9461-9465. [PMID: 26327754 PMCID: PMC4548107 DOI: 10.3748/wjg.v21.i32.9461] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2014] [Revised: 02/23/2015] [Accepted: 06/09/2015] [Indexed: 02/06/2023] Open
Abstract
Hepatitis D virus (HDV) is the smallest single stranded RNA virus infecting humans. The hepatitis B surface antigen envelope protein protects the HDV nucleocapsid antigen and provides a means for the virus to enter and exit the hepatocyte. Hepatitis B and D viruses exploit the human sodium taurocholate co-transporting polypeptide (NTCP), a receptor, for their entry into hepatocytes. Prenylation of the large delta antigen is a critical determinant of HDV particle assembly. Treatment with pegylated interferon results in sustained virological response six months post-treatment in one fourth of the patients. Nucleos(t)ide analogs (NAs) have been widely tested in hepatitis delta, but they appear to be ineffective. Combination treatment of NAs with interferon also proved to be disappointing so there is a need for novel therapeutic options. The receptor function of NTCP is blocked by Myrcludex B, a synthetic N-acylated preS1 lipopeptide that competes with infectious virions for receptor binding. There are already some approved drugs available, including irbesartan, ezetimibe, and ritonavir and cyclosporin A, with documented inhibitory effects on NTCP's metabolic function. These drugs may have a role in HDV treatment. Interference with host-mediated post-translational changes of proteins that are crucial to the HDV life cycle, such as prenylation may become an important tool to control HDV infection and prevent replication. Lonafarnib, a prenylation inhibitor significantly reduces virus levels in hepatitis delta patients. Antisense oligodeoxynucleotides which are complementary to genomic HDV ribozyme self-cleavage site and stem I regions can inhibit genomic HDV ribozyme activity.
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Balique F, Lecoq H, Raoult D, Colson P. Can plant viruses cross the kingdom border and be pathogenic to humans? Viruses 2015; 7:2074-98. [PMID: 25903834 PMCID: PMC4411691 DOI: 10.3390/v7042074] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2015] [Revised: 03/20/2015] [Accepted: 04/06/2015] [Indexed: 12/30/2022] Open
Abstract
Phytoviruses are highly prevalent in plants worldwide, including vegetables and fruits. Humans, and more generally animals, are exposed daily to these viruses, among which several are extremely stable. It is currently accepted that a strict separation exists between plant and vertebrate viruses regarding their host range and pathogenicity, and plant viruses are believed to infect only plants. Accordingly, plant viruses are not considered to present potential pathogenicity to humans and other vertebrates. Notwithstanding these beliefs, there are many examples where phytoviruses circulate and propagate in insect vectors. Several issues are raised here that question if plant viruses might further cross the kingdom barrier to cause diseases in humans. Indeed, there is close relatedness between some plant and animal viruses, and almost identical gene repertoires. Moreover, plant viruses can be detected in non-human mammals and humans samples, and there are evidence of immune responses to plant viruses in invertebrates, non-human vertebrates and humans, and of the entry of plant viruses or their genomes into non-human mammal cells and bodies after experimental exposure. Overall, the question raised here is unresolved, and several data prompt the additional extensive study of the interactions between phytoviruses and non-human mammals and humans, and the potential of these viruses to cause diseases in humans.
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Affiliation(s)
- Fanny Balique
- Aix-Marseille Université, Unité de Recherche sur les Maladies Infectieuses et Tropicales Émergentes (URMITE) UM 63 CNRS 7278 IRD 3R198 INSERM U1095, Facultés de Médecine et de Pharmacie, 27 boulevard Jean Moulin, 13385 Marseille cedex 05, France.
- Institut National de la Recherche Agronomique (INRA), UR 407, Pathologie Végétale, 84140 Montfavet, France.
| | - Hervé Lecoq
- Institut National de la Recherche Agronomique (INRA), UR 407, Pathologie Végétale, 84140 Montfavet, France.
| | - Didier Raoult
- Aix-Marseille Université, Unité de Recherche sur les Maladies Infectieuses et Tropicales Émergentes (URMITE) UM 63 CNRS 7278 IRD 3R198 INSERM U1095, Facultés de Médecine et de Pharmacie, 27 boulevard Jean Moulin, 13385 Marseille cedex 05, France.
- Institut Hospitalo-Universitaire (IHU) Méditerranée Infection, Pôle des Maladies Infectieuses et Tropicales Clinique et Biologique, Fédération de Bactériologie-Hygiène-Virologie, Centre Hospitalo-Universitaire Timone, Assistance publique - hôpitaux de Marseille, 264 rue Saint-Pierre, 13385 Marseille cedex 05, France.
| | - Philippe Colson
- Aix-Marseille Université, Unité de Recherche sur les Maladies Infectieuses et Tropicales Émergentes (URMITE) UM 63 CNRS 7278 IRD 3R198 INSERM U1095, Facultés de Médecine et de Pharmacie, 27 boulevard Jean Moulin, 13385 Marseille cedex 05, France.
- Institut Hospitalo-Universitaire (IHU) Méditerranée Infection, Pôle des Maladies Infectieuses et Tropicales Clinique et Biologique, Fédération de Bactériologie-Hygiène-Virologie, Centre Hospitalo-Universitaire Timone, Assistance publique - hôpitaux de Marseille, 264 rue Saint-Pierre, 13385 Marseille cedex 05, France.
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Virus world as an evolutionary network of viruses and capsidless selfish elements. Microbiol Mol Biol Rev 2015; 78:278-303. [PMID: 24847023 DOI: 10.1128/mmbr.00049-13] [Citation(s) in RCA: 160] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Viruses were defined as one of the two principal types of organisms in the biosphere, namely, as capsid-encoding organisms in contrast to ribosome-encoding organisms, i.e., all cellular life forms. Structurally similar, apparently homologous capsids are present in a huge variety of icosahedral viruses that infect bacteria, archaea, and eukaryotes. These findings prompted the concept of the capsid as the virus "self" that defines the identity of deep, ancient viral lineages. However, several other widespread viral "hallmark genes" encode key components of the viral replication apparatus (such as polymerases and helicases) and combine with different capsid proteins, given the inherently modular character of viral evolution. Furthermore, diverse, widespread, capsidless selfish genetic elements, such as plasmids and various types of transposons, share hallmark genes with viruses. Viruses appear to have evolved from capsidless selfish elements, and vice versa, on multiple occasions during evolution. At the earliest, precellular stage of life's evolution, capsidless genetic parasites most likely emerged first and subsequently gave rise to different classes of viruses. In this review, we develop the concept of a greater virus world which forms an evolutionary network that is held together by shared conserved genes and includes both bona fide capsid-encoding viruses and different classes of capsidless replicons. Theoretical studies indicate that selfish replicons (genetic parasites) inevitably emerge in any sufficiently complex evolving ensemble of replicators. Therefore, the key signature of the greater virus world is not the presence of a capsid but rather genetic, informational parasitism itself, i.e., various degrees of reliance on the information processing systems of the host.
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Viroids, the simplest RNA replicons: How they manipulate their hosts for being propagated and how their hosts react for containing the infection. Virus Res 2015; 209:136-45. [PMID: 25738582 DOI: 10.1016/j.virusres.2015.02.027] [Citation(s) in RCA: 68] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2014] [Revised: 02/23/2015] [Accepted: 02/23/2015] [Indexed: 12/31/2022]
Abstract
The discovery of viroids about 45 years ago heralded a revolution in Biology: small RNAs comprising around 350 nt were found to be able to replicate autonomously-and to incite diseases in certain plants-without encoding proteins, fundamental properties discriminating these infectious agents from viruses. The initial focus on the pathological effects usually accompanying infection by viroids soon shifted to their molecular features-they are circular molecules that fold upon themselves adopting compact secondary conformations-and then to how they manipulate their hosts to be propagated. Replication of viroids-in the nucleus or chloroplasts through a rolling-circle mechanism involving polymerization, cleavage and circularization of RNA strands-dealt three surprises: (i) certain RNA polymerases are redirected to accept RNA instead of their DNA templates, (ii) cleavage in chloroplastic viroids is not mediated by host enzymes but by hammerhead ribozymes, and (iii) circularization in nuclear viroids is catalyzed by a DNA ligase redirected to act upon RNA substrates. These enzymes (and ribozymes) are most probably assisted by host proteins, including transcription factors and RNA chaperones. Movement of viroids, first intracellularly and then to adjacent cells and distal plant parts, has turned out to be a tightly regulated process in which specific RNA structural motifs play a crucial role. More recently, the advent of RNA silencing has brought new views on how viroids may cause disease and on how their hosts react to contain the infection; additionally, viroid infection may be restricted by other mechanisms. Representing the lowest step on the biological size scale, viroids have also attracted considerable interest to get a tentative picture of the essential characteristics of the primitive replicons that populated the postulated RNA world.
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Aldabe R, Suárez-Amarán L, Usai C, González-Aseguinolaza G. Animal models of chronic hepatitis delta virus infection host-virus immunologic interactions. Pathogens 2015; 4:46-65. [PMID: 25686091 PMCID: PMC4384072 DOI: 10.3390/pathogens4010046] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2014] [Accepted: 02/05/2015] [Indexed: 02/08/2023] Open
Abstract
Hepatitis delta virus (HDV) is a defective RNA virus that has an absolute requirement for a virus belonging to the hepadnaviridae family like hepatitis B virus (HBV) for its replication and formation of new virions. HDV infection is usually associated with a worsening of HBV-induced liver pathogenesis, which leads to more frequent cirrhosis, increased risk of hepatocellular carcinoma (HCC), and fulminant hepatitis. Importantly, no selective therapies are available for HDV infection. The mainstay of treatment for HDV infection is pegylated interferon alpha; however, response rates to this therapy are poor. A better knowledge of HDV–host cell interaction will help with the identification of novel therapeutic targets, which are urgently needed. Animal models like hepadnavirus-infected chimpanzees or the eastern woodchuck have been of great value for the characterization of HDV chronic infection. Recently, more practical animal models in which to perform a deeper study of host virus interactions and to evaluate new therapeutic strategies have been developed. Therefore, the main focus of this review is to discuss the current knowledge about HDV host interactions obtained from cell culture and animal models.
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Affiliation(s)
- Rafael Aldabe
- Gene Therapy and Regulation of Gene Expression Program, Centro de Investigación Médica Aplicada (CIMA), Universidad de Navarra (UNAV), Pamplona 31008, Spain.
| | - Lester Suárez-Amarán
- Gene Therapy and Regulation of Gene Expression Program, Centro de Investigación Médica Aplicada (CIMA), Universidad de Navarra (UNAV), Pamplona 31008, Spain
| | - Carla Usai
- Gene Therapy and Regulation of Gene Expression Program, Centro de Investigación Médica Aplicada (CIMA), Universidad de Navarra (UNAV), Pamplona 31008, Spain.
| | - Gloria González-Aseguinolaza
- Gene Therapy and Regulation of Gene Expression Program, Centro de Investigación Médica Aplicada (CIMA), Universidad de Navarra (UNAV), Pamplona 31008, Spain.
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Abstract
Viroids are the smallest autonomous infectious nucleic acids known so far. With a small circular RNA genome of about 250-400 nt, which apparently does not code for any protein, viroids replicate and move systemically in host plants. Since the discovery of the first viroid almost forty-five years ago, many different viroids have been isolated, characterized and, frequently, identified as the causal agents of plant diseases. The first viroid classification scheme was proposed in the early 1990s and adopted by the International Committee on Taxonomy of Viruses (ICTV) a few years later. Here, the current viroid taxonomy scheme and the criteria for viroid species demarcation are discussed, highlighting the main taxonomic questions currently under consideration by the ICTV Viroid Study Group. The impact of correct taxonomic annotation of viroid sequence variants is also addressed, taking into consideration the increasing application of next-generation sequencing and bioinformatics for known and previously unrecognized viroids.
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Sripathi KN, Tay WW, Banáš P, Otyepka M, Šponer J, Walter NG. Disparate HDV ribozyme crystal structures represent intermediates on a rugged free-energy landscape. RNA (NEW YORK, N.Y.) 2014; 20:1112-28. [PMID: 24854621 PMCID: PMC4114689 DOI: 10.1261/rna.044982.114] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/23/2014] [Accepted: 04/16/2014] [Indexed: 06/03/2023]
Abstract
The hepatitis delta virus (HDV) ribozyme is a member of the class of small, self-cleaving catalytic RNAs found in a wide range of genomes from HDV to human. Both pre- and post-catalysis (precursor and product) crystal structures of the cis-acting genomic HDV ribozyme have been determined. These structures, together with extensive solution probing, have suggested that a significant conformational change accompanies catalysis. A recent crystal structure of a trans-acting precursor, obtained at low pH and by molecular replacement from the previous product conformation, conforms to the product, raising the possibility that it represents an activated conformer past the conformational change. Here, using fluorescence resonance energy transfer (FRET), we discovered that cleavage of this ribozyme at physiological pH is accompanied by a structural lengthening in magnitude comparable to previous trans-acting HDV ribozymes. Conformational heterogeneity observed by FRET in solution appears to have been removed upon crystallization. Analysis of a total of 1.8 µsec of molecular dynamics (MD) simulations showed that the crystallographically unresolved cleavage site conformation is likely correctly modeled after the hammerhead ribozyme, but that crystal contacts and the removal of several 2'-oxygens near the scissile phosphate compromise catalytic in-line fitness. A cis-acting version of the ribozyme exhibits a more dynamic active site, while a G-1 residue upstream of the scissile phosphate favors poor fitness, allowing us to rationalize corresponding changes in catalytic activity. Based on these data, we propose that the available crystal structures of the HDV ribozyme represent intermediates on an overall rugged RNA folding free-energy landscape.
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Affiliation(s)
- Kamali N. Sripathi
- Department of Medicinal Chemistry, University of Michigan, Ann Arbor, Michigan 48109-1065, USA
| | - Wendy W. Tay
- Program in Chemical Biology, University of Michigan, Ann Arbor, Michigan 48109-1055, USA
| | - Pavel Banáš
- Regional Centre of Advance Technologies and Materials, Department of Physical Chemistry, Faculty of Science, Palacký University, 771 46 Olomouc, Czech Republic
| | - Michal Otyepka
- Regional Centre of Advance Technologies and Materials, Department of Physical Chemistry, Faculty of Science, Palacký University, 771 46 Olomouc, Czech Republic
| | - Jiří Šponer
- Institute of Biophysics, Academy of Sciences of the Czech Republic, 612 65 Brno, Czech Republic
- Masaryk University, Campus Bohunice, 625 00 Brno, Czech Republic
| | - Nils G. Walter
- Department of Chemistry, Single Molecule Analysis Group, University of Michigan, Ann Arbor, Michigan 48109-1055, USA
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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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Fernández-Montero JV, Vispo E, Barreiro P, Sierra-Enguita R, de Mendoza C, Labarga P, Soriano V. Hepatitis delta is a major determinant of liver decompensation events and death in HIV-infected patients. Clin Infect Dis 2014; 58:1549-53. [PMID: 24633686 DOI: 10.1093/cid/ciu167] [Citation(s) in RCA: 73] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Coinfection with hepatitis viruses is common in individuals infected with human immunodeficiency virus (HIV) and has become a leading cause of complications and death in those receiving antiretroviral therapy (ART). METHODS We retrospectively examined the effect of coinfection with hepatitis B, C, and/or D viruses (HBV, HCV, HDV, respectively) on liver decompensation events (ascites, variceal bleeding, encephalopathy, and/or hepatocellular carcinoma) and liver-related mortality in HIV-positive patients on regular follow-up since the year 2004 at a reference HIV clinic in Madrid, Spain. RESULTS A total of 1147 HIV-infected patients (mean age, 42 years; 81% males; 46% intravenous drug users, 85.4% on ART) were analyzed. Mean follow-up was 81.2 ± 17.8 months. At baseline, 521 patients (45.4%) were HCV-antibody positive, 85 (7.4%) were hepatitis B surface antigen positive, and 17 (1.5%) were anti-HDV positive. A total of 233 HIV/HCV-coinfected patients received antiviral therapy for HCV, of whom 106 (45%) achieved sustained virologic response (SVR). Overall, 15 patients died of liver-related complications and 26 developed hepatic decompensation events. Taking as controls the 524 HIV-monoinfected patients, HDV coinfection (adjusted hazard ratio [AHR], 7.5; 95% confidence interval [CI], 1.84-30.8; P = .005) and baseline liver stiffness (AHR, 1.1; 95% CI, 1.07-1.13; P < .0001) were associated with a higher rate of liver-related morbidity and mortality. In contrast, SVR following hepatitis C therapy in HIV/HCV-coinfected patients was protective (AHR, 0.11; 95% CI, .01-.86; P = .03). CONCLUSIONS Hepatitis delta is associated with a high rate of death and liver decompensation events in HIV-infected patients on ART.
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Noureddin M, Gish R. Hepatitis delta: epidemiology, diagnosis and management 36 years after discovery. Curr Gastroenterol Rep 2014; 16:365. [PMID: 24293018 PMCID: PMC3918112 DOI: 10.1007/s11894-013-0365-x] [Citation(s) in RCA: 69] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/02/2023]
Abstract
With recent studies showing increased prevalence of hepatitis delta (HDV) even in the US, Australia, and some countries in Europe, and very high prevalence in endemic regions, HDV infection is far from being a disappearing disease. Although immigrants from endemic countries have been shown to have increased risk, studies have clearly shown that the disease is not solely appearing in traditional high-risk groups. Recent studies provide increasing evidence that sexual transmission may be an important factor in HDV infection spread. Based on the totality of evidence showing increased disease progression and substantially increased risk of cirrhosis in HDV-infected CHB patients, and the current studies showing higher than expected prevalence, it is time to call for HDV screening of all CHB patients. HDV viral load detection and measurement should be considered in all patients whether or not they are anti-HDV-positive. With universal screening of CHB patients for HDV, earlier diagnosis and consideration of treatment would be possible. Current treatment of HDV is IFN-based therapy with or without HBV antivirals, but current research indicates the possibility that prenylation inhibitors, entry inhibitors, HBsAg release inhibitors, or other therapies currently in the pipeline may provide more effective therapy in the future. In addition, universal screening would serve the important public health goal of allowing patients to be educated on their status and on the need for HDV-negative patients to protect themselves against superinfection and for HDV-infected patients to protect against transmission to others. Further studies and global awareness of HDV infection are needed.
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Affiliation(s)
- Mazen Noureddin
- Division of Gastroenterology and Hepatology, Keck School of Medicine, University of Southern California, 2011 Zonal Avenue, HMR 101, Los Angeles, CA 90033 USA
| | - Robert Gish
- Robert G. Gish Consultants, LLC, San Diego, CA USA
- St. Joseph’s Hospital and Medical Center, Phoenix, AZ USA
- University of Nevada, Las Vegas, 6022 La Jolla Mesa Drive, San Diego, CA 92037 USA
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Abbas Z, Afzal R. Life cycle and pathogenesis of hepatitis D virus: A review. World J Hepatol 2013; 5:666-675. [PMID: 24409335 PMCID: PMC3879688 DOI: 10.4254/wjh.v5.i12.666] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2013] [Revised: 11/06/2013] [Accepted: 11/15/2013] [Indexed: 02/06/2023] Open
Abstract
Hepatitis D virus (HDV) is a defective RNA virus which requires the help of hepatitis B virus (HBV) virus for its replication and assembly of new virions. HDV genome contains only one actively transcribed open reading frame which encodes for two isoforms of hepatitis delta antigen. Post-translational modifications of small and large delta antigens (S-HDAg and L-HDAg) involving phosphorylation and isoprenylation respectively confer these antigens their specific properties. S-HDAg is required for the initiation of the viral genome replication, whereas L-HDAg serves as a principal inhibitor of replication and is essential for the assembly of new virion particles. Immune mediation has usually been implicated in HDV-associated liver damage. The pathogenesis of HDV mainly involves interferon-α signaling inhibition, HDV-specific T-lymphocyte activation and cytokine responses, and tumor necrosis factor-alpha and nuclear factor kappa B signaling. Due to limited protein coding capacity, HDV makes use of host cellular proteins to accomplish their life cycle processes, including transcription, replication, post-transcriptional and translational modifications. This intimate host-pathogen interaction significantly alters cell proteome and is associated with an augmented expression of pro-inflammatory, growth and anti-apoptotic factors which explains severe necroinflammation and increased cell survival and an early progression to hepatocellular carcinoma in HDV patients. The understanding of the process of viral replication, HBV-HDV interactions, and etio-pathogenesis of the severe course of HDV infection is helpful in identifying the potential therapeutic targets in the virus life cycle for the prophylaxis and treatment of HDV infection and complications.
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Affiliation(s)
- Zaigham Abbas
- Zaigham Abbas, Rafia Afzal, Department of Hepatogastroenterology, Sindh Institute of Urology and Transplantation, Karachi 75500, Pakistan
| | - Rafia Afzal
- Zaigham Abbas, Rafia Afzal, Department of Hepatogastroenterology, Sindh Institute of Urology and Transplantation, Karachi 75500, Pakistan
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Villarreal LP, Witzany G. Rethinking quasispecies theory: From fittest type to cooperative consortia. World J Biol Chem 2013; 4:79-90. [PMID: 24340131 PMCID: PMC3856310 DOI: 10.4331/wjbc.v4.i4.79] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2013] [Revised: 08/20/2013] [Accepted: 09/04/2013] [Indexed: 02/05/2023] Open
Abstract
Recent investigations surprisingly indicate that single RNA “stem-loops” operate solely by chemical laws that act without selective forces, and in contrast, self-ligated consortia of RNA stem-loops operate by biological selection. To understand consortial RNA selection, the concept of single quasi-species and its mutant spectra as drivers of RNA variation and evolution is rethought here. Instead, we evaluate the current RNA world scenario in which consortia of cooperating RNA stem-loops (not individuals) are the basic players. We thus redefine quasispecies as RNA quasispecies consortia (qs-c) and argue that it has essential behavioral motifs that are relevant to the inherent variation, evolution and diversity in biology. We propose that qs-c is an especially innovative force. We apply qs-c thinking to RNA stem-loops and evaluate how it yields altered bulges and loops in the stem-loop regions, not as errors, but as a natural capability to generate diversity. This basic competence-not error-opens a variety of combinatorial possibilities which may alter and create new biological interactions, identities and newly emerged self identity (immunity) functions. Thus RNA stem-loops typically operate as cooperative modules, like members of social groups. From such qs-c of stem-loop groups we can trace a variety of RNA secondary structures such as ribozymes, viroids, viruses, mobile genetic elements as abundant infection derived agents that provide the stem-loop societies of small and long non-coding RNAs.
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Moelling K. What contemporary viruses tell us about evolution: a personal view. Arch Virol 2013; 158:1833-48. [PMID: 23568292 PMCID: PMC3755228 DOI: 10.1007/s00705-013-1679-6] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2012] [Accepted: 02/14/2013] [Indexed: 12/11/2022]
Abstract
Recent advances in information about viruses have revealed novel and surprising properties such as viral sequences in the genomes of various organisms, unexpected amounts of viruses and phages in the biosphere, and the existence of giant viruses mimicking bacteria. Viruses helped in building genomes and are driving evolution. Viruses and bacteria belong to the human body and our environment as a well-balanced ecosystem. Only in unbalanced situations do viruses cause infectious diseases or cancer. In this article, I speculate about the role of viruses during evolution based on knowledge of contemporary viruses. Are viruses our oldest ancestors?
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Affiliation(s)
- Karin Moelling
- Max Planck Institute for Molecular Genetics, Ihnestr 63-73, 14195, Berlin, Germany.
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Abstract
Hepatitis D is returning to western Europe through immigration. The clinical presentation recapitulates the typical features of a florid hepatitis D. Hepatitis D is also being rediscovered in the developing world and in the United States. Hepatitis D virus (HDV) remains endemic in many countries and efforts are underway to map the infection at local levels and improve the medical alert to hepatitis D. In the United States it is generally thought that HDV has gone and hepatitis D is no longer a problem. Awareness of hepatitis D in the country has recently been revived.
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Affiliation(s)
- Mario Rizzetto
- Division of Gastroenterology, University of Torino, Molinette, c.so Bramante 88, Torino 10126, Italy.
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Koonin EV, Dolja VV. A virocentric perspective on the evolution of life. Curr Opin Virol 2013; 3:546-57. [PMID: 23850169 PMCID: PMC4326007 DOI: 10.1016/j.coviro.2013.06.008] [Citation(s) in RCA: 159] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2013] [Revised: 06/12/2013] [Accepted: 06/13/2013] [Indexed: 01/12/2023]
Abstract
Viruses and/or virus-like selfish elements are associated with all cellular life forms and are the most abundant biological entities on Earth, with the number of virus particles in many environments exceeding the number of cells by one to two orders of magnitude. The genetic diversity of viruses is commensurately enormous and might substantially exceed the diversity of cellular organisms. Unlike cellular organisms with their uniform replication-expression scheme, viruses possess either RNA or DNA genomes and exploit all conceivable replication-expression strategies. Although viruses extensively exchange genes with their hosts, there exists a set of viral hallmark genes that are shared by extremely diverse groups of viruses to the exclusion of cellular life forms. Coevolution of viruses and host defense systems is a key aspect in the evolution of both viruses and cells, and viral genes are often recruited for cellular functions. Together with the fundamental inevitability of the emergence of genomic parasites in any evolving replicator system, these multiple lines of evidence reveal the central role of viruses in the entire evolution of life.
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Affiliation(s)
- Eugene V Koonin
- National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD 20894, USA.
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