|
1
|
Zulian V, Salichos L, Taibi C, Pauciullo S, Dong L, D’Offizi G, Biliotti E, Rianda A, Federici L, Bibbò A, De Sanctis M, McPhee F, Garbuglia AR. Exploring Predictive Factors for Bulevirtide Treatment Response in Hepatitis Delta-Positive Patients. Biomedicines 2025; 13:280. [PMID: 40002694 PMCID: PMC11852621 DOI: 10.3390/biomedicines13020280] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2024] [Revised: 01/17/2025] [Accepted: 01/21/2025] [Indexed: 02/27/2025] Open
Abstract
Background: Hepatitis delta virus (HDV) infection represents the most severe form of viral hepatitis and is a significant global health challenge. Bulevirtide (BLV) is a novel therapeutic treatment that has resulted in variable response rates in HBV/HDV-coinfected patients. We evaluated clinical, virological, and polymorphic factors for the purpose of predicting BLV treatment success. Methods: Thirty HBV/HDV-coinfected patients received BLV monotherapy (2 mg/day) for 24 to 48 weeks. Baseline (BL) serum samples were collected to assess clinical parameters and virological markers (HDV RNA, HBV DNA, HBsAg, HBcrAg, anti-HBc IgG) at treatment weeks 24 (TW24) and 48 (TW48). Additionally, full-genome HDV sequencing and a phylogenetic analysis were performed. Finally, analyses of the HDAg protein sequence and HDV RNA secondary structure were conducted to evaluate potential associations with treatment response. Results: A significant reduction in HDV RNA levels was observed at TW48, with a virological response (HDV RNA undetectable or ≥2 Log decline from BL) achieved by 58% of patients. Median BL levels of anti-HBc IgG were significantly different between virological responders (39.3 COI; interquartile range [IQR] 31.6-47.1) and virological non-responders (244.7 COI; IQR 127.0-299.4) (p = 0.0001). HDV genotype 1e was predominant across the cohort, and no specific HDAg polymorphisms predicted the response. However, secondary structure analysis of HDV RNA revealed that a specific pattern of internal loops in the region 63-100 nucleotides downstream of the editing site may influence treatment response by impacting editing efficacy. Conclusions: This study revealed key factors influencing BLV efficacy in HBV/HDV coinfection. Lower baseline anti-HBc IgG levels strongly correlated with a positive virological response, suggesting that the liver's inflammatory state affects treatment success. Additionally, the analysis of HDV RNA secondary structure in patients receiving BLV treatment revealed a higher editing efficiency in virological responders, highlighting areas for further research.
Collapse
Affiliation(s)
- Verdiana Zulian
- Virology Laboratory, National Institute for Infectious Diseases Lazzaro Spallanzani IRCCS, 00149 Rome, Italy; (S.P.); (L.F.); (A.B.); (M.D.S.); (A.R.G.)
| | - Leonidas Salichos
- Department of Biological and Chemical Sciences, New York Institute of Technology, New York, NY 10023, USA; (L.S.); (L.D.)
| | - Chiara Taibi
- Infectious Diseases and Hepatology Unit, National Institute for Infectious Diseases Lazzaro Spallanzani IRCCS, 00149 Rome, Italy; (C.T.); (G.D.); (E.B.); (A.R.)
| | - Silvia Pauciullo
- Virology Laboratory, National Institute for Infectious Diseases Lazzaro Spallanzani IRCCS, 00149 Rome, Italy; (S.P.); (L.F.); (A.B.); (M.D.S.); (A.R.G.)
| | - Levi Dong
- Department of Biological and Chemical Sciences, New York Institute of Technology, New York, NY 10023, USA; (L.S.); (L.D.)
| | - Gianpiero D’Offizi
- Infectious Diseases and Hepatology Unit, National Institute for Infectious Diseases Lazzaro Spallanzani IRCCS, 00149 Rome, Italy; (C.T.); (G.D.); (E.B.); (A.R.)
| | - Elisa Biliotti
- Infectious Diseases and Hepatology Unit, National Institute for Infectious Diseases Lazzaro Spallanzani IRCCS, 00149 Rome, Italy; (C.T.); (G.D.); (E.B.); (A.R.)
| | - Alessia Rianda
- Infectious Diseases and Hepatology Unit, National Institute for Infectious Diseases Lazzaro Spallanzani IRCCS, 00149 Rome, Italy; (C.T.); (G.D.); (E.B.); (A.R.)
| | - Luigi Federici
- Virology Laboratory, National Institute for Infectious Diseases Lazzaro Spallanzani IRCCS, 00149 Rome, Italy; (S.P.); (L.F.); (A.B.); (M.D.S.); (A.R.G.)
| | - Angela Bibbò
- Virology Laboratory, National Institute for Infectious Diseases Lazzaro Spallanzani IRCCS, 00149 Rome, Italy; (S.P.); (L.F.); (A.B.); (M.D.S.); (A.R.G.)
| | - Martina De Sanctis
- Virology Laboratory, National Institute for Infectious Diseases Lazzaro Spallanzani IRCCS, 00149 Rome, Italy; (S.P.); (L.F.); (A.B.); (M.D.S.); (A.R.G.)
| | | | - Anna Rosa Garbuglia
- Virology Laboratory, National Institute for Infectious Diseases Lazzaro Spallanzani IRCCS, 00149 Rome, Italy; (S.P.); (L.F.); (A.B.); (M.D.S.); (A.R.G.)
| |
Collapse
|
|
2
|
Hsu CW, Hsu HY, Chen CH, Chao M. Unbranched rod-like RNA is required for RNA editing of hepatitis delta virus genotype 2 and genotype 4. Virus Res 2023; 338:199239. [PMID: 37827303 PMCID: PMC10590747 DOI: 10.1016/j.virusres.2023.199239] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Revised: 10/09/2023] [Accepted: 10/09/2023] [Indexed: 10/14/2023]
Abstract
RNA editing of the hepatitis delta virus (HDV) is essential for generating the large delta antigen, which is crucial for virion assembly. In HDV genotype 1 (HDV-1), editing occurs within the context of the unbranched rod-like structure characteristic of HDV RNA, while RNA editing in HDV-3 requires a branched double-hairpin structure. The regulation of RNA editing in HDV-2 and HDV-4 remains uncertain. Based on predictions of the unbranched rod-like RNA structures of HDV-2 and HDV-4, the editing site occurs as an A.C mismatch pair, surrounded by four base pairs upstream and two base pairs downstream of the editing site, respectively. To investigate HDV-2 and HDV-4 RNA editing, cultured cells were transfected with non-replicating editing reporters carrying wild-type sequences or specific mutations. The results revealed that the editing rates observed for wild-type HDV-2 and HDV-4 were fairly similar, albeit lower than that of HDV-1. Like HDV-1, both HDV-2 and HDV-4 showed a reduction in editing rate when the A.C mismatch pair and the immediately upstream base-paired region were disturbed. Notably, extending the downstream base-paired region from two to three or four (forming a structure identical to that of HDV-1) base pairs increased editing rate. Furthermore, we presented novel evidence that indicates the importance of the first bulge's size, located upstream of the editing site, and the base-pairing length within 7-13 and 28-39 nucleotides downstream of the editing site in influencing the HDV-4 editing rate. To summarize, our analyses suggest that the unbranched rod-like structures surrounding the editing site of HDV-2 and HDV-4 play a crucial role in regulating their RNA editing rates.
Collapse
Affiliation(s)
- Chao-Wei Hsu
- Liver Research Center, Department of Hepato-Gastroenterology, Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Guishan, Taoyang 33302, Taiwan
| | - Hsueh-Ying Hsu
- Liver Research Center, Department of Hepato-Gastroenterology, Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Guishan, Taoyang 33302, Taiwan
| | - Chien-Hung Chen
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan
| | - Mei Chao
- Liver Research Center, Department of Hepato-Gastroenterology, Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Guishan, Taoyang 33302, Taiwan; Department of Microbiology and Immunology and Division of Microbiology, Graduate Institute of Biomedical Sciences, Chang Gung University, Guishan, Taoyang 33302, Taiwan.
| |
Collapse
|
|
3
|
Zhu T, Niu G, Zhang Y, Chen M, Li CY, Hao L, Zhang Z. Host-mediated RNA editing in viruses. Biol Direct 2023; 18:12. [PMID: 36978112 PMCID: PMC10043548 DOI: 10.1186/s13062-023-00366-w] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Accepted: 03/17/2023] [Indexed: 03/30/2023] Open
Abstract
Viruses rely on hosts for life and reproduction, cause a variety of symptoms from common cold to AIDS to COVID-19 and provoke public health threats claiming millions of lives around the globe. RNA editing, as a crucial co-/post-transcriptional modification inducing nucleotide alterations on both endogenous and exogenous RNA sequences, exerts significant influences on virus replication, protein synthesis, infectivity and toxicity. Hitherto, a number of host-mediated RNA editing sites have been identified in diverse viruses, yet lacking a full picture of RNA editing-associated mechanisms and effects in different classes of viruses. Here we synthesize the current knowledge of host-mediated RNA editing in a variety of viruses by considering two enzyme families, viz., ADARs and APOBECs, thereby presenting a landscape of diverse editing mechanisms and effects between viruses and hosts. In the ongoing pandemic, our study promises to provide potentially valuable insights for better understanding host-mediated RNA editing on ever-reported and newly-emerging viruses.
Collapse
Affiliation(s)
- Tongtong Zhu
- National Genomics Data Center & CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, 100101, China
- China National Center for Bioinformation, Beijing, 100101, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Guangyi Niu
- National Genomics Data Center & CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, 100101, China
- China National Center for Bioinformation, Beijing, 100101, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Yuansheng Zhang
- National Genomics Data Center & CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, 100101, China
- China National Center for Bioinformation, Beijing, 100101, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Ming Chen
- National Genomics Data Center & CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, 100101, China
- China National Center for Bioinformation, Beijing, 100101, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Chuan-Yun Li
- Laboratory of Bioinformatics and Genomic Medicine, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine, Peking University, Beijing, 100871, China
| | - Lili Hao
- National Genomics Data Center & CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, 100101, China.
- China National Center for Bioinformation, Beijing, 100101, China.
| | - Zhang Zhang
- National Genomics Data Center & CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, 100101, China.
- China National Center for Bioinformation, Beijing, 100101, China.
- University of Chinese Academy of Sciences, Beijing, 100049, China.
| |
Collapse
|
|
4
|
Hepatitis Delta Antigen Regulates mRNA and Antigenome RNA Levels during Hepatitis Delta Virus Replication. J Virol 2019; 93:JVI.01989-18. [PMID: 30728256 DOI: 10.1128/jvi.01989-18] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2018] [Accepted: 01/18/2019] [Indexed: 01/17/2023] Open
Abstract
Hepatitis delta virus (HDV) is a satellite of hepatitis B virus that increases the severity of acute and chronic liver disease. HDV produces three processed RNAs that accumulate in infected cells: the circular genome; the circular antigenome, which serves as a replication intermediate; and lesser amounts of the mRNA, which encodes the sole viral protein, hepatitis delta antigen (HDAg). The HDV genome and antigenome RNAs form ribonucleoprotein complexes with HDAg. Although HDAg is required for HDV replication, it is not known how the relative amounts of HDAg and HDV RNA affect replication, or whether HDAg synthesis is regulated by the virus. Using a novel transfection system in which HDV replication is initiated using in vitro-synthesized circular HDV RNAs, HDV replication was found to depend strongly on the relative amounts of HDV RNA and HDAg. HDV controls these relative amounts via differential effects of HDAg on the production of HDV mRNA and antigenome RNA, both of which are synthesized from the genome RNA template. mRNA synthesis is favored at low HDAg levels but becomes saturated at high HDAg concentrations. Antigenome RNA accumulation increases linearly with HDAg and dominates at high HDAg levels. These results provide a conceptual model for how HDV antigenome RNA production and mRNA transcription are controlled from the earliest stage of infection onward and also demonstrate that, in this control, HDV behaves similarly to other negative-strand RNA viruses, even though there is no genetic similarity between them.IMPORTANCE Hepatitis delta virus (HDV) is a satellite of hepatitis B virus that increases the severity of liver disease; approximately 15 million people are chronically infected worldwide. There are no licensed therapies available. HDV is not related to any known virus, and few details regarding its replication cycle are known. One key question is whether and how HDV regulates the relative amounts of viral RNA and protein in infected cells. Such regulation might be important because the HDV RNA and protein form complexes that are essential for HDV replication, and the proper stoichiometry of these complexes could be critical for their function. Our results show that the relative amounts of HDV RNA and protein in cells are indeed important for HDV replication and that the virus does control them. These observations indicate that further study of these regulatory mechanisms is required to better understand replication of this serious human pathogen.
Collapse
|
|
5
|
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.
Collapse
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
Collapse
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.
| |
Collapse
|
|
6
|
Pyne M, Mallory M, Xie H, Mei Y, Schlaberg R, Hillyard D. Sequencing of the Hepatitis D Virus RNA WHO International Standard. J Clin Virol 2017; 90:52-56. [PMID: 28359844 DOI: 10.1016/j.jcv.2017.03.009] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2017] [Revised: 03/10/2017] [Accepted: 03/15/2017] [Indexed: 01/16/2023]
|
|
7
|
Nguyen HM, Sy BT, Trung NT, Hoan NX, Wedemeyer H, Velavan TP, Bock CT. Prevalence and genotype distribution of hepatitis delta virus among chronic hepatitis B carriers in Central Vietnam. PLoS One 2017; 12:e0175304. [PMID: 28403190 PMCID: PMC5389633 DOI: 10.1371/journal.pone.0175304] [Citation(s) in RCA: 16] [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: 10/19/2016] [Accepted: 03/23/2017] [Indexed: 02/07/2023] Open
Abstract
Hepatitis D virus (HDV) infection plays an important role in liver diseases. However, the molecular epidemiology and impact of HDV infection in chronic hepatitis B (CHB) remain uncertain in Vietnam. This cross-sectional study aimed to investigate the prevalence and genotype distribution of HDV among HBsAg-positive patients in Central Vietnam. 250 CHB patients were tested for HDV using newly established HDV-specific RT-PCR techniques. HDV genotypes were determined by direct sequencing. Of the 250 patients 25 (10%) had detectable copies of HDV viral RNA. HDV-2 was predominant (20/25; 80%) followed by HDV-1 (5/25; 20%). Proven HDV genotypes share the Asian nomenclature. Chronic hepatitis B patients with concomitant HDV-1 showed higher HBV loads as compared to HDV-2 infected patients [median log10 (HBV-DNA copies/ml): 8.5 vs. 4.4, P = 0.036]. Our findings indicate that HDV infection is highly prevalent and HDV-2 is predominant in Central Vietnam. The data will add new information to the management of HBsAg-positive patients in a highly HBV endemic region to in- or exclude HDV infection in terms of diagnostic and treatment options.
Collapse
Affiliation(s)
- Hung Minh Nguyen
- Center for Molecular Biology, Institute of Research and Development, Duy Tan University, Da Nang, Vietnam
| | - Bui Tien Sy
- Department of Molecular Biology, 108 Military Central Hospital, Hanoi, Vietnam
| | - Nguyen Thanh Trung
- Center for Molecular Biology, Institute of Research and Development, Duy Tan University, Da Nang, Vietnam
| | - Nghiem Xuan Hoan
- Institute of Tropical Medicine, University of Tübingen, Tübingen, Germany
| | - Heiner Wedemeyer
- German Center for Infection Research, Department for Gastroenterology, Hepatology, and Endocrinology, Medical School Hannover, Hannover, Germany
| | - Thirumalaisamy P. Velavan
- Center for Molecular Biology, Institute of Research and Development, Duy Tan University, Da Nang, Vietnam
- Institute of Tropical Medicine, University of Tübingen, Tübingen, Germany
- Vietnamese-German Center for Medical Research, Hanoi, Vietnam
| | - C-Thomas Bock
- Department of Infectious Diseases, Robert Koch Institute, Berlin, Germany
| |
Collapse
|
|
8
|
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: 12] [Impact Index Per Article: 1.2] [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.
Collapse
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.
| |
Collapse
|
|
9
|
Rivera-Molina YA, Martínez FP, Tang Q. Nuclear domain 10 of the viral aspect. World J Virol 2013; 2:110-122. [PMID: 24255882 PMCID: PMC3832855 DOI: 10.5501/wjv.v2.i3.110] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2013] [Revised: 05/31/2013] [Accepted: 07/11/2013] [Indexed: 02/05/2023] Open
Abstract
Nuclear domain 10 (ND10) are spherical bodies distributed throughout the nucleoplasm and measuring around 0.2-1.0 μm. First observed under an electron microscope, they were originally described as dense bodies found in the nucleus. They are known by a number of other names, including Promyelocytic Leukemia bodies (PML bodies), Kremer bodies, and PML oncogenic domains. ND10 are frequently associated with Cajal bodies and cleavage bodies. It has been suggested that they play a role in regulating gene transcription. ND10 were originally characterized using human autoantisera, which recognizes Speckled Protein of 100 kDa, from patients with primary biliary cirrhosis. At the immunohistochemical level, ND10 appear as nuclear punctate structures, with 10 indicating the approximate number of dots per nucleus observed. ND10 do not colocalize with kinetochores, centromeres, sites of mRNA processing, or chromosomes. Resistance of ND10 antigens to nuclease digestion and salt extraction suggest that ND10 are associated with the nuclear matrix. They are often identified by immunofluorescent assay using specific antibodies against PML, Death domain-associated protein, nuclear dot protein (NDP55), and so on. The role of ND10 has long been the subject of investigation, with the specific connection of ND10 and viral infection having been a particular focus for almost 20 years. This review summarizes the relationship of ND10 and viral infection. Some future study directions are also discussed.
Collapse
|
|
10
|
RNA editing and drug discovery for cancer therapy. ScientificWorldJournal 2013; 2013:804505. [PMID: 23737728 PMCID: PMC3655661 DOI: 10.1155/2013/804505] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2013] [Accepted: 04/08/2013] [Indexed: 12/26/2022] Open
Abstract
RNA editing is vital to provide the RNA and protein complexity to regulate the gene expression. Correct RNA editing maintains the cell function and organism development. Imbalance of the RNA editing machinery may lead to diseases and cancers. Recently, RNA editing has been recognized as a target for drug discovery although few studies targeting RNA editing for disease and cancer therapy were reported in the field of natural products. Therefore, RNA editing may be a potential target for therapeutic natural products. In this review, we provide a literature overview of the biological functions of RNA editing on gene expression, diseases, cancers, and drugs. The bioinformatics resources of RNA editing were also summarized.
Collapse
|