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1
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Constant companion: clinical and developmental aspects of torque teno virus infections. Arch Virol 2020; 165:2749-2757. [PMID: 33040309 DOI: 10.1007/s00705-020-04841-x] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Accepted: 09/04/2020] [Indexed: 12/18/2022]
Abstract
Torque teno virus (TTV) is a commensal human virus observed as a circular single-negative-strand DNA molecule in various tissues and biological samples, notably in blood serum and lymphocytes. TTV has no apparent clinical significance, although it might be very useful as a prospective tool for gene delivery or as an epidemiological marker. Human populations are ubiquitously infected with TTV; the prevalence may reach 100%. The majority of babies become spontaneously infected with TTV, so that by the end of the first year of life, the prevalence reaches 'adult' values. TTV positivity in healthy early infancy and the presence of TTV in umbilical cord blood samples have been reported. The mechanism of infection and the dynamics of TTV prevalence in infants with age remain understudied. Meanwhile, the potential diagnostic and prognostic value of TTV as a marker deserves special attention and study, along with the possibility, causes and consequences of placental transmission of TTV under normal or pathological conditions.
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2
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Tyschik EA, Rasskazova AS, Degtyareva AV, Rebrikov DV, Sukhikh GT. Torque teno virus dynamics during the first year of life. Virol J 2018; 15:96. [PMID: 29843750 PMCID: PMC5975406 DOI: 10.1186/s12985-018-1007-6] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2018] [Accepted: 05/21/2018] [Indexed: 01/03/2023] Open
Abstract
Background Torque teno virus is a small chronically persisting circular negative ssDNA virus reaching near 100% prevalence. It is reported to be a marker for immune function in immunocompromised patients. The possibility of vertical maternal-fetal transmission remains controversial but incidence rate of TTV DNA in children increased with age. TTV dynamics well studied for allogeneic hematopoietic stem cell transplantation as a predictor of post-transplant complications but there is no viral proliferation kinetics data for other patient groups or healthy individuals. The aim of this study was to determine TTV dynamics during the first year of life of healthy infants. Methods Ninety eight clinically healthy breastfeeding infants (1–12 months of age) were analyzed by quantitative PCR for the whole blood TTV load with the test sensitivity of about 1000 viral copies per milliliter of blood (total number of samples including repeatedly tested infants was 109). Results 67% of all analyzed samples were TTV-positive demonstrating significant positive correlation between age and TTV load (r = 0.81, p < 0.01). Conclusions This is the first study to suggest that viral load increases during the first year of life reaching a plateau after 6 months with strong proliferation for the first 60 days. Our data well correlates with TTV dynamics in patients following allogeneic hematopoietic stem cell transplantation.
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Affiliation(s)
- Elena A Tyschik
- Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Oparina 4, Moscow, 117513, Russia
| | - Anastasiya S Rasskazova
- Pirogov Russian National Research Medical University, Ostrovityanova 1, Moscow, 117997, Russia
| | - Anna V Degtyareva
- Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Oparina 4, Moscow, 117513, Russia
| | - Denis V Rebrikov
- Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Oparina 4, Moscow, 117513, Russia. .,Pirogov Russian National Research Medical University, Ostrovityanova 1, Moscow, 117997, Russia.
| | - Gennady T Sukhikh
- Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Oparina 4, Moscow, 117513, Russia
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3
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Tyschik EA, Shcherbakova SM, Ibragimov RR, Rebrikov DV. Transplacental transmission of torque teno virus. Virol J 2017; 14:92. [PMID: 28482844 PMCID: PMC5422867 DOI: 10.1186/s12985-017-0762-0] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2017] [Accepted: 05/02/2017] [Indexed: 01/03/2023] Open
Abstract
Background TTV has been detected in almost every human tissue type or body fluid reaching near 100% prevalence. Several studies report mother-to-child postnatal transmission of TTV in infancy but the risk of transplacental transmission of TTV is still unclear. Methods The blood and plasma collected postpartum from 100 mother-child pairs were analyzed using TTV-specific qPCR. Samples were collected from the peripheral vein of the mother and the umbilical cord. Results Eighty four percent of pregnant women were TTV positive (median titers: 8 × 104 copies/mL; range: 103 – 3 × 107). The TTV load in plasma was approximately 100 times lower than in whole blood. TTV was not detected in any of cord blood samples. Conclusions Our data demonstrate the lack of transplacental transmission of TTV (or effective prenatal inhibition of viral proliferation). The presence of the virus in infants may be associated with mother-to-child transmission through breast feeding or other routes of transmission.
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Affiliation(s)
- Elena A Tyschik
- Kulakov Research Center for Obstetrics, Gynecology and Perinatology, 117997, Oparina 4, Moscow, Russia
| | - Sophia M Shcherbakova
- Pirogov Russian National Research Medical University, 117997, Ostrovityanova 1, Moscow, Russia
| | - Ruslan R Ibragimov
- Kulakov Research Center for Obstetrics, Gynecology and Perinatology, 117997, Oparina 4, Moscow, Russia
| | - Denis V Rebrikov
- Kulakov Research Center for Obstetrics, Gynecology and Perinatology, 117997, Oparina 4, Moscow, Russia. .,Pirogov Russian National Research Medical University, 117997, Ostrovityanova 1, Moscow, Russia.
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Furuta RA, Sakamoto H, Kuroishi A, Yasiui K, Matsukura H, Hirayama F. Metagenomic profiling of the viromes of plasma collected from blood donors with elevated serum alanine aminotransferase levels. Transfusion 2015; 55:1889-99. [PMID: 25721073 DOI: 10.1111/trf.13057] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2014] [Revised: 12/10/2014] [Accepted: 01/17/2015] [Indexed: 12/11/2022]
Affiliation(s)
- Rika A. Furuta
- Japanese Red Cross Kinki Block Blood Center; Osaka Japan
| | | | - Ayumu Kuroishi
- Japanese Red Cross Kinki Block Blood Center; Osaka Japan
| | - Kazuta Yasiui
- Japanese Red Cross Kinki Block Blood Center; Osaka Japan
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5
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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: 188] [Impact Index Per Article: 18.8] [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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6
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Chen T, Väisänen E, Mattila PS, Hedman K, Söderlund-Venermo M. Antigenic diversity and seroprevalences of Torque teno viruses in children and adults by ORF2-based immunoassays. J Gen Virol 2012; 94:409-417. [PMID: 23114629 DOI: 10.1099/vir.0.046862-0] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Torque teno viruses (TTVs) circulate widely among humans, causing persistent viraemia in healthy individuals. Numerous TTV isolates with high genetic variability have been identified and segregated into 29 species of five major phylogenetic groups. To date, the diversity of TTV sequences, challenges in protein expression and the subsequent lack of serological assays have hampered TTV seroprevalence studies. Moreover, the antigenic relationships of different TTVs and their specific seroprevalences in humans remain unknown. For five TTV strains--belonging to different species of four genogroups--we developed, using recombinant glutathione S-transferase (GST)-fused TTV ORF2 proteins, glutathione-GST capture enzyme immunoassays (EIAs) detecting antibodies towards conformational epitopes. We then analysed serum samples from 178 healthy adults and 108 children; IgG reactivities were observed either towards a single strain or towards multiple strains, which pointed to antigenic distinction of TTV species. The overall seroprevalence for the five TTVs peaked at 43 % (18 of 42) in children 2-4 years of age, subsequently declined, and again reached 42 % (74 of 178) among adults. TTV6 species-specific IgG predominated in children, whereas that for TTV13 predominated in adults. During a 3 year follow-up of the same children, both species-specific seroconversions and seroreversions occurred. This is the first EIA-based study of different TTVs, providing a new approach for seroepidemiology and diagnosis of TTV infections. Our data suggest that different TTVs in humans may differ in antiviral antibody profiles, infection patterns and epidemiology.
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Affiliation(s)
- Tingting Chen
- Department of Virology, Haartman Institute, University of Helsinki, Helsinki, Finland
| | - Elina Väisänen
- Department of Virology, Haartman Institute, University of Helsinki, Helsinki, Finland
| | - Petri S Mattila
- Department of Otorhinolaryngology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland
| | - Klaus Hedman
- Department of Virology and Immunology, Helsinki University Central Hospital Laboratory Division, Helsinki, Finland.,Department of Virology, Haartman Institute, University of Helsinki, Helsinki, Finland
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7
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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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8
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Torque teno virus (TTV) infection in sows and suckling piglets. Vet Microbiol 2009; 137:354-8. [DOI: 10.1016/j.vetmic.2009.01.008] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2008] [Revised: 12/12/2008] [Accepted: 01/02/2009] [Indexed: 11/21/2022]
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9
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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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10
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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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Davidson I, Shulman LM. Unraveling the puzzle of human anellovirus infections by comparison with avian infections with the chicken anemia virus. Virus Res 2008; 137:1-15. [PMID: 18656506 DOI: 10.1016/j.virusres.2008.06.014] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2008] [Revised: 06/15/2008] [Accepted: 06/17/2008] [Indexed: 10/21/2022]
Abstract
Current clinical studies on human annelloviruses infections are directed towards finding an associated disease. In this review we have emphasized the many similarities between human anellovirus and avian circoviruses and the cell and tissue types infected by these pathogens. We have done this in order to explore whether knowledge acquired from natural and experimental avian infections could reflect and be extrapolated to the less well-characterized human annellovirus infections. The knowledge gained from the avian system may provide suggestions for decoding the enigmatic human anellovirus infections, and finding the specific disease or diseases caused by these human anellovirus infections. Each additional parallelism between chicken anemia virus (CAV) and Torque teno virus (TTV) further strengthens this premise. As we have seen information from human infections can also be used to better understand avian infections as well. Increased attention must be focused on the "hidden" or unrecognized, seemingly asymptomatic effects of circovirus and anellovirus infections. Understanding the facilitating effect of these infections on disease progression caused by other pathogens may help to explain differences in outcome of complicated poultry and human diseases. The final course of a pathogenic infection is determined by variations in the state of health of the host before, during and after contact with a pathogen, in addition to the phenotype of the pathogen and host. The health burden of circoviridae and anellovirus infections may be underestimated, due to lack of awareness of the need to search past the predominant clinical effect of identified pathogens and look for modulation of cellular-based immunity caused by co-infecting circoviruses, and by analogy, human anneloviruses.
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Affiliation(s)
- I Davidson
- Division of Avian Diseases, Kimron Veterinary Institute, Bet Dagan, Israel.
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12
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Ninomiya M, Takahashi M, Nishizawa T, Shimosegawa T, Okamoto H. Development of PCR assays with nested primers specific for differential detection of three human anelloviruses and early acquisition of dual or triple infection during infancy. J Clin Microbiol 2008; 46:507-14. [PMID: 18094127 PMCID: PMC2238095 DOI: 10.1128/jcm.01703-07] [Citation(s) in RCA: 104] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2007] [Revised: 10/22/2007] [Accepted: 12/12/2007] [Indexed: 11/20/2022] Open
Abstract
We recently identified a novel human virus classifiable into a third group in the genus Anellovirus, tentatively designated torque teno midi virus (TTMDV), with a circular DNA genome of 3.2 kb and genomic organization resembling those of torque teno virus (TTV) (3.8 to 3.9 kb) and torque teno mini virus (TTMV) (2.8 to 2.9 kb). TTMDV was characterized by extreme genetic diversity similar to the TTV and TTMV genomes. Taking advantage of universal and virus species-specific primers derived from a highly conserved area located just downstream of the TATA box of the TTV, TTMDV, and TTMV genomes, a PCR method with simultaneous amplification of the genomic DNAs of these three anelloviruses in the first round and subsequent differential amplifications of these viruses in the second round was developed. High prevalence of TTMDV viremia was seen in adults (75/100 [75%]), comparable with the prevalences of TTV viremia (100%) and TTMV viremia (82%). Although none of 10 cord blood samples had detectable TTV, TTMDV, and TTMV DNAs, the prevalences of these three anelloviruses increased with the number of months after birth of the individual and reached 100% for individuals at one year of age. Dual or triple infection of TTV, TTMDV, and/or TTMV was seen in 10 (47.6%) of 21 infants 9 to 180 days of age and more frequently among infants 181 to 364 days of age (20/23 [86.9%]), comparable with the 93.1% (243/261) prevalence among subjects 1 to 81 years of age, indicating early acquisition of dual or triple anellovirus infection during infancy.
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Affiliation(s)
- Masashi Ninomiya
- Division of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, Tochigi-Ken 329-0498, Japan
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13
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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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14
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Wagner M, Klussmann JP, Dirsch O, Rose VA, Guntinas-Lichius O, Theegarten D, Sudhoff H, Linder R. Low prevalence of transfusion transmitted virus (TTV)-like DNA sequences in cystadenolymphoma and pleomorphic adenoma of the salivary glands. Eur Arch Otorhinolaryngol 2006; 263:759-63. [PMID: 16703387 DOI: 10.1007/s00405-006-0052-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2005] [Accepted: 09/05/2005] [Indexed: 10/24/2022]
Abstract
Titers of transfusion transmitted virus (TTV)-like DNA in saliva samples have been reported 100-1,000 times higher than those of the corresponding sera, suggesting viral transmission by saliva droplets. The present study was conducted to determine whether TTV-like DNA sequence elements play a role in the pathogenesis of cystadenolymphoma or pleomorphic adenoma and if the parotid or the submandibular gland is a major source of TTV persistence. Sixty-two archival salivary gland samples (16 cystadenolymphomas, 13 pleomorphic adenomas, and 33 controls) and 23 corresponding saliva samples were examined using a polymerase chain reaction (PCR) for TTV DNA. All PCR products that displayed DNA bands were sequenced. Leder's stain and immunohistochemistry (anti-CD8, anti-CD20, anti-CD45R0, anti-CD68, and anti-Ki67/MiB1) were applied to detect possible changes associated with findings of TTV-like DNA sequences. Tissue displayed TTV-like DNA sequences in 8.1% (5/62; saliva: 47.8%, 11/23). Tissue that contained TTV-like DNA sequences was histologically indistinguishable from samples lacking such DNA. TTV appears to be only a bystander in cystadenolymphoma, pleomorphic adenoma, and other salivary gland affections. Neither of the glands seems to be a major source of TTV persistence.
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Affiliation(s)
- Mathias Wagner
- Department of General and Special Pathology, Saarland University, 66421, Homburg-Saar, Germany.
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Komatsu H, Inui A, Sogo T, Kuroda K, Tanaka T, Fujisawa T. TTV infection in children born to mothers infected with TTV but not with HBV, HCV, or HIV. J Med Virol 2004; 74:499-506. [PMID: 15368510 DOI: 10.1002/jmv.20204] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
The TT virus (TTV) was isolated recently from the serum of a patient with post-transfusion hepatitis. TTV infection is widespread in the general population, and its prevalence increases continuously with age. The pathogenic role of TTV in liver disease remains controversial, and the source of transmission is still unclear. We investigated the pathogenicity and epidemiology of TTV infection in infants born to TTV DNA-positive mothers. Enrolled in this study were 22 mother-child pairs testing negative for antibodies to hepatitis B, hepatitis C, and the human immunodeficiency viruses (HIVs). The children were followed for 30 months after birth. Serum TTV DNA was detected by N22-PCR, and the PCR products were cloned and sequenced. The prevalence of TTV infection in children increased with age. Of the 22 children, 13 (59%) became positive for TTV DNA during the follow-up period. Of these 13 children, 6 (46%) had elevated levels of serum alanine aminotransferase (ALT), although the elevations were transient and mild. TTV viremia was not associated significantly with the abnormal ALT levels. Children with TTV viremia developed neither severe liver disease nor fulminant hepatitis. Phylogenetic analysis showed that, in 11 (85%) of the 13 pairs, the mother and child had the same genotype at the first PCR-positive time point. Among those 11 mother-child pairs, 6 (55%) had identical TTV nucleotide sequences. However, the genotype of predominant clones changed in 5 (50%) of 10 children who were positive for TTV DNA at two or more time points during the follow-up period. In conclusion, this study did not provide evidence that TTV infection is related to liver disease in children. Although the main source of TTV infection in children is presumed to be their mothers, transmitted via non-parenteral routes in the course of daily contact, intrafamilial carriers may also be sources of TTV infection.
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Affiliation(s)
- Haruki Komatsu
- Department of Pediatrics, National Defense Medical College, Saitama, Japan.
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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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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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18
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Hu ZJ, Lang ZW, Zhou YS, Yan HP, Huang DZ, Chen WR, Luo ZX. Clinicopathological study on TTV infection in hepatitis of unknown etiology. World J Gastroenterol 2002; 8:288-93. [PMID: 11925609 PMCID: PMC4658368 DOI: 10.3748/wjg.v8.i2.288] [Citation(s) in RCA: 20] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the state of infection, replication site, pathogenicity and clinical significance of transfusion transmitted virus (TTV) in patients with hepatitis, especially in patients of unknown etiology.
METHODS: Liver tissues taken from 136 cases of non-A non-G hepatitis were tested for TT virus antigen and nucleic acid by in situ hybridization (ISH) and nested-polymerase chain reaction (PCR). Among them, TT virus genome and its complemental strand were also detected in 24 cases of autopsy liver and extrahepatic tissues with ISH. Meanwhile, TTV DNA was detected in the sera of 187 hepatitis patients by nested-PCR. The pathological and clinical data of the cases infected with TTV only were analyzed.
RESULTS: In liver, the total positive rate of TTV DNA was 32.4% and the positive signals were located in the nuclei of hepatocytes. In serus, TTV DNA was detected in 21.4% cases of hepatitis A-G, 34.4% of non-A non-G hepatitis and 15% of healthy donors. The correspondence rate of TTV DNA detection between liver tissue with ISH and sera with PCR was 63.2% and 89.3% in the same liver tissues by ISH and by PCR, respectively. Using double-strand probes and single-strand probes designed to detect TTV genome, the correspondence rate of TTV DNA detected in liver and extrahepatic tissues was 85.7%. Using single-strand probes, TTV genome could be detected in liver and extrahepatic tissues by PCR, but its complemental strands (replication strands) could be observed only in livers. The liver function of most cases infected with TTV alone was abnormal and the liver tissues had different pathological damage such as ballooning, acidophilia degeneration, formation of apoptosis bodies and focus of necrosis, but the inflammation in the lobule and portal area was mild.
CONCLUSION: The positive rate of TTV DNA among cases of hepatitis was higher than that of donors, especially in patients with non-A non-G hepatitis, but most of them were coinfected with other hepatitis viruses. TTV can infect not only hepatocytes, but also extrahepatic tissues. However, the chief replication place may be liver. The infection of TTV may have some pathogenicity. Although the pathogenicity is comparatively weak, it can still damage the liver tissues. The lesions in acute hepatitis (AH) and chronic hepatitis (CH) are mild, but in severe hepatitis (SH), it can be very serious and cause liver function failure, therefore, we should pay more attention to TTV when studying the possible pathogens of so-called “Liver hepatitis of unknown etiology”.
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Affiliation(s)
- Zhong-Jie Hu
- Department of Pathology, Beijing You'an Hospital, 8 You'an Men Wai, Beijing 100054, China.
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19
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Lin HH, Kao JH, Lee PI, Chen DS. Early acquisition of TT virus in infants: possible minor role of maternal transmission. J Med Virol 2002; 66:285-90. [PMID: 11782941 DOI: 10.1002/jmv.2143] [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: 11/10/2022]
Abstract
This study assessed the prevalence of TT virus (TTV) viremia in pregnant women and evaluated the role of maternal transmission in early acquisition of TTV in infants in Taiwan. Two groups of pregnant women were screened for TTV using polymerase chain reaction. The first group included 135 healthy pregnant women attending the obstetrics department for routine prenatal care and the second group from 25 GB virus-C/hepatitis G virus (GBV-C/HGV)-infected mothers. In both groups, when TTV infection was found in mothers, serial serum samples were collected for the infants at regular intervals until 1 year of age and were tested for TTV DNA. The results showed that 40% (54/135) of the women undergoing routine prenatal care and 56% (14/25) of GBV-C/HGV-infected pregnant women were positive for TTV DNA (P = 0.137). Of the 54 TTV-infected mothers in the routine prenatal group, 29 and their 30 infants received regular follow-up. The positive rate of TTV DNA in infants was 40% (12/30) in the routine prenatal group and 29% (4/14) in the group with GBV-C/HGV-infected mothers (P = 0.463). All but 2 of the 16 TTV-infected infants had normal serum alanine aminotransferase levels during follow-up. The phylogenetic analysis in 7 mother-infant pairs showed that the homology was diverse in each pair and a close genetic relatedness was found in 2 mother-infant pairs. In conclusion, TTV viremia is common in pregnant Taiwanese women and their infants. However, the results suggest that maternal transmission may play only a minor role in early acquisition of TTV in infants.
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MESH Headings
- DNA Virus Infections/complications
- DNA Virus Infections/epidemiology
- DNA Virus Infections/transmission
- DNA Virus Infections/virology
- DNA, Viral/blood
- Female
- Flaviviridae/isolation & purification
- Flaviviridae Infections/complications
- Flaviviridae Infections/virology
- Hepatitis, Viral, Human/complications
- Hepatitis, Viral, Human/virology
- Humans
- Infant
- Infant, Newborn
- Infectious Disease Transmission, Vertical
- Molecular Sequence Data
- Phylogeny
- Polymerase Chain Reaction
- Pregnancy
- Pregnancy Complications, Infectious/epidemiology
- Pregnancy Complications, Infectious/virology
- RNA, Viral/blood
- Sequence Analysis, DNA
- Taiwan/epidemiology
- Torque teno virus/genetics
- Torque teno virus/isolation & purification
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Affiliation(s)
- Ho-Hsiung Lin
- Department of Obstetrics and Gynecology, College of Medicine and the Hospital, National Taiwan University, Taipei, Taiwan.
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20
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Yokoyama H, Yasuda J, Okamoto H, Iwakura Y. Pathological changes of renal epithelial cells in mice transgenic for the TT virus ORF1 gene. J Gen Virol 2002; 83:141-150. [PMID: 11752710 DOI: 10.1099/0022-1317-83-1-141] [Citation(s) in RCA: 19] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
TT virus (TTV) is a newly identified human DNA virus of the family Circoviridae. Its genome consists of six putative open reading frames (ORFs). TTV was isolated originally from a patient with cryptogenic hepatitis and the association of TTV with hepatitis has been studied extensively, while its significance in other diseases is unknown. To examine the pathogenicity of TTV, mice transgenic for the ORF genes in various combinations were produced. A total of 11 independent founder mice was produced: two mice, which were found to carry the ORF1 gene, showed pathological changes in the kidney; other tissues were not affected. In these mice, the transgene was expressed most strongly in the kidney and the transcript was shown to be spliced to encode a protamine-like, highly basic protein. Mice from a line with high transgene expression developed renal failure with severe renal epithelial cell abnormalities resembling those seen in humans with nephrotic syndrome. The transgenic mice with severe ascites died before reaching the age of 5 weeks. Another founder mouse with low expression levels also showed similar, but milder, renal epithelial cell changes, indicating that these effects were not caused by the insertion of the transgene, but, rather, were caused by the ORF1 gene product. These observations suggest that TTV affects renal epithelial cells as part of the naturally occurring infection.
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Affiliation(s)
- Hiroshi Yokoyama
- Center for Experimental Medicine, Institute of Medical Science, University of Tokyo, Shirokanedai, Minato-ku, Tokyo 108-8639, Japan1
| | - Jiro Yasuda
- Division of Molecular Virology, Institute for Genetic Medicine, Hokkaido University, Hokkaido, Japan2
- Center for Experimental Medicine, Institute of Medical Science, University of Tokyo, Shirokanedai, Minato-ku, Tokyo 108-8639, Japan1
| | - Hiroaki Okamoto
- Immunology Division and Division of Molecular Virology, Jichi Medical School, Tochigi-Ken, Japan3
| | - Yoichiro Iwakura
- Center for Experimental Medicine, Institute of Medical Science, University of Tokyo, Shirokanedai, Minato-ku, Tokyo 108-8639, Japan1
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Krekulova L, Rehak V, Killoran P, Madrigal N, Riley LW. Genotypic distribution of TT virus (TTV) in a Czech population: evidence for sexual transmission of the virus. J Clin Virol 2001; 23:31-41. [PMID: 11595582 DOI: 10.1016/s1386-6532(01)00185-8] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND TTV is a new DNA virus distinguished by its high degree of strain heterogeneity. The geographic clustering of viral genotypes suggests frequent community transmission. While no specific human disease has yet been linked to it, a transmission mechanism that facilitates strain diversity may eventually select for a strain that will become pathogenic. OBJECTIVE This study was performed to examine the prevalence, genotypic distribution, and mode of transmission of TTV in detail. STUDY DESIGN Three groups of study subjects were recruited between October 1998 and January 2000 in Prague, Czech Republic. Group 1 included 152 injection drug users with liver disease; group 2 included 102 persons with liver disease who denied ever using injection drugs; group 3 included 111 prospective blood donors. TTV DNA was detected from blood by a semi-nested PCR assay, and a selected set of PCR products was genotyped by direct sequencing. Factors associated with TTV prevalence in groups 1 and 2 subjects were compared. RESULTS TTV was detected in 15.8, 13.7, and 13.5% of Groups 1, 2, and 3 subjects, respectively (P>0.05). The most common genotype was 2 (54%), followed by 1 (13%). The prevalence of TTV viremia was nearly three times higher in persons with a present or past history of hepatitis B compared to those without (P<0.05). TTV prevalence increased proportionately with the number of lifetime sex partners in both groups (P<0.05); it was highest (32%) among non-users of injection drugs who had five or more lifetime sex partners. CONCLUSION TTV prevalence in the Czech population is similar among blood donors, persons with liver disease, as well as in a high-risk population of injection drug users. TTV appears to be sexually transmitted.
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Affiliation(s)
- L Krekulova
- Division of Infectious Diseases, School of Public Health, University of California, Berkeley, 140 Warren Hall, Berkeley, CA 94720, USA
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Kondili LA, Pisani G, Beneduce F, Morace G, Gentili G, Ballati G, Rapicetta M. Prevalence of TT virus in healthy children and thalassemic pediatric and young adult patients. J Pediatr Gastroenterol Nutr 2001; 33:629-32. [PMID: 11740244 DOI: 10.1097/00005176-200111000-00025] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
BACKGROUND The recently discovered TT virus (TTV) has been shown to be highly prevalent in patients with cryptogenetic chronic liver disease and fulminant hepatitis. To study the frequency of TTV and to evaluate the possible association with liver disease, 37 pediatric and young adult patients with thalassemia, and 36 healthy children were included in the study. The sera of 100 blood donors selected randomly in the same period were also tested for TTV DNA. METHODS The TTV amplification by polymerase chain reaction (PCR) was performed using a first set of primers that recognize an internal sequence into N22 and a second set of primers amplifying a sequence within 5;NCR (5; noncoding region). RESULTS The first set of primers revealed TTV DNA in 73% of thalassemic patients, in 8% of healthy children, and in 5% of healthy blood donors. With the second set of primers, the prevalence of TTV DNA was, respectively, 100% in thalassemic patients, 44.5% in healthy pediatric patients, and 87% in healthy blood donors. All individuals who tested positive for TTV by the first set of primers were also positive by the second primer set. The TTV infection seemed not to be the cause of altered transaminase levels. Sequencing of TTV clones from thalassemic patients showed the presence of different TTV variants in the same serum. CONCLUSION The prevalence of TTV in polytransfused children is similar to that detected in blood donors. Moreover, TTV can be detected in healthy children of all ages. The presence of TTV seems to have no clinical significance.
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Affiliation(s)
- L A Kondili
- Laboratory of Virology, Istituto Superiore di Sanità, Viale Regina Elena, 299 00161 Rome, Italy
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Sugiyama K, Goto K, Ando T, Mizutani F, Terabe K, Yokoyama T. Highly diverse TTV population in infants and their mothers. Virus Res 2001; 73:183-8. [PMID: 11172922 DOI: 10.1016/s0168-1702(00)00242-2] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Infants born to serum HCV-positive 12 mothers were enrolled in the study. Nucleotide sequences amplified by primers deduced from a noncoding region were compared between mothers and their infants. The rates for detection of serum TTV in 12 mothers and their infants were 10/12 (83%) and 9/12 (75%), respectively. Serum TTV DNA was not detected in any infant at 1 month of age, but was detected for the first time between 1.5 and 8 months after birth. Positivity persisted thereafter throughout the follow-up period. In seven randomly selected mother-infant pairs, intrahost TTV heterogeneity was lower in infants than in mothers. Furthermore, one of seven mother-infant pairs showed a high degree of similarity (98.7-100%) in all clones, while in four infants, all nucleotide sequences differed by >10% from those of their mothers. However, the degree of homology in the two mother-infant pairs was 89-98.7% in family 2 and 88.1-99.4% in family 5. In the present study, with only one exception, it was shown that TTV from infants is not identical to TTV from mothers. The mechanism is discussed briefly in this paper.
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Affiliation(s)
- K Sugiyama
- Department of Pediatrics, Nagoya City University Medical School, Kawasumi-cho, Mizuho-ku, 467-8601, Nagoya, Japan.
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