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Brani P, Manzoor HZ, Spezia PG, Vigezzi A, Ietto G, Dalla Gasperina D, Minosse C, Bosi A, Giaroni C, Carcano G, Maggi F, Baj A. Torque Teno Virus: Lights and Shades. Viruses 2025; 17:334. [PMID: 40143262 PMCID: PMC11945719 DOI: 10.3390/v17030334] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2025] [Revised: 02/21/2025] [Accepted: 02/25/2025] [Indexed: 03/28/2025] Open
Abstract
Torque Teno Virus (TTV) is a highly prevalent non-pathogenic DNA virus whose plasma levels may be related to the host's immune status. TTV gained attention about 25 years ago, but its replication is not fully understood, nor is its relationship with the host's immune system. Despite this lack of knowledge, TTV is currently being investigated as a functional biomarker of the immune system in patients with immunological damage and inflammatory diseases. Monitoring TTV viral load over time may help clinicians in making therapeutic decisions regarding immunosuppression as well as the likelihood of infectious complications. This review summarizes what we do and do not know about this enigmatic virus.
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Affiliation(s)
- Paola Brani
- Department of Medicine and Technological Innovation, University of Insubria, 21100 Varese, Italy
- Laboratory of Microbiology, ASST Sette Laghi, 21100 Varese, Italy
| | - Hafza Zahira Manzoor
- Department of Medicine and Technological Innovation, University of Insubria, 21100 Varese, Italy
| | - Pietro Giorgio Spezia
- Laboratory of Virology and Biosafety Laboratories, National Institute for Infectious Diseases “Lazzaro Spallanzani”-IRCCS, 00149 Rome, Italy
| | - Andrea Vigezzi
- Department of Medicine and Technological Innovation, University of Insubria, 21100 Varese, Italy
| | - Giuseppe Ietto
- Department of Medicine and Technological Innovation, University of Insubria, 21100 Varese, Italy
| | - Daniela Dalla Gasperina
- Department of Medicine and Technological Innovation, University of Insubria, 21100 Varese, Italy
| | - Claudia Minosse
- Laboratory of Virology and Biosafety Laboratories, National Institute for Infectious Diseases “Lazzaro Spallanzani”-IRCCS, 00149 Rome, Italy
| | - Annalisa Bosi
- Department of Medicine and Technological Innovation, University of Insubria, 21100 Varese, Italy
| | - Cristina Giaroni
- Department of Medicine and Technological Innovation, University of Insubria, 21100 Varese, Italy
| | - Giulio Carcano
- Department of Medicine and Technological Innovation, University of Insubria, 21100 Varese, Italy
| | - Fabrizio Maggi
- Laboratory of Virology and Biosafety Laboratories, National Institute for Infectious Diseases “Lazzaro Spallanzani”-IRCCS, 00149 Rome, Italy
| | - Andreina Baj
- Department of Medicine and Technological Innovation, University of Insubria, 21100 Varese, Italy
- Laboratory of Microbiology, ASST Sette Laghi, 21100 Varese, Italy
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Kandathil AJ, Thomas DL. The Blood Virome: A new frontier in biomedical science. Biomed Pharmacother 2024; 175:116608. [PMID: 38703502 PMCID: PMC11184943 DOI: 10.1016/j.biopha.2024.116608] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Revised: 04/12/2024] [Accepted: 04/17/2024] [Indexed: 05/06/2024] Open
Abstract
Recent advances in metagenomic testing opened a new window into the mammalian blood virome. Comprised of well-known viruses like human immunodeficiency virus, hepatitis C virus, and hepatitis B virus, the virome also includes many other eukaryotic viruses and phages whose medical significance, lifecycle, epidemiology, and impact on human health are less well known and thus regarded as commensals. This review synthesizes available information for the so-called commensal virome members that circulate in the blood of humans considering their restriction to and interaction with the human host, their natural history, and their impact on human health and physiology.
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Affiliation(s)
- Abraham J Kandathil
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - David L Thomas
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
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First Report of TTSuV1 in Domestic Swiss Pigs. Viruses 2022; 14:v14050870. [PMID: 35632612 PMCID: PMC9146045 DOI: 10.3390/v14050870] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Revised: 04/08/2022] [Accepted: 04/21/2022] [Indexed: 12/14/2022] Open
Abstract
Serum prevalence of Torque teno sus viruses (TTSuV1 and k2; family Anelloviridae) is known to be high in the porcine population worldwide but pathogenesis and associated pathomorphological lesions remain to be elucidated. In this study, quantitative real-time PCR for detection of TTSuV1 was performed in 101 porcine samples of brain tissue, with animals showing inflammatory lesions or no histological changes. Additionally, a pathomorphological and immunohistochemical characterization of possible lesions was carried out. Selected cases were screened by TTSuV1 in situ hybridization. Furthermore, TTSuV1 quantitative real-time PCR in splenic and pulmonary tissue and in situ hybridization (ISH) in spleen, lungs, mesenteric lymph node, heart, kidney, and liver were performed in 22 animals. TTSuV1 was detected by PCR not only in spleen and lung but also in brain tissue (71.3%); however, in general, spleen and lung tissue displayed lower Ct values than the brain. Positive TTSuV1 results were frequently associated with the morphological diagnosis of non-suppurative encephalitis. Single TTSuV1-positive lymphocytes were detected by ISH in the brain but also in lungs, spleen, mesenteric lymph node and in two cases of non-suppurative myocarditis. A pathogenetic role of a TTSuV1 infection as a co-factor for non-suppurative encephalitides cannot be ruled out.
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Desingu PA, Nagarajan K, Dhama K. Can a Torque Teno Virus (TTV) Be a Naked DNA Particle Without a Virion Structure? FRONTIERS IN VIROLOGY 2022; 2. [DOI: 10.3389/fviro.2022.821298] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Kyathanahalli C, Snedden M, Hirsch E. Human Anelloviruses: Prevalence and Clinical Significance During Pregnancy. FRONTIERS IN VIROLOGY 2021; 1. [DOI: 10.3389/fviro.2021.782886] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
Although the bacterial microbiota of various compartments (e.g. vagina, amniotic fluid, and placenta) have been studied in pregnancy, there has been far less emphasis on normal and pathological viral communities. Cumulative evidence shows the presence of a number of apathogenic viruses in various tissues of healthy people, including pregnant individuals. What role, if any, these viruses play in human physiology is unknown. Anelloviruses (family Anelloviridae) are circular, single-stranded DNA viruses commonly detected with high prevalence in vertebrate hosts, including primates. Humans are nearly always colonized with at least 1 of 3 anellovirus subtypes, namely Alphatorquevirus (torque teno virus, TTV), Betatorquevirus (torque teno midi virus, TTMDV), and Gammatorquevirus (torque teno mini virus, TTMV). In healthy pregnant people, the prototype anellovirus, TTV, has been found in maternal and (variably) fetal blood, amniotic fluid, cervical and vaginal secretions, breast milk, and saliva. Nonetheless, the relevance of human anelloviruses in pregnancy and labor is unclear. There is evidence suggesting a link between anellovirus colonization and preterm birth. In this review, we discuss what is known about this family of commensal viruses in health and disease, and specifically the roles they might play during pregnancy and in the timing of delivery.
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Stefani D, Hegedues B, Collaud S, Zaatar M, Ploenes T, Valdivia D, Elsner C, Bleekmann B, Widera M, Dittmer U, Aigner C. Torque Teno Virus load in lung cancer patients correlates with age but not with tumor stage. PLoS One 2021; 16:e0252304. [PMID: 34077485 PMCID: PMC8171866 DOI: 10.1371/journal.pone.0252304] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2020] [Accepted: 04/20/2021] [Indexed: 11/30/2022] Open
Abstract
Background Torque teno virus (TTV) is a ubiquitous non-pathogenic virus, which is suppressed in immunological healthy individuals but replicates in immune compromised patients. Thus, TTV load is a suitable biomarker for monitoring the immunosuppression also in lung transplant recipients. Since little is known about the changes of TTV load in lung cancer patients, we analyzed TTV plasma DNA levels in lung cancer patients and its perioperative changes after lung cancer surgery. Material and methods Patients with lung cancer and non-malignant nodules as control group were included prospectively. TTV DNA levels were measured by quantiative PCR using DNA isolated from patients plasma and correlated with routine circulating biomarkers and clinicopathological variables. Results 47 patients (early stage lung cancer n = 30, stage IV lung cancer n = 10, non-malignant nodules n = 7) were included. TTV DNA levels were not detected in seven patients (15%). There was no significant difference between the stage IV cases and the preoperative TTV plasma DNA levels in patients with early stage lung cancer or non-malignant nodules (p = 0.627). While gender, tumor stage and tumor histology showed no correlation with TTV load patients below 65 years of age had a significantly lower TTV load then older patients (p = 0.022). Regarding routine blood based biomarkers, LDH activity was significantly higher in patients with stage IV lung cancer (p = 0.043), however, TTV load showed no correlation with LDH activity, albumin, hemoglobin, CRP or WBC. Comparing the preoperative, postoperative and discharge day TTV load, no unequivocal pattern in the kinetics were. Conclusion Our study suggest that lung cancer has no stage dependent impact on TTV plasma DNA levels and confirms that elderly patients have a significantly higher TTV load. Furthermore, we found no uniform perioperative changes during early stage lung cancer resection on plasma TTV DNA levels.
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Affiliation(s)
- Dirk Stefani
- Department of Thoracic Surgery, Ruhrlandklinik, University of Duisburg-Essen, Essen, Germany
| | - Balazs Hegedues
- Department of Thoracic Surgery, Ruhrlandklinik, University of Duisburg-Essen, Essen, Germany
| | - Stephane Collaud
- Department of Thoracic Surgery, Ruhrlandklinik, University of Duisburg-Essen, Essen, Germany
| | - Mohamed Zaatar
- Department of Thoracic Surgery, Ruhrlandklinik, University of Duisburg-Essen, Essen, Germany
| | - Till Ploenes
- Department of Thoracic Surgery, Ruhrlandklinik, University of Duisburg-Essen, Essen, Germany
| | - Daniel Valdivia
- Department of Thoracic Surgery, Ruhrlandklinik, University of Duisburg-Essen, Essen, Germany
| | - Carina Elsner
- Institute of Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Barbara Bleekmann
- Institute of Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Marek Widera
- Institute of Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
- Institute of Medical Virology, University Hospital Frankfurt am Main, Goethe University, Frankfurt am Main, Germany
| | - Ulf Dittmer
- Institute of Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Clemens Aigner
- Department of Thoracic Surgery, Ruhrlandklinik, University of Duisburg-Essen, Essen, Germany
- * E-mail:
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Kaczorowska J, van der Hoek L. Human anelloviruses: diverse, omnipresent and commensal members of the virome. FEMS Microbiol Rev 2021; 44:305-313. [PMID: 32188999 PMCID: PMC7326371 DOI: 10.1093/femsre/fuaa007] [Citation(s) in RCA: 110] [Impact Index Per Article: 27.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2019] [Accepted: 03/02/2020] [Indexed: 12/12/2022] Open
Abstract
Anelloviruses are small, single stranded circular DNA viruses. They are extremely diverse and have not been associated with any disease so far. Strikingly, these small entities infect most probably the complete human population, and there are no convincing examples demonstrating viral clearance from infected individuals. The main transmission could be via fecal-oral or airway route, as infections occur at an early age. However, due to the lack of an appropriate culture system, the virus–host interactions remain enigmatic. Anelloviruses are obviously mysterious viruses, and their impact on human life is not yet known, but, with no evidence of a disease association, a potential beneficial effect on human health should also be investigated.
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Affiliation(s)
- Joanna Kaczorowska
- Laboratory of Experimental Virology, Department of Medical Microbiology, Amsterdam UMC, Location AMC, University of Amsterdam, Meibergdreef 9, Amsterdam, the Netherlands
| | - Lia van der Hoek
- Laboratory of Experimental Virology, Department of Medical Microbiology, Amsterdam UMC, Location AMC, University of Amsterdam, Meibergdreef 9, Amsterdam, the Netherlands
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Maev IV, Karlovich TI, Burmistrov AI, Chekmazov IA, Andreev DN, Reshetnyak VI. Current Views of Torque Teno Virus (TTV) in Liver Diseases. RUSSIAN JOURNAL OF GASTROENTEROLOGY, HEPATOLOGY, COLOPROCTOLOGY 2020; 30:7-22. [DOI: 10.22416/1382-4376-2020-30-4-7-22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/28/2023]
Affiliation(s)
- I. V. Maev
- Moscow State University of Medicine and Dentistry
| | - T. I. Karlovich
- Central Clinical Hospital with Outpatient Care of the Russian President Administration
| | | | - I. A. Chekmazov
- Central Clinical Hospital with Outpatient Care of the Russian President Administration
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Reshetnyak VI, Maev IV, Burmistrov AI, Chekmazov IA, Karlovich TI. Torque teno virus in liver diseases: On the way towards unity of view. World J Gastroenterol 2020; 26:1691-1707. [PMID: 32351287 PMCID: PMC7183866 DOI: 10.3748/wjg.v26.i15.1691] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2019] [Revised: 03/23/2020] [Accepted: 03/27/2020] [Indexed: 02/06/2023] Open
Abstract
The review presents the data accumulated for more than 20 years of research of torque teno virus (TTV). Its molecular genetic structure, immunobiology, epidemiology, diagnostic methods, possible replication sites, and pathogenicity factors are described. TTV is a virus that is frequently detectable in patients with different viral hepatitides, in cases of hepatitis without an obvious viral agent, as well as in a healthy population. There is evidence suggesting that biochemical and histological changes occur in liver tissue and bile duct epithelium in TTV monoinfection. There are sufficient histological signs of liver damage, which confirm that the virus can undergo a replicative cycle in hepatocytes. Along with this, cytological hybridization in TTV-infected cells has shown no substantial cytopathic (cell-damaging) effects that are characteristic of pathogenic hepatotropic viruses. Studying TTV has led to the evolution of views on its role in the development of human pathology. The first ideas about the hepatotropism of the virus were gradually reformed as new data became available on the prevalence of the virus and its co-infection with other viruses, including the viruses of the known types of hepatitides. The high prevalence of TTV in the human population indicates its persistence in the body as a virome and a non-pathogenic virus. It has recently been proposed that the level of TTV DNA in the blood of patients undergoing organ transplantation should be used as an endogenous marker of the body's immune status. The available data show the polytropism of the virus and deny the fact that TTV can be assigned exclusively to hepatitis viruses. Fortunately, the rare detection of the damaging effect of TTV on hepatic and bile duct epithelial cells may be indirect evidence of its conditionally pathogenic properties. The ubiquity of the virus and the variability of its existence in humans cannot put an end to its study.
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Affiliation(s)
- Vasiliy I Reshetnyak
- Department of Propaedeutic of Internal Diseases and Gastroenterology, A.I. Yevdokimov Moscow State University of Medicine and Dentistry, Moscow 127473, Russia
| | - Igor V Maev
- Department of Propaedeutic of Internal Diseases and Gastroenterology, A.I. Yevdokimov Moscow State University of Medicine and Dentistry, Moscow 127473, Russia
| | - Alexandr I Burmistrov
- Department of Propaedeutic of Internal Diseases and Gastroenterology, A.I. Yevdokimov Moscow State University of Medicine and Dentistry, Moscow 127473, Russia
| | - Igor A Chekmazov
- Central Clinical Hospital with Polyclinic, Presidential Administration of the Russian Federation, Moscow 121359, Russia
| | - Tatiana I Karlovich
- Central Clinical Hospital with Polyclinic, Presidential Administration of the Russian Federation, Moscow 121359, Russia
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Rosario K, Mettel KA, Greco AM, Breitbart M. Prevalence of a vertically transmitted single-stranded DNA virus in spinybacked orbweavers (Gasteracantha cancriformis) from Florida, USA. J Gen Virol 2019; 100:1253-1265. [PMID: 31210632 DOI: 10.1099/jgv.0.001293] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
Spiders (order Araneae, class Arachnida) are an important group of predatory arthropods in terrestrial ecosystems that have been recently identified as an untapped reservoir of single-stranded (ss)DNA viruses. Specifically, spiders harbour a diversity of ssDNA viruses encoding a replication-associated protein (Rep) within a circular genome. However, little is known about the ecology of novel circular Rep-encoding ssDNA (CRESS DNA) viruses. Here we investigated two CRESS DNA viruses recently identified in spinybacked orbweavers (Gasteracantha cancriformis), namely spinybacked orbweaver circular virus (SpOrbCV) 1 and 2. SpOrbCV-1 was detected in the majority (> 65 %) of spider specimens from all life stages, including eggs, spiderlings and adults, demonstrating that this virus is active within spinybacked orbweavers. In contrast, SpOrbCV-2 was only detected in adults at a lower (36 %) prevalence. Since we also detected SpOrbCV-2 in other spider species and this virus has been reported from a dragonfly, we suggest that SpOrbCV-2 is accumulated in these predators through common insect prey. The prevalence of SpOrbCV-1 in collected specimens allowed us to design assays to characterize this virus, which represents a new group of CRESS DNA viruses, the 'circularisviruses'. To our knowledge, SpOrbCV-1 is the first example of a vertically transmitted virus in spiders, which may explain its high prevalence in spinybacked orbweavers. Since vertically transmitted viruses infecting insects (class Insecta) can manipulate their host's behaviour and physiology, future studies should investigate the ecological role of vertically transmitted viruses in spiders.
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Affiliation(s)
- Karyna Rosario
- College of Marine Science, University of South Florida, 140 7th Avenue South, Saint Petersburg, FL, 33701, USA
| | - Kaitlin A Mettel
- College of Marine Science, University of South Florida, 140 7th Avenue South, Saint Petersburg, FL, 33701, USA
| | - Anthony M Greco
- College of Marine Science, University of South Florida, 140 7th Avenue South, Saint Petersburg, FL, 33701, USA
| | - Mya Breitbart
- College of Marine Science, University of South Florida, 140 7th Avenue South, Saint Petersburg, FL, 33701, USA
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Abstract
Single-stranded (ss)DNA viruses are extremely widespread, infect diverse hosts from all three domains of life and include important pathogens. Most ssDNA viruses possess small genomes that replicate by the rolling-circle-like mechanism initiated by a distinct virus-encoded endonuclease. High throughput genome sequencing and improved bioinformatics tools have yielded vast information on presence of ssDNA viruses in diverse habitats. The simple genome of ssDNA viruses have high propensity to undergo mutation and recombination often emerging as threat to human civilization. Interestingly their genome is found embedded in fossils dating back to million years. The unusual evolutionary history of ssDNA viruses reveal evidences of horizontal gene transfer, sometimes between different species and genera.
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Sawata T, Bando M, Nakayama M, Mato N, Yamasawa H, Takahashi M, Okamoto H, Sugiyama Y. Clinical significance of changes in Torque teno virus DNA titer after chemotherapy in patients with primary lung cancer. Respir Investig 2018; 56:173-178. [PMID: 29548656 DOI: 10.1016/j.resinv.2017.12.004] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2017] [Revised: 09/30/2017] [Accepted: 12/08/2017] [Indexed: 11/30/2022]
Abstract
BACKGROUND Several studies have reported that viral infections are related to lung cancer. We previously reported the involvement of Torque teno virus (TTV) in patients with lung cancer and idiopathic pulmonary fibrosis. However, the role of TTV in lung cancer growth, and its influence on changes in TTV DNA titers due to idiopathic pulmonary fibrosis (IPF) in lung cancer patients are poorly understood. METHODS Serum TTV DNA titers were measured in serum samples obtained from patients with lung cancer. Forty-eight patients with primary lung cancer, including 8 patients with IPF, were enrolled. Serum TTV DNA titers were quantitated before and after chemotherapy. In addition, patients were classified into two groups according to the presence or absence of IPF, and clinical characteristics were compared between these two groups. RESULTS Among the 33 patients with partial response to treatment or stable disease in the lung cancer, the mean TTV DNA titer in 28 patients without IPF had significantly decreased after chemotherapy. In contrast, the mean TTV DNA titer in the 5 patients with IPF tended to increase after chemotherapy. In the 15 patients with progressive lung cancer, TTV DNA titers were significantly elevated in those with and without IPF. CONCLUSION In lung cancer patients without IPF, changes in TTV titers may be correlated with tumor growth. However, in lung cancer patients with IPF, TTV titers were not consistently associated with chemotherapy responses. Therefore, IPF may have an influence on changes in TTV DNA titers.
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Affiliation(s)
- Tetsuro Sawata
- Division of Pulmonary Medicine, Department of Medicine, Jichi Medical University School of Medicine, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, Japan.
| | - Masashi Bando
- Division of Pulmonary Medicine, Department of Medicine, Jichi Medical University School of Medicine, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, Japan
| | - Masayuki Nakayama
- Division of Pulmonary Medicine, Department of Medicine, Jichi Medical University School of Medicine, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, Japan
| | - Naoko Mato
- Division of Pulmonary Medicine, Department of Medicine, Jichi Medical University School of Medicine, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, Japan
| | - Hideaki Yamasawa
- Division of Pulmonary Medicine, Department of Medicine, Jichi Medical University School of Medicine, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, Japan
| | - Masaharu Takahashi
- Division of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, Japan
| | - Hiroaki Okamoto
- Division of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, Japan
| | - Yukihiko Sugiyama
- Division of Pulmonary Medicine, Department of Medicine, Nerima Hikarigaoka Hospital, Tokyo, Japan
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Human anelloviruses: an update of molecular, epidemiological and clinical aspects. Arch Virol 2015; 160:893-908. [PMID: 25680568 DOI: 10.1007/s00705-015-2363-9] [Citation(s) in RCA: 190] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2014] [Accepted: 02/03/2015] [Indexed: 12/14/2022]
Abstract
Human torque teno viruses (TTVs) are new, emerging infectious agents, recently assigned to the family Anelloviridae. The first representative of the genus, torque teno virus (TTV), was discovered in 1997, followed by torque teno mini virus (TTMV) in 2000, and torque teno midi virus (TTMDV) in 2007. These viruses are characterized by an extremely high prevalence, with relatively uniform distribution worldwide and a high level of genomic heterogeneity, as well as an apparent pan-tropism at the host level. Although these viruses have a very high prevalence in the general population across the globe, neither their interaction with their hosts nor their direct involvement in the etiology of specific diseases are fully understood. Since their discovery, human anelloviruses, and especially TTV, have been suggested to be associated with various diseases, such as hepatitis, respiratory diseases, cancer, hematological and autoimmune disorders, with few arguments for their direct involvement. Recent studies have started to reveal interactions between TTVs and the host's immune system, leading to new hypotheses for potential pathological mechanisms of these viruses. In this review article, we discuss the most important aspects and current status of human TTVs in order to guide future studies.
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Bando M, Nakayama M, Takahashi M, Hosono T, Mato N, Yamasawa H, Okamoto H, Sugiyama Y. Serum torque teno virus DNA titer in idiopathic pulmonary fibrosis patients with acute respiratory worsening. Intern Med 2015; 54:1015-9. [PMID: 25948340 DOI: 10.2169/internalmedicine.54.3610] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
OBJECTIVE Acute respiratory worsening is defined as the unexpected rapid deterioration of idiopathic pulmonary fibrosis (IPF), and idiopathic acute respiratory worsening is known as an acute exacerbation of IPF. Torque teno virus (TTV) is a circular single-stranded DNA virus whose pathological significance remains unclear. The aim of the present study was to investigate the prevalence and titer of TTV DNA in IPF patients with acute respiratory worsening. METHODS The serum TTV DNA titer was measured using real-time PCR in nine IPF patients (two treated with steroids and immunosuppressants; seven treated without steroids or immunosuppressants) who developed acute worsening, including five patients with acute exacerbation. The serum TTV DNA titer was also measured in eight stable IPF cases and four IPF cases of lung cancer. In addition, in order to examine time course changes in the TTV DNA titer, the titer was measured more than once, with an interval of four weeks or longer, in eight patients. RESULTS Among the nine IPF patients with acute worsening, the TTV DNA titer was above 1×10(6) copies/mL in two subjects without acute exacerbation who had been continuously treated with steroids and immunosuppressants. Meanwhile, the mean TTV DNA titer was 2.4±2.6 (×10(4) copies/mL) in the five patients with acute exacerbation and 3.1±3.4 (×10(4) copies/mL) in the eight patients with stable IPF. Moreover, the TTV DNA titers were increased in all three IPF patients who started treatment with steroids and immunosuppressants. CONCLUSION Our results suggest that it is unlikely that TTV is directly involved in the onset of acute exacerbation of IPF and that the serum TTV DNA titer potentially reflects the immunosuppressive state of the host due to treatment.
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Affiliation(s)
- Masashi Bando
- Division of Pulmonary Medicine, Department of Medicine, Jichi Medical University, Japan
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Zanotta N, Maximova N, Campisciano G, Del Savio R, Pizzol A, Casalicchio G, Berton E, Comar M. Up-regulation of the monocyte chemotactic protein-3 in sera from bone marrow transplanted children with torquetenovirus infection. J Clin Virol 2014; 63:6-11. [PMID: 25600596 DOI: 10.1016/j.jcv.2014.11.028] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2014] [Revised: 11/06/2014] [Accepted: 11/22/2014] [Indexed: 12/12/2022]
Abstract
BACKGROUND Torquetenovirus (TTV) represents a commensal human virus producing life-long viremia in approximately 80% of healthy individuals of all ages. A potential pathogenic role for TTV has been suggested in immunocompromised patients with hepatitis of unknown etiology sustained by strong proinflammatory cytokines. OBJECTIVES The aim of this study was to investigate the sera immunological profile linked to TTV infection in bone marrow transplant (BMT) children with liver injury. STUDY DESIGN TTV infection was assessed in sera from 27 BMT patients with altered hepatic parameters and histological features, by the use of quantitative real-time PCR, along with TTV genogroups and coinfection with HEV. The qualitative and quantitative nature of soluble inflammatory factors was evaluated studying a large set of cytokines using the Bioplex platform. As controls, sera from 22 healthy children negative for serological and molecular hepatitis markers including TTV and HEV, and for autoimmune diseases, were selected. RESULTS AND CONCLUSIONS TTV was detected in 81.4% of BMT patients with a viral load ranging from 10(5) to 10(9) copies/mL. All samples were HEV-RNA negative. A pattern of cytokines, IFN-γ, TNF-α, FGF-basic (p<0.01) and MCP-3 (p<0.001) was found significantly highly expressed in TTV-positive patients compared to TTV-negative and controls. Of note, MCP-3 chemokine showed the highest sera concentration independently of the amount of TTV load and the status of immune system deregulation (p<0.001). In this pilot study for the first time, a positive association was found between TTV and increased level of MCP-3 suggesting a indirect role of TTV in liver injury.
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Affiliation(s)
- Nunzia Zanotta
- Institute for Maternal and Child Health, IRCCS "Burlo Garofolo", Trieste, Italy
| | - Natalia Maximova
- Institute for Maternal and Child Health, IRCCS "Burlo Garofolo", Trieste, Italy
| | | | - Rossella Del Savio
- Institute for Maternal and Child Health, IRCCS "Burlo Garofolo", Trieste, Italy
| | - Antonio Pizzol
- Institute for Maternal and Child Health, IRCCS "Burlo Garofolo", Trieste, Italy
| | - Giorgia Casalicchio
- Institute for Maternal and Child Health, IRCCS "Burlo Garofolo", Trieste, Italy
| | - Emanuela Berton
- Institute for Maternal and Child Health, IRCCS "Burlo Garofolo", Trieste, Italy
| | - Manola Comar
- Institute for Maternal and Child Health, IRCCS "Burlo Garofolo", Trieste, Italy; Department of Medical Science, University of Trieste, Trieste, Italy.
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16
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Rodríguez-Negrete EA, Sánchez-Campos S, Cañizares MC, Navas-Castillo J, Moriones E, Bejarano ER, Grande-Pérez A. A sensitive method for the quantification of virion-sense and complementary-sense DNA strands of circular single-stranded DNA viruses. Sci Rep 2014; 4:6438. [PMID: 25241765 PMCID: PMC5377365 DOI: 10.1038/srep06438] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2014] [Accepted: 09/01/2014] [Indexed: 12/16/2022] Open
Abstract
Circular single-stranded DNA (ssDNA) viruses are the smallest viruses known to infect eukaryotes. High recombination and mutation rates have conferred these viruses with an evolutionary potential that has facilitated their emergence. Their damaging effects on livestock (circoviruses) and crops (geminiviruses and nanoviruses), and the ubiquity of anelloviruses in human populations and other mammalian species, have resulted in increased interest in better understanding their epidemiology and infection mechanisms. Circular ssDNA viral replication involves the synthesis of dsDNA intermediates containing complementary-sense (CS) and virion-sense (VS) strands. Precise quantification of VS and CS accumulation during viral infections can provide insights into the molecular mechanisms underlying viral replication and the host invasion process. Although qPCR protocols for quantifying viral molecules exist, none of them discriminate VS and CS strands. Here, using a two-step qPCR protocol we have quantified VS and CS molecule accumulation during the infection process of Tomato yellow leaf curl virus (TYLCV) and Tomato yellow leaf curl Sardinia virus (TYLCSV) (genus Begomovirus, family Geminiviridae). Our results show that the VS/CS strand ratio and overall dsDNA amounts vary throughout the infection process. Moreover, we show that these values depend on the virus-host combination, and that most CS strands are present as double-stranded molecules.
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Affiliation(s)
- Edgar A. Rodríguez-Negrete
- Instituto de Hortofruticultura Subtropical y Mediterránea “La Mayora”, Universidad de Málaga - Consejo Superior de Investigaciones Científicas, (IHSM-UMA-CSIC) Área de Genética, Campus de Teatinos, 29071 Málaga, Spain
- Current address: Centro de Investigación y Estudios Avanzados (Cinvestav) Irapuato Km. 9.6 Libramiento Norte Irapuato, Guanajuato. 36821 Mexico
| | - Sonia Sánchez-Campos
- Instituto de Hortofruticultura Subtropical y Mediterránea “La Mayora”, Universidad de Málaga - Consejo Superior de Investigaciones Científicas, (IHSM-UMA-CSIC) Estación Experimental “La Mayora”, 29750 Algarrobo-Costa, Málaga, Spain
| | - M. Carmen Cañizares
- Instituto de Hortofruticultura Subtropical y Mediterránea “La Mayora”, Universidad de Málaga - Consejo Superior de Investigaciones Científicas, (IHSM-UMA-CSIC) Estación Experimental “La Mayora”, 29750 Algarrobo-Costa, Málaga, Spain
| | - Jesús Navas-Castillo
- Instituto de Hortofruticultura Subtropical y Mediterránea “La Mayora”, Universidad de Málaga - Consejo Superior de Investigaciones Científicas, (IHSM-UMA-CSIC) Estación Experimental “La Mayora”, 29750 Algarrobo-Costa, Málaga, Spain
| | - Enrique Moriones
- Instituto de Hortofruticultura Subtropical y Mediterránea “La Mayora”, Universidad de Málaga - Consejo Superior de Investigaciones Científicas, (IHSM-UMA-CSIC) Estación Experimental “La Mayora”, 29750 Algarrobo-Costa, Málaga, Spain
| | - Eduardo R. Bejarano
- Instituto de Hortofruticultura Subtropical y Mediterránea “La Mayora”, Universidad de Málaga - Consejo Superior de Investigaciones Científicas, (IHSM-UMA-CSIC) Área de Genética, Campus de Teatinos, 29071 Málaga, Spain
| | - Ana Grande-Pérez
- Instituto de Hortofruticultura Subtropical y Mediterránea “La Mayora”, Universidad de Málaga - Consejo Superior de Investigaciones Científicas, (IHSM-UMA-CSIC) Área de Genética, Campus de Teatinos, 29071 Málaga, Spain
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17
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Kew MC. Hepatitis viruses (other than hepatitis B and C viruses) as causes of hepatocellular carcinoma: an update. J Viral Hepat 2013; 20:149-57. [PMID: 23383653 DOI: 10.1111/jvh.12043] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2012] [Accepted: 11/01/2012] [Indexed: 12/13/2022]
Abstract
Chronic hepatitis B and C virus infections are universally accepted as causes of hepatocellular carcinoma in humans. Hepatitis A and E viruses cause only acute self-limiting infections of the liver. Of the remaining hepatitis viruses - Delta hepatitis, hepatitis G (GB-C), TT and SEN - all have at some time been incriminated as causes of hepatocellular carcinoma. Delta hepatitis virus requires helper functions from hepatitis B virus to become invasive. Chronic Delta/hepatitis B viral co-infection runs a more severe course than that resulting from chronic hepatitis B virus infection alone, with progression to cirrhosis being more likely and more rapid. A substantial majority of the early studies did not find an increased incidence of hepatocellular carcinoma in co-infected individuals. But more recently, an increased incidence of the tumour has been recorded more often than no increase. Further studies are needed to draw a firm conclusion with regard to the hepatocarcinogenic effect of dual Delta/hepatitis B virus co-infection. With one exception, no published study (of 13) has incriminated chronic infection with hepatitis G virus as a cause of hepatocellular carcinoma. The dissenting study, published in 1999, was the only one performed in the United States. Fewer studies of the hepatocarcinogenic effect of TT virus have been performed. Apart from one study, published in 1999, no convincing evidence is available that supports a causal role for TT virus in hepatocarcinogenesis. The exception was in Japanese patients with high hepatitis C viral loads but independent of chronic hepatitis C virus infection. No evidence has been produced to indicate that SEN virus causes hepatocellular carcinoma.
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Affiliation(s)
- M C Kew
- Department of Medicine, Groote Schuur Hospital and University of Cape Town, Cape Town, South Africa.
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18
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García-Álvarez M, Berenguer J, Alvarez E, Guzmán-Fulgencio M, Cosín J, Miralles P, Catalán P, López JC, Rodríguez JM, Micheloud D, Muñoz-Fernández MA, Resino S. Association of torque teno virus (TTV) and torque teno mini virus (TTMV) with liver disease among patients coinfected with human immunodeficiency virus and hepatitis C virus. Eur J Clin Microbiol Infect Dis 2012; 32:289-97. [PMID: 22983402 DOI: 10.1007/s10096-012-1744-1] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2012] [Accepted: 08/30/2012] [Indexed: 01/03/2023]
Abstract
Torque teno virus (TTV) and torque teno mini virus (TTMV) have been potentially related to liver diseases. The aim of the study was to quantify TTV and TTMV in human immunodeficiency virus (HIV)/hepatitis C virus (HCV)-coinfected patients to study the relationship between the TTV and TTMV viral loads and the severity of liver disease. We carried out a cross-sectional study in 245 patients coinfected with HIV and HCV (HIV/HCV-group), 114 patients monoinfected with HIV (HIV-group), and 100 healthy blood donors (Control-group). Plasma samples were tested for TTV and TTMV by quantitative real-time polymerase chain reaction (PCR). The prevalences of TTV and TTMV infections in the HIV/HCV-group and the HIV-group were significantly higher than the Control-group (p < 0.05). Furthermore, TTV and TTMV coinfections were found in 92.2 % (226/245) in the HIV/HCV-group, 84.2 % (96/114) in the HIV-group, and 63 % (63/100 %) in the Control-group (p ≤ 0.05). HIV/HCV-coinfected patients with HIV viral load ≥50 copies/mL and patients with severe activity grade had the highest viral loads of TTV and TTMV (p ≤ 0.05). HIV/HCV-coinfected patients with high TTV load (>2.78 log copies/μL) had increased odds of having advanced fibrosis or severe necroinflammatory activity grade in the liver biopsy. Moreover, HIV/HCV-coinfected patients with high TTMV load (>1.88 log copies/μL) had decreased odds of having no/minimal fibrosis and no/mild activity grade, and increased odds of having a high fibrosis progression rate. In conclusion, TTV and TTMV might play a role in the development of liver disease in immunodeficiency patients, such as the patients coinfected with HIV and HCV.
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Affiliation(s)
- M García-Álvarez
- HIV and Hepatitis co-infection Unit, National Centre of Microbiology, Instituto de Salud Carlos III, Majadahonda, Madrid, Spain
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19
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Martin DP, Biagini P, Lefeuvre P, Golden M, Roumagnac P, Varsani A. Recombination in eukaryotic single stranded DNA viruses. Viruses 2011; 3:1699-738. [PMID: 21994803 PMCID: PMC3187698 DOI: 10.3390/v3091699] [Citation(s) in RCA: 162] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2011] [Revised: 08/18/2011] [Accepted: 09/05/2011] [Indexed: 12/23/2022] Open
Abstract
Although single stranded (ss) DNA viruses that infect humans and their domesticated animals do not generally cause major diseases, the arthropod borne ssDNA viruses of plants do, and as a result seriously constrain food production in most temperate regions of the world. Besides the well known plant and animal-infecting ssDNA viruses, it has recently become apparent through metagenomic surveys of ssDNA molecules that there also exist large numbers of other diverse ssDNA viruses within almost all terrestrial and aquatic environments. The host ranges of these viruses probably span the tree of life and they are likely to be important components of global ecosystems. Various lines of evidence suggest that a pivotal evolutionary process during the generation of this global ssDNA virus diversity has probably been genetic recombination. High rates of homologous recombination, non-homologous recombination and genome component reassortment are known to occur within and between various different ssDNA virus species and we look here at the various roles that these different types of recombination may play, both in the day-to-day biology, and in the longer term evolution, of these viruses. We specifically focus on the ecological, biochemical and selective factors underlying patterns of genetic exchange detectable amongst the ssDNA viruses and discuss how these should all be considered when assessing the adaptive value of recombination during ssDNA virus evolution.
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Affiliation(s)
- Darren P. Martin
- Computational Biology Group, Institute of Infectious Diseases and Molecular Medicine, University of Cape Town, Cape Town 4579, South Africa; E-Mail:
| | - Philippe Biagini
- UMR CNRS 6578 Anthropologie Bioculturelle, Equipe “Emergence et co-évolution virale”, Etablissement Français du Sang Alpes-Méditerranée, Université de la Méditerranée, 27 Bd. Jean Moulin, 13005 Marseille, France; E-Mail:
| | - Pierre Lefeuvre
- CIRAD, UMR 53 PVBMT CIRAD-Université de la Réunion, Pôle de Protection des Plantes, Ligne Paradis, 97410, Saint Pierre, La Réunion, France; E-Mail:
| | - Michael Golden
- Computational Biology Group, Institute of Infectious Diseases and Molecular Medicine, University of Cape Town, Cape Town 4579, South Africa; E-Mail:
| | - Philippe Roumagnac
- CIRAD, UMR BGPI, TA A-54/K, Campus International de Montferrier-Baillarguet, 34398 Montpellier, France; E-Mail:
| | - Arvind Varsani
- Electron Microscope Unit, University of Cape Town, Rondebosch, Cape Town 7701, South Africa; E-Mail:
- Biomolecular Interaction Centre, University of Canterbury, Private Bag 4800, Christchurch 8140, New Zealand
- School of Biological Sciences, University of Canterbury, Private Bag 4800, Christchurch 8140, New Zealand
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20
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Hou Z, Xiao G. Total chemical synthesis, assembly of human torque teno virus genome. Virol Sin 2011; 26:181-9. [PMID: 21667338 DOI: 10.1007/s12250-011-3187-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2011] [Accepted: 03/02/2011] [Indexed: 10/18/2022] Open
Abstract
Torque teno virus (TTV) is a nonenveloped virus containing a single-stranded, circular DNA genome of approximately 3.8kb. We completely synthesized the 3 808 nucleotides of the TTV (SANBAN isolate) genome, which contains a hairpin structure and a GC-rich region. More than 100 overlapping oligonucleotides were chemically synthesized and assembled by polymerase chain assembly reaction (PCA), and the synthesis was completed with splicing by overlap extension (SOEing). This study establishes the methodological basis of the chemical synthesis of a viral genome for use as a live attenuated vaccine or gene therapy vector.
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Affiliation(s)
- Zheng Hou
- State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, China
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21
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The diversity of torque teno viruses: in vitro replication leads to the formation of additional replication-competent subviral molecules. J Virol 2011; 85:7284-95. [PMID: 21593173 DOI: 10.1128/jvi.02472-10] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
The family Anelloviridae comprises torque teno viruses (TTVs) diverse in genome structure and organization. The isolation of a large number of TTV genomes (TTV Heidelberg [TTV-HD]) of 26 TTV types is reported. Several isolates from the same type indicate sequence variation within open reading frame 1 (ORF1), resulting in considerably modified open reading frames. We demonstrate in vitro replication of 12 full-length genomes of TTV-HD in 293TT cells. Propagation of virus was achieved by several rounds of infections using supernatant and frozen whole cells of initially infected cells. Replication of virus was measured by PCR amplification and transcription analyses. Subgenomic molecules (μTTV), arising early during propagation and ranging in size from 401 to 913 bases, were cloned and characterized. Propagation of these μTTV in in vitro cultures was demonstrated in the absence of full-length genomes.
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Abstract
Torque teno virus and related anelloviruses are a recent addition to the list of agents that cause chronic productive infections and high levels of plasma viraemia in humans. Many aspects of the natural history and pathogenesis of these under many respects surprising viruses are still poorly understood. In this review, we briefly outline the general properties of anelloviruses, examine what is currently known about the interactions they establish with the central nervous system (CNS), and discuss the possible pathological consequences.
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Affiliation(s)
- Fabrizio Maggi
- Virology Section and Retrovirus Centre, Department of Experimental Pathology, University of Pisa, Italy
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23
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Kekarainen T, Segalés J. Torque teno virus infection in the pig and its potential role as a model of human infection. Vet J 2009; 180:163-8. [DOI: 10.1016/j.tvjl.2007.12.005] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2007] [Revised: 12/02/2007] [Accepted: 12/13/2007] [Indexed: 01/01/2023]
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24
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Ng TFF, Suedmeyer WK, Wheeler E, Gulland F, Breitbart M. Novel anellovirus discovered from a mortality event of captive California sea lions. J Gen Virol 2009; 90:1256-1261. [PMID: 19264590 DOI: 10.1099/vir.0.008987-0] [Citation(s) in RCA: 74] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
A viral metagenomic study was performed to investigate potential viral pathogens associated with a mortality event of three captive California sea lions (Zalophus californianus). This study identified a novel California sea lion anellovirus (ZcAV), with 35 % amino acid identity in the ORF1 region to feline anelloviruses. The double-stranded replicative form of ZcAV was detected in lung tissue, suggesting that ZcAV replicates in sea lion lungs. Specific PCR revealed the presence of ZcAV in the lung tissue of all three sea lions involved in the mortality event, but not in three other sea lions from the same zoo. In addition, ZcAV was detected at low frequency (11 %) in the lungs of wild sea lions. The higher prevalence of ZcAV and presence of the double-stranded replicative form in the lungs of sea lions from the mortality event suggest that ZcAV was associated with the death of these animals.
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Affiliation(s)
| | | | | | | | - Mya Breitbart
- University of South Florida, Saint Petersburg, FL, USA
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25
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Kakkola L, Hedman K, Qiu J, Pintel D, S”derlund-Venermo M. Replication of and Protein Synthesis by TT Viruses. Curr Top Microbiol Immunol 2009; 331:53-64. [DOI: 10.1007/978-3-540-70972-5_4] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/03/2022]
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de Villiers EM, Kimmel R, Leppik L, Gunst K. Intragenomic rearrangement in TT viruses: a possible role in the pathogenesis of disease. Curr Top Microbiol Immunol 2009; 331:91-107. [PMID: 19230559 DOI: 10.1007/978-3-540-70972-5_6] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
A role for the ubiquitous Torque teno (TT) viruses in the pathogenesis of disease has not been resolved. In vivo and in vitro intragenomic rearrangement of TT virus genomes has been demonstrated. Replication in cell culture of a subviral molecule (411 bp) occurs through oligomerisation of RNA transcripts. Although the functions of the respective TT viral genes, as well as the newly formed genes in the rearranged subviral molecules, are largely unknown, certain similarities to genes of plant viruses of the family Geminiviridae will be described. A degree of similarity to certain cellular genes poses the question as to a role of molecular mimicry in the pathogenesis of autoimmune disease and diabetes.
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Affiliation(s)
- E M de Villiers
- E.-M. de Villiers Division for the Characterisation of Tumour Viruses, Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 242, 69120 Heidelberg, Germany.
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27
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Abstract
Since 1997, groups of novel nonenveloped DNA viruses with a circular, single-stranded (negative sense) DNA genome of 3.6-3.9 kb, 3.2 kb, or 2.8-2.9 kb in size have been discovered and designated Torque teno virus (TTV), Torque teno midi virus (TTMDV), and Torque teno mini virus (TTMV), respectively, in the floating genus Anellovirus. These three anelloviruses frequently and ubiquitously infect humans, and the infections are characterized by lifelong viremia and great genetic variability. Although TTV infection has been epidemiologically suggested to be associated with many diseases including liver diseases, respiratory disorders, hematological disorders, and cancer, there is no direct causal evidence for links between TTV infection and specific clinical diseases. The pathogenetic role of TTMV and TTMDV infections remains unknown. The changing ratio of the three anelloviruses to each other over time, relative viral load, or combination of different genotype(s) of each anellovirus may be associated with the pathogenicity or the disease-inducing potential of these three human anelloviruses. To clarify their disease association, polymerase chain reaction (PCR) systems for accurately detecting, differentiating, and quantitating all of the genotypes and/or genogroups of TTV, TTMDV, and TTMV should be established and standardized, as should methods to detect past infections and immunological responses to anellovirus infections.
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Affiliation(s)
- H Okamoto
- Division of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, 3311-1 Yakushiji, Shimotsuke-Shi, Tochigi-Ken 329-0498, Japan.
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Abstract
Infection with TT virus (Torque teno virus, TTV), a small, nonenveloped virus with a circular, single-stranded DNA genome classified in the floating genus Anellovirus, is not restricted to humans. Using highly conserved primers derived from the untranslated region of the human TTV genome, a variety of TTV-like viruses have been found circulating in nonhuman primates such as chimpanzees, macaques, and tamarins. TTV variants in nonhuman primates are species-specific, although some genetic groups of human and chimpanzee TTVs cluster to make human/chimpanzee clades. TTVs from macaques and tamarins are increasingly divergent from TTV variants infecting humans and chimpanzees. TTV-like mini virus (TTMV) infections have also been detected in chimpanzees, with genotypes distinct but interspersed with human TTMV genotypes. Pets are also naturally infected with species-specific TTVs, and several isolates have been found in cats and dogs. In addition, other mammals such as tupaias and pigs have species-specific TTVs: swine TTVs are found among pigs worldwide. The genomic organization and proposed transcriptional profiles of TTVs infecting nonhuman primate and other mammalian species are similar to those of human TTVs, and co-evolution of TTVs with their hosts has been suggested. To date, TTVs infecting nonhuman primates and other mammalian species have been under-examined. It is likely that essentially all animals are naturally infected with species-specific TTVs.
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29
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Discovery of a novel single-stranded DNA virus from a sea turtle fibropapilloma by using viral metagenomics. J Virol 2008; 83:2500-9. [PMID: 19116258 DOI: 10.1128/jvi.01946-08] [Citation(s) in RCA: 93] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
Abstract
Viral metagenomics, consisting of viral particle purification and shotgun sequencing, is a powerful technique for discovering viruses associated with diseases with no definitive etiology, viruses that share limited homology with known viruses, or viruses that are not culturable. Here we used viral metagenomics to examine viruses associated with sea turtle fibropapillomatosis (FP), a debilitating neoplastic disease affecting sea turtles worldwide. By means of purifying and shotgun sequencing the viral community directly from the fibropapilloma of a Florida green sea turtle, a novel single-stranded DNA virus, sea turtle tornovirus 1 (STTV1), was discovered. The single-stranded, circular genome of STTV1 was approximately 1,800 nucleotides in length. STTV1 has only weak amino acid level identities (25%) to chicken anemia virus in short regions of its genome; hence, STTV1 may represent the first member of a novel virus family. A total of 35 healthy turtles and 27 turtles with FP were tested for STTV1 using PCR, and only 2 turtles severely afflicted with FP were positive. The affected turtles were systemically infected with STTV1, since STTV1 was found in blood and all major organs. STTV1 exists as a quasispecies, with several genome variants identified in the fibropapilloma of each positive turtle, suggesting rapid evolution of this virus. The STTV1 variants were identical over the majority of their genomes but contained a hypervariable region with extensive divergence. This study demonstrates the potential of viral metagenomics for discovering novel viruses directly from animal tissue, which can enhance our understanding of viral evolution and diversity.
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Irshad M, Singh S, Irshad K, Agarwal SK, Joshi YK. Torque teno virus: its prevalence and isotypes in North India. World J Gastroenterol 2008; 14:6044-6051. [PMID: 18932284 PMCID: PMC2760200 DOI: 10.3748/wjg.14.6044] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2008] [Revised: 08/11/2008] [Accepted: 08/18/2008] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the prevalence and genotype distribution of Torque teno virus (TTV) in patients with different liver diseases and chronic renal failure treated at a referral hospital in North India. METHODS Whereas prevalence of TTV was based on amplification of conserved region of ORF2 of TTV genome, the genotyping of TTV was carried out using restriction fragment length polymorphism (RFLP) procedure on the N22 region of ORF1. RESULTS TTV-DNA was detected in 137 of 513 (26.7%) patients with liver diseases and 38 of 65 (58.5%) patients with chronic renal failure. TTV was also detected in 27% of healthy controls. The sequence analysis of the PCR product from 10 randomly selected cases failed to show a significant sequence divergence when compared with that of the TRM1 isolate of TTV genotype 1. The results of genotyping in 55 randomly selected patients showed the presence of genotype 1 (G1) in 53 (96.4%) and genotype 2 (G2) in 2 cases (3.6%), respectively. Other genotypes were not identified in this patient subgroup, suggesting that G1 is predominant in this area. The results of genotyping by RFLP were also supported by phylogenetic tree analysis, where G1 was found to be the major genotype. CONCLUSION These results indicate that TTV is moderately present in Indian patients, with G1 to be the major genotype in North India. The pathogenicity and etiological role of TTV in different diseases is still a question mark and warrant further studies.
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31
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Griffin JS, Plummer JD, Long SC. Torque teno virus: an improved indicator for viral pathogens in drinking waters. Virol J 2008; 5:112. [PMID: 18834517 PMCID: PMC2569923 DOI: 10.1186/1743-422x-5-112] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2008] [Accepted: 10/03/2008] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Currently applied indicator organism systems, such as coliforms, are not fully protective of public health from enteric viruses in water sources. Waterborne disease outbreaks have occurred in systems that tested negative for coliforms, and positive coliform results do not necessarily correlate with viral risk. It is widely recognized that bacterial indicators do not co-occur exclusively with infectious viruses, nor do they respond in the same manner to environmental or engineered stressors. Thus, a more appropriate indicator of health risks from infectious enteric viruses is needed. PRESENTATION OF THE HYPOTHESIS Torque teno virus is a small, non-enveloped DNA virus that likely exhibits similar transport characteristics to pathogenic enteric viruses. Torque teno virus is unique among enteric viral pathogens in that it appears to be ubiquitous in humans, elicits seemingly innocuous infections, and does not exhibit seasonal fluctuations or epidemic spikes. Torque teno virus is transmitted primarily via the fecal-oral route and can be assayed using rapid molecular techniques. We hypothesize that Torque teno virus is a more appropriate indicator of viral pathogens in drinking waters than currently used indicator systems based solely on bacteria. TESTING THE HYPOTHESIS To test the hypothesis, a multi-phased research approach is needed. First, a reliable Torque teno virus assay must be developed. A rapid, sensitive, and specific PCR method using established nested primer sets would be most appropriate for routine monitoring of waters. Because PCR detects both infectious and inactivated virus, an in vitro method to assess infectivity also is needed. The density and occurrence of Torque teno virus in feces, wastewater, and source waters must be established to define spatial and temporal stability of this potential indicator. Finally, Torque teno virus behavior through drinking water treatment plants must be determined with co-assessment of traditional indicators and enteric viral pathogens to assess whether correlations exist. IMPLICATIONS OF THE HYPOTHESIS If substantiated, Torque teno virus could provide a completely new, reliable, and efficient indicator system for viral pathogen risk. This indicator would have broad application to drinking water utilities, watershed managers, and protection agencies and would provide a better means to assess viral risk and protect public health.
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Affiliation(s)
- Jennifer S Griffin
- Department of Civil and Environmental Engineering, 100 Institute Road, Worcester Polytechnic Institute, Worcester, MA 01609, USA
| | - Jeanine D Plummer
- Department of Civil and Environmental Engineering, 100 Institute Road, Worcester Polytechnic Institute, Worcester, MA 01609, USA
| | - Sharon C Long
- Department of Soil Science and Wisconsin State Laboratory of Hygiene, 2601 Agriculture Drive, Madison, WI 53718, USA
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BANDO M, TAKAHASHI M, OHNO S, HOSONO T, HIRONAKA M, OKAMOTO H, SUGIYAMA Y. Torque teno virus DNA titre elevated in idiopathic pulmonary fibrosis with primary lung cancer. Respirology 2008; 13:263-9. [DOI: 10.1111/j.1440-1843.2007.01217.x] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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Kakkola L, Tommiska J, Boele LCL, Miettinen S, Blom T, Kekarainen T, Qiu J, Pintel D, Hoeben RC, Hedman K, Söderlund-Venermo M. Construction and biological activity of a full-length molecular clone of human Torque teno virus (TTV) genotype 6. FEBS J 2007; 274:4719-30. [PMID: 17714512 DOI: 10.1111/j.1742-4658.2007.06020.x] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Torque teno virus (TTV) is a non-enveloped human virus with a circular negative-sense (approximately 3800 nucleotides) ssDNA genome. TTV resembles in genome organization the chicken anemia virus, the animal pathogen of the Circoviridae family, and is currently classified as a member of a new, floating genus, Anellovirus. Molecular and cell biological research on TTV has been restricted by the lack of permissive cell lines and functional, replication-competent plasmid clones. In order to examine the key biological activities (i.e. RNA transcription and DNA replication) of this still poorly characterized ssDNA virus, we cloned the full-length genome of TTV genotype 6 and transfected it into cells of several types. TTV mRNA transcription was detected by RT-PCR in all the cell types: KU812Ep6, Cos-1, 293, 293T, Chang liver, Huh7 and UT7/Epo-S1. Replicating TTV DNA was detected in the latter five cell types by a DpnI-based restriction enzyme method coupled with Southern analysis, a novel approach to assess TTV DNA replication. The replicating full-length clone, the cell lines found to support TTV replication, and the methods presented here will facilitate the elucidation of the molecular biology and the life cycle of this recently identified human virus.
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Affiliation(s)
- Laura Kakkola
- Department of Virology, Haartman Institute and Helsinki University Central Hospital, University of Helsinki, Finland.
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Leppik L, Gunst K, Lehtinen M, Dillner J, Streker K, de Villiers EM. In vivo and in vitro intragenomic rearrangement of TT viruses. J Virol 2007; 81:9346-56. [PMID: 17596318 PMCID: PMC1951432 DOI: 10.1128/jvi.00781-07] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
The in vitro replication of the Torque teno virus (TT virus) tth8 full-length genome and particle formation in a Hodgkin's lymphoma-derived cell line after transfection with cloned viral DNA were demonstrated. Analyses of the transcription patterns of tth8 and tth7 TT virus isolates in a number of lymphoma and T-cell leukemia cell lines indicated differential additional splicing events and intragenomic rearrangement generating open reading frames which could not be deducted from the genomic sequence. We also demonstrated the presence of rearranged TT virus genomes in vivo in sera taken from pregnant mothers whose children later developed childhood leukemia, as well as sera from control mothers. Control experiments using religated cloned genomic tth8 DNA mixed with cellular DNA did not result in such subviral molecules. These subviral isolates ranged from 172 bp to full-length TT virus genomes. Possible in vivo selection for specific rearranged molecules was indicated by the presence of one isolate (561 bp) in 11 serum samples. It remains to be clarified whether selected rearranged subviral components resulting from specific TT virus types may contribute to the initiation of disease. These data demonstrate new features of TT viruses suggesting possible similarities to plant viruses of the family Geminiviridae, as well as raise questions about the documented plurality and diversity of anelloviruses.
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MESH Headings
- Cell Line, Tumor
- Child
- DNA Virus Infections/virology
- DNA, Viral/chemistry
- DNA, Viral/genetics
- Female
- Genome, Viral
- Humans
- Infant
- Molecular Sequence Data
- Mothers
- RNA, Messenger/biosynthesis
- RNA, Messenger/genetics
- RNA, Viral/biosynthesis
- RNA, Viral/genetics
- Recombination, Genetic
- Sequence Analysis, DNA
- Serum/virology
- Torque teno virus/genetics
- Torque teno virus/isolation & purification
- Torque teno virus/physiology
- Transcription, Genetic
- Virus Replication
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Affiliation(s)
- Ludmila Leppik
- Division for the Characterization of Tumor Viruses, Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 242, 69120 Heidelberg, Germany
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Abstract
Torque teno virus (TTV), currently classified into the family Circoviridae, genus Anellovirus, was first found in a patient with non-A-E hepatitis. TTV has a single stranded circular DNA of approximately 3.8 kb. TTVs are extraordinarily diverse, spanning five groups including SANBAN and SEN viruses. Torque teno mini virus (TTMV) with approximately 2.9 kb genome also has wide variants. Recently, two related 2.2- and 2.6-kb species joined this community. Recombinations between variants are frequent. This extensive TTV diversity remains unexplained; it is unclear how TTVs could be viable, and why they require such genetic variation. An unequivocal culture system is still not available. TTVs are ubiquitous in > 90% of adults worldwide but no human pathogenicity of TTV has been fully established. Epidemiological surveys need to specify the variants being studied and clinical targets, and must calibrate the sensitivity of the assay used. Potentially interesting observations include a higher viral load in patients with severe idiopathic inflammatory myopathies, cancer and lupus. Active replication was also found in infants with acute respiratory diseases. TTV/TTMV-related viruses were found in chimpanzees, apes, African monkeys and tupaias, and also in chickens, pigs, cows, sheep and dogs. Experimentally, rhesus monkeys were persistently infected by TTV, but only 1/53 chimpanzees. TTV transcribes three species of mRNAs, 3.0-, 1.2- and 1.0-kb in the ratio of 60:5:35. Recently, at least three mRNAs were shown in chicken anaemia virus. The genomic region -154/-76 contains a critical promoter. TTV seems to have at least three proteins; however, the definite functions of these proteins await further research work.
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Affiliation(s)
- Shigeo Hino
- Department of Virology, Faculty of Medicine, Tottori University, Nishi, Yonago, Japan.
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Abstract
Hemophilia is a congenital disorder due to the deficiency of the activity of factor VIII (classical hemophilia A) or IX (Christmas disease or hemophilia B). Bleeding is common and may result in long-term complications or even death. Bleeding may be treated or prevented by infusion of factor concentrates however these drugs are not without risk. Clinicians often feel ill prepared to provide accurate and impartial information regarding these drugs. This review will provide the reader with an historical yet up to date perspective on blood safety as it relates to the choice of concentrates to treat hemophilia.
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Affiliation(s)
- Leonard A Valentino
- RUSH Hemophilia and Thrombophilia Center, Department of Pediatrics, Rush University Medical Center, Chicago, Illinois 60612, USA.
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Irshad M, Joshi YK, Sharma Y, Dhar I. Transfusion transmitted virus: A review on its molecular characteristics and role in medicine. World J Gastroenterol 2006; 12:5122-5134. [PMID: 16937521 PMCID: PMC4088008 DOI: 10.3748/wjg.v12.i32.5122] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2006] [Revised: 05/15/2006] [Accepted: 05/22/2006] [Indexed: 02/06/2023] Open
Abstract
The present review gives an updated overview of transfusion transmitted virus (TTV), a novel agent, in relation to its molecular characteristics, epidemiological features, modes of transmission, tissue tropism, pathogenesis, role in various diseases and its eradication from the body. TTV, a DNA virus, is a single stranded, non-enveloped, 3.8 kb long DNA virus with a small and covalently closed circular genome comprising 3852 bases. It was tentatively designated Circinoviridae virus. TTV genome sequence is heterogeneous and reveals the existence of six different genotypes and several subtypes. TTV has been reported to transmit not only via parenteral routes, but also via alternate routes. This virus has been detected in different non-human primates as well. At present, TTV is detected by polymerase chain reaction (PCR) with no other available diagnostic assays. It shows its presence globally and was detected in high percent populations of healthy persons as well as in various disease groups. Initially it was supposed to have strong association with liver disease; however, there is little evidence to show its liver tropism and contribution in causing liver diseases. It shows high prevalence in hemodialysis patients, pointing towards its significance in renal diseases. In addition, TTV is associated with several infectious and non-infectious diseases. Though, its exact pathogenesis is not yet clear, TTV virus possibly resides and multiplies in bone marrow cells and peripheral blood mononuclear cells (PBMCs). Recently, attempts have been made to eradicate this virus with interferon treatment. More information is still needed to extricate various mysteries related to TTV.
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Affiliation(s)
- M Irshad
- Clinical Biochemistry Division, Department of Laboratory Medicine, PO Box -4938, A I I M S, New Delhi-110029, India.
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Thom K, Petrik J. Progression towards AIDS leads to increased torque teno virus and torque teno minivirus titers in tissues of HIV infected individuals. J Med Virol 2006; 79:1-7. [PMID: 17133553 DOI: 10.1002/jmv.20756] [Citation(s) in RCA: 74] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
Torque teno virus (TTV) and Torque teno minivirus (TTMV) are highly prevalent in the general population and although no disease has been associated with these viruses yet, co-infections with other pathological viruses are frequent. Both viruses are extremely heterogeneous, especially for DNA viruses, and the role of the immune system in controlling the infections has yet to be established. In this study the TTV/TTMV viral loads in HIV positive tissues have been investigated for the first time. The titers of both TTV and TTMV were compared in the bone marrow and spleen tissues from three groups: HIV negative individuals, HIV positive individuals and HIV positive individuals who had progressed to AIDS, leading to immunosuppression. Limiting dilution PCR using primers situated in the UTR region of the genome were used to semi-quantitate the virus, and TTV and TTMV were differentiated using melting curve analysis of the PCR product. The AIDS group had significantly higher titers compared with both the HIV positive and negative groups for both bone marrow (AIDS vs. HIV positive P = 0.006, AIDS vs. HIV negative P < 0.001) and spleen (AIDS vs. HIV positive P = 0.022, AIDS vs. HIV negative P < 0.001). Analysis of TTV/TTMV titer with CD4 T lymphocyte count showed a significant inverse correlation however neither HCV co-infection or type of Anellovirus infection (single TTV or TTMV, or mixed TTV/TTMV) showed any significant correlation with virus titer. The results show a link between deterioration of the immune system and increased the viral loads in studied tissues.
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Affiliation(s)
- K Thom
- Transfusion Transmitted Infection Group, Scottish National Blood Transfusion Service and University of Edinburgh, Royal Dick Vet School, Summerhall, Edinburgh, UK
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Desai M, Pal R, Deshmukh R, Banker D. Replication of TT virus in hepatocyte and leucocyte cell lines. J Med Virol 2005; 77:136-43. [PMID: 16032745 DOI: 10.1002/jmv.20426] [Citation(s) in RCA: 38] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
The TT virus (TTV) is a non-enveloped, single-stranded, circular, DNA virus, first isolated from a patient with hepatitis of unexplained etiology. The much deliberated pathological role of the virus continues to be conjectural in the absence of a suitable in vitro replication model. So far, the liver and the bone marrow have been shown to be the main sites of TTV replication. In this study, the human cell lines HepG2 and Chang Liver, the rat hepatoma cell line MH1C1, phytohemagglutinin (PHA)-stimulated TTV-negative peripheral blood mononuclear cell (PBMC) cultures and the B lymphoblast cell line, Raji were investigated as potential in vitro replication systems for TTV. The cell lines were infected with an inoculum prepared by pooling TTV genotype1 DNA positive sera and monitored for virus replication. Of the three hepatocyte cell lines, while the HepG2 and MH1C1 cell lines did not support TTV replication, the Chang Liver cell line showed clear morphological changes as a result of the in vitro infection, which included clumping and granular degeneration of the entire cell sheet over a period of 6 days. The infected cells also showed presence of virus-specific mRNA representative of viral transcription. The consistent presence of infectious viral particles in the supernatant culture fluid at 24-hr fluid replacement intervals indicated limited extra-cellular release of viral particles. The PHA-stimulated TTV-negative PBMC cultures and the Raji cell line were also able to support TTV replication and released significant levels of infectious viral particles into the supernantant culture fluid.
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Affiliation(s)
- Mayura Desai
- Department of Microbiology, Sir Hurkisondas Nurrotumdas Medical Research Society, Mumbai, India
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40
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Desai MM, Pal RB, Banker DD. Molecular epidemiology and clinical implications of TT virus (TTV) infection in Indian subjects. J Clin Gastroenterol 2005; 39:422-9. [PMID: 15815211 DOI: 10.1097/01.mcg.0000159219.93160.bc] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Abstract
GOALS This study was aimed at obtaining data on the epidemiology and clinical course of TT virus (TTV) infections among Indian subjects. BACKGROUND The TTV is a nonenveloped DNA virus, first identified in the peripheral blood of individuals with posttransfusion hepatitis of unknown etiology. There has been much conjecture regarding the disease association of this virus. STUDY A total of 494 serum specimens from various groups of high-risk and control subjects were screened for TTV DNA by a semi-nested PCR, using the ORF1-derived N22 primers. The sera were also screened for the HBsAg surface antigen by an ELISA, HCV RNA by a 5' NCR-based RT-PCR and GBV-C/HGV RNA by a 5' UTR-based RT-PCR. The clinical and hepatic profiles of the various subjects were also studied. Seventy-one randomly picked TTV isolates were directly sequenced and their phylogeny was studied. RESULTS TTV showed an overall positivity rate of 45.34% with a significant higher prevalence of 52.9% among the high-risk subjects as against a prevalence of 28% among healthy control subjects (P < 0.001). Abnormal liver function profiles were frequent among TTV viremic individuals and among the acute hepatitis cases studied a higher mortality rate correlated with a superimposed TTV infection. The 71 TTV isolates sequenced were found to belong to genotype 1a being closely homologous to TTV prototype TA278. CONCLUSION The TT virus shows a significant prevalence in the Indian population, particularly among subjects at risk for acquiring parenterally transmitted infections. Our study corroborates a putative role of the virus in the etiology of liver disease, particularly in coinfection with other agents.
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Affiliation(s)
- Mayura M Desai
- Department of Microbiology, Sir Hurkisondas Nurrotumdas Medical Research Society, Sir H. N. Hospital and Research Centre, Mumbai, India
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41
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Oza VM, Jabbar AA, Hakobyan N, Kazarian T, Valentino LA. Transfusion-transmitted virus is not present in factor IX concentrates commonly used to treat haemophilia B. Haemophilia 2005; 10:732-4. [PMID: 15569169 DOI: 10.1111/j.1365-2516.2004.01048.x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
Transfusion-transmitted virus (TTV) is a potential cause of post-transfusion hepatitis in patients with haemophilia. Plasma-derived clotting factor concentrates currently undergo processes that are effective in removal and inactivation of viruses such as HIV, hepatitis B and C; however, their effectiveness with respect to TTV is unknown. To determine if TTV DNA is present in plasma-derived concentrates of factor IX, we tested 14 lots of Mononine and compared the results with BeneFix. Nucleic acid isolation, followed by a two-round polymerase chain reaction (PCR) and agarose gel analysis indicated that all 17 lots were negative for TTV. Although TTV may be considered an emerging pathogen, no evidence of the virus was detected in the commercially available plasma-derived concentrate of FIX most commonly used to treat haemophilia B.
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Affiliation(s)
- V M Oza
- The Department of Pediatrics and the Rush Hemophilia and Thrombophilia Center, Rush University Medical Center and Rush Children's Hospital, Chicago, IL 60612, USA
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Jelcic I, Hotz-Wagenblatt A, Hunziker A, Zur Hausen H, de Villiers EM. Isolation of multiple TT virus genotypes from spleen biopsy tissue from a Hodgkin's disease patient: genome reorganization and diversity in the hypervariable region. J Virol 2004; 78:7498-507. [PMID: 15220423 PMCID: PMC434092 DOI: 10.1128/jvi.78.14.7498-7507.2004] [Citation(s) in RCA: 66] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
We report the isolation of 24 novel genotypes of TT viruses from a surgically removed spleen of a patient with Hodgkin's disease. The sequence analysis of our 24 isolates revealed the remarkable heterogeneity of TT virus isolates not only from the same patient but also from the same biopsy material. These isolates belong to four phylogenetic groups of TT viruses. Nucleotide sequence analyses revealed five distinct genotypes (tth3, tth4, tth5, tth6, and tth7). The limited variation in sequence identity of the other isolates defines the latter as variants of four of these genotypes. A group of 6 isolates (the tth7 group) revealed a reorganization of open reading frame 1 (ORF1) leading to one larger and a varying number of smaller ORFs. The nucleotide difference of the full-length genomes was less than 1%. A variation of 69 to 97% in amino acids of a second group of 8 isolates (the tth3 group) was restricted to the hypervariable region of ORF1, indicating the existence of a quasi-species. These isolates differed by less than 2% in the remainder of their nucleotide sequences. An alignment of these isolates with 79 previously reported TT virus genotypes permits the proposal of TT virus genera and species within the family Anelloviridae in analogy to a previous proposal for the papillomaviruses (family Papillomaviridae).
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Affiliation(s)
- Ilijas Jelcic
- Division for the Characterization of Tumorviruses, Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 242, 69120 Heidelberg, Germany
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Kamada K, Kamahora T, Kabat P, Hino S. Transcriptional regulation of TT virus: promoter and enhancer regions in the 1.2-kb noncoding region. Virology 2004; 321:341-8. [PMID: 15051393 DOI: 10.1016/j.virol.2003.12.024] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2003] [Accepted: 12/22/2003] [Indexed: 11/23/2022]
Abstract
Since the discovery of TT virus (TTV) in 1997, its mechanism of transcriptional control has remained unsolved. Molecular analysis points at the 1.2-kb noncoding region (NCR) as being responsible for transcriptional control. The 5' terminus of TTV mRNA was located at nt 114 using the primer extension method (nt 114 will be referred to as position +1). This employed the PE1 primer, designed to start approximately 100 nt downstream of the predicted initiation site. Overall promoter and enhancer activity of the NCR was analyzed using dual luciferase assays in K562, Jurkat, U937, A549, HepG2, Huh7, and HeLaS3 cells. Of those tested, K562 showed the highest relative luciferase activity of 31.1, and activity in HepG2 (14.6) was significantly higher than that in Huh7 (2.8). Fragments of <250 nt length, spanning the NCR, were inserted into a luciferase vector possessing an SV40 promoter. Fragments F5(-542/-311) and F6(-310/-197) showed promoter-enhancing activities of >6.0 by insertion not only in the sense orientation, but also both in the antisense orientation and downstream of the luciferase gene. The 5' deletion of NCR from -1201 to -370 resulted in no significant decrease in the level of luciferase activity. A gradual decrease in the activity of the 5'-deletion mutants from position -370 through -155 was consistent with the loss of enhancer binding sites detected during fragment analysis. A further deletion at position -76 completely abolished luciferase expression, indicating that region -154/-76 contains the critical regulatory element for functioning of the TTV promoter.
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Affiliation(s)
- Kazuya Kamada
- Division of Immunology, Faculty of Medicine, Tottori University, Yonago 683-8503, Japan
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44
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Moen EM, Sagedal S, Bjøro K, Degré M, Opstad PK, Grinde B. Effect of immune modulation on TT virus (TTV) and TTV-like-mini-virus (TLMV) viremia. J Med Virol 2003; 70:177-82. [PMID: 12629661 DOI: 10.1002/jmv.10356] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
The present study was designed to investigate how two chronically replicating viruses, TT virus (TTV) and TTV-like mini virus (TLMV), interact with host defence systems. Successive serum samples from three groups of subjects, undergoing modifications of their antiviral defence, were tested by real-time PCR to measure changes in viral titers, and by sequence analyses to indicate whether increases in viremia could be attributed to infection with an unfamiliar strain: 1) in patients receiving immunosuppressants subsequent to kidney transplantation, viral titers tended to increase; 2) in soldiers undergoing extreme training known to cause immunosuppression, insignificant increases in titers were observed; and 3) interferon treatment of patients with hepatitis C virus caused a temporary decrease in TTV and TLMV titers. Increases in viremia were associated only occasionally with the appearance of novel strains. The above results add to knowledge on how these viruses are influenced by the host.
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Affiliation(s)
- Eva Merethe Moen
- Division of Infectious Disease Control, Norwegian Institute of Public Health, Oslo, Norway
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Vasconcelos HCF, Cataldo M, Niel C. Mixed infections of adults and children with multiple TTV-like mini virus isolates. J Med Virol 2002; 68:291-8. [PMID: 12210422 DOI: 10.1002/jmv.10187] [Citation(s) in RCA: 20] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
Testing of the DNA of TTV-like mini virus (TLMV) was done with serum samples obtained from 184 patients (children and adults) who visited different outpatient clinics at a university hospital in Florianopolis, south of Brazil. TLMV DNA was detected by PCR primers from the non-coding region of the genome. A global TLMV prevalence of 78% was found (94% among children below 11 years). PCR products from three serum samples (patients A-C) were cloned, and the sequences with a length of 201-227 nucleotides were determined for 16-19 clones derived from each of the sera. Among the 16 clones derived from patient C, 15 were identical, and the remaining one had a sequence homology of 99%. In contrast, eight different sequences were obtained among the 19 clones derived from patient A, and 10 distinct sequences were depicted among the 17 clones derived from the serum of patient B. Additionally, 13 clones derived from a saliva sample of patient B were sequenced, and seven different nucleotide sequences obtained. One particular sequence was predominant in both serum (8/17 clones) and saliva (7/13 clones) of patient B. On a phylogenetic tree, sequences derived from patient A (a 6-year-old boy), as well as those derived from patient B (a 24-year-old man), were located in five distinct evolutionary branches, taking a minimum divergence of 5% between branches. This suggested that adults and children are coinfected frequently with several TLMV isolates of different origins.
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Affiliation(s)
- Helena C F Vasconcelos
- Department of Clinical Analyses, Federal University of Santa Catarina, Florianopolis, Brazil
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Mariscal LF, López-Alcorocho JM, Rodríguez-Iñigo E, Ortiz-Movilla N, de Lucas S, Bartolomé J, Carreño V. TT virus replicates in stimulated but not in nonstimulated peripheral blood mononuclear cells. Virology 2002; 301:121-9. [PMID: 12359452 DOI: 10.1006/viro.2002.1545] [Citation(s) in RCA: 71] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
TT virus (TTV) is an unenveloped, single-stranded, circular-DNA virus which resembles members of the Circoviridae, that is commonly found in humans and which lacks pathological consequences for the infected host. TTV replication has been demonstrated in bone marrow cells but not in peripheral blood mononuclear cells (PBMC), suggesting that hematopoietic cells must be activated to support TTV replication. To test this hypothesis, PBMC from two naturally TTV-infected individuals and from two healthy TTV-DNA negative donors infected in vitro with a TTV-DNA-positive serum were cultured in the presence (stimulated) or absence (unstimulated) of phytohemagglutinin, lipopolysaccharide, and interleukin-2. TTV-DNA was detected in both stimulated and unstimulated PBMC. However, TTV-DNA replicative intermediates and mRNA were detected only in stimulated PBMC. Furthermore, TTV-DNA and mRNA were detected in PBMC from two TTV negative donors reinfected with supernatants from TTV-infected stimulated cells but not when using culture supernatants from unstimulated cells. These results demonstrate that TTV replicates in PBMC only when stimulated.
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Affiliation(s)
- Luisa F Mariscal
- Institute of Hepatology, Hospital Pardo de Aravaca and Fundación para el Estudio de las Hepatitis Virales, Madrid, Spain
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47
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Moen EM, Sleboda J, Grinde B. Serum concentrations of TT virus and TT virus-like mini virus in patients developing AIDS. AIDS 2002; 16:1679-82. [PMID: 12172090 DOI: 10.1097/00002030-200208160-00014] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Changes in viraemia of two chronically replicating circoviruses, TT virus (TTV) and TTV-like mini virus (TLMV), were investigated in patients developing HIV-related immune deficiency. In a few cases, episodes of a considerable increase in viraemia were observed, but in most patients there were no discernible increases as immune deficiency progressed. The deterioration of immune function associated with AIDS did not by itself have any obvious effect on TTV and TLMV.
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Affiliation(s)
- Eva M Moen
- Division of Infectious Disease Control, Norwegian Institute for Public Health, Oslo, Norway
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Tokita H, Murai S, Kamitsukasa H, Yagura M, Harada H, Takahashi M, Okamoto H. High TT virus load as an independent factor associated with the occurrence of hepatocellular carcinoma among patients with hepatitis C virus-related chronic liver disease. J Med Virol 2002; 67:501-9. [PMID: 12115995 DOI: 10.1002/jmv.10129] [Citation(s) in RCA: 51] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
The TT virus (TTV) load was estimated in sera obtained from 237 patients with hepatitis C virus (HCV)-related chronic liver disease including 42 patients with hepatocellular carcinoma (HCC), by real-time detection PCR using primers and a probe derived from the well-conserved untranslated region of the TTV genome, which can detect all known TTV genotypes. Of the 237 patients studied, 18 (8%) were negative for TTV DNA, 87 (37%) had low TTV viremia (1.3 x 10(2)-9.9 x 10(3) copies/ml), and 132 (56%) had high TTV viremia (1.0 x 10(4)-2.1 x 10(6) copies/ml). Various features were compared between the patients with high TTV load (n = 132) and those with no TTV viremia or low viral load (n = 105). High TTV viremia (> or =10(4) copies/ml) was significantly associated with higher age (P < 0.05), past history of blood transfusion (P < 0.001), complication of cirrhosis (P < 0.05) or HCC (P < 0.0005), lower HCV RNA titer (P < 0.05), and lower platelet count (P < 0.01). On multivariate logistic regression analysis, high TTV viral load was a significant risk factor for HCC (P < 0.05), independent from known risk factors such as complication of liver cirrhosis (P < 0.0001) and high age (> or =65 years, P < 0.05), among all 237 patients. Furthermore, high TTV viral load was an independent risk factor for HCC among the 90 cirrhotic patients (P < 0.05). These results suggest that a high TTV viral load is associated independently with the complication of HCC and may have prognostic significance in patients with HCV-related chronic liver disease, although whether high TTV viremia mediates the progression of HCV-related chronic liver disease remains to be defined.
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Affiliation(s)
- Hajime Tokita
- Department of Gastroenterology, National Tokyo Hospital, Japan
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Okamoto H, Takahashi M, Nishizawa T, Tawara A, Fukai K, Muramatsu U, Naito Y, Yoshikawa A. Genomic characterization of TT viruses (TTVs) in pigs, cats and dogs and their relatedness with species-specific TTVs in primates and tupaias. J Gen Virol 2002; 83:1291-1297. [PMID: 12029143 DOI: 10.1099/0022-1317-83-6-1291] [Citation(s) in RCA: 162] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Using PCR with primers derived from a non-coding region of the human TT virus (TTV) genome, the TTV sequence in serum samples obtained from pigs (Sus domesticus), dogs (Canis familiaris) and cats (Felis catus) was identified and the entire genomic sequence was determined for each representative isolate. Three TTV isolates (Sd-TTV31 from a pig, Cf-TTV10 from a dog and Fc-TTV4 from a cat) comprising 2878, 2797 and 2064 nucleotides, respectively, each had three open reading frames (ORFs) encoding 436-635 (ORF1), 73-105 (ORF2) and 224-243 (ORF3) aa but lacked ORF4, similar to tupaia TTV. ORF3 was presumed to arise from a splicing of TTV mRNA, similar to human prototype TTV. Although the nucleotide sequence of Sd-TTV31, Cf-TTV10 and Fc-TTV4 differed by more than 50% from each other and from previously reported TTVs of 3.4-3.9 kb and TTV-like mini viruses (TLMVs) of 2.8-3.0 kb isolated from humans and non-human primates as well as tupaia TTVs of 2.2 kb, they resembled known TTVs and TLMVs with regard to genomic organization and presumed transcriptional profile rather than animal circoviruses of 1.7-2.3 kb. Phylogenetic analysis revealed that Sd-TTV31, Cf-TTV10 and Fc-TTV4 were closer to TTVs from lower-order primates and tupaias than to TTVs from higher-order primates and TLMVs. These results indicate that domestic pigs, cats and dogs are naturally infected with species-specific TTVs with small genomic size and suggest a wide distribution of TTVs with extremely divergent genomic sequence and length in animals.
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Affiliation(s)
- Hiroaki Okamoto
- Immunology Division and Division of Molecular Virology, Jichi Medical School, Tochigi-Ken 329-0498, Japan1
| | - Masaharu Takahashi
- Immunology Division and Division of Molecular Virology, Jichi Medical School, Tochigi-Ken 329-0498, Japan1
| | - Tsutomu Nishizawa
- Immunology Division and Division of Molecular Virology, Jichi Medical School, Tochigi-Ken 329-0498, Japan1
| | - Akio Tawara
- First Department of Internal Medicine, Yamanashi Medical University, Yamanashi-Ken 409-3898, Japan2
| | - Katsuhiko Fukai
- Central Animal Hygiene Service Center of Tochigi Prefecture, Tochigi-Ken 321-0905, Japan3
| | - Umetaro Muramatsu
- Central Animal Hygiene Service Center of Tochigi Prefecture, Tochigi-Ken 321-0905, Japan3
| | - Yoshihisa Naito
- Department of Clinical Veterinary Medicine, Faculty of Agriculture, Iwate University, Iwate-Ken 020-8550, Japan4
| | - Akira Yoshikawa
- Japanese Red Cross Saitama Blood Center, Saitama-Ken 338-0001, Japan5
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Abstract
TT virus (TTV) was found in 1997 from a hepatitis patient without virus markers. However, the real impact of TTV on liver diseases remains uncertain to date. Due to the lack of suitable cell systems to support the growth of TTV, the biology of TTV is still obscure. This review tries to summarise the current status of TTV on aspects other than the taxonomic diversity of TTV. TTV was the first human virus with a single stranded circular DNA genome. TTV was considered to be a member of Circoviridae, but others suggested it conformed to a new family. TTV is distinct from ambisense viruses in the genus Circovirus, since the former genome is negative stranded. The genome structure of TTV is more related to chicken anaemia virus in the genus Gyrovirus, however, the sequence similarity is minimal except for a short stretch at 3816-3851 of TA278. Currently the working group is proposing the full name for TTV as TorqueTenoVirus and the TTV-like mini virus as TorqueTenoMiniVirus (TTMV) in a new genus Anellovirus (ring). TTVs are prevalent in non-human primates and human TTV can cross-infect chimpanzees. Furthermore, TTV sequences have been detected in chickens, pigs, cows and sheep. TTV can be transmitted by mother-to-child infection. However, within a year after birth, the prevalence reaches the same level for children born to both TTV-positive and TTV-negative mothers even without breast-feeding. The non-coding region surrounding a short 113 nt GC-rich stretch and occupying approximately one-third of the genome is considered to contain the putative replication origin. Three mRNAs are expressed by TTV, 3.0 and 1.2 and 1.0 kb species. A protein translated from the 3.0 kb mRNA is considered to be the major capsid protein as well as replicase. The nature of the proteins translated by the other two mRNAs are still putative.
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Affiliation(s)
- Shigeo Hino
- Department of Virology, School of Medicine, Faculty of Medicine, Tottori University, 86 Nishi, Yonago 683-8503, Japan.
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