TT Virus Infection in Patients with Hepatitis C: Frequency, Persistence, and Sequence Heterogeneity

Irving, William L.; Ball, Jonathan K.; Berridge, Selina; Curran, Rebecca; Grabowska, Anna; Jameson, Claire L.; Neal, Keith; Ryder, Steven D.; Thomson, Brian J.

doi:10.1086/314825

Cited by 45 publications

(38 citation statements)

References 16 publications

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“…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).TT viruses (TTV) are ubiquitous in nature and have been demonstrated in more than 90% of serum samples from healthy individuals where they persist over time (14,16,27,41). Viral particles have been purified from feces (17, 34) and, in addition, are excreted in saliva, breast milk, and bile juice (9,38,47,49).…”

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confidence: 75%

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Isolation of Multiple TT Virus Genotypes from Spleen Biopsy Tissue from a Hodgkin's Disease Patient: Genome Reorganization and Diversity in the Hypervariable Region

Jelčić¹,

Hotz‐Wagenblatt

Hunziker³

et al. 2004

J Virol

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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).TT viruses (TTV) are ubiquitous in nature and have been demonstrated in more than 90% of serum samples from healthy individuals where they persist over time (14,16,27,41). Viral particles have been purified from feces (17, 34) and, in addition, are excreted in saliva, breast milk, and bile juice (9,38,47,49). Transplacental transmission from mother to child has been controversial, but postnatal transmission has been confirmed repeatedly (15,20,24,30,33,37,48,51,52,57 (39,44). Peripheral blood mononuclear cells act as a reservoir for TTV (41), but the highest viral load is found in the granulocytes (54). Viral transcription naturally occurs in bone marrow cells and not in peripheral blood mononuclear cells (40), although transcription in vitro has been achieved by DNA transfection into stimulated peripheral blood monocytes (29) and in a monkey cell line (19).A large number of full-length or near full-length genomes of TTV has been isolated from humans and primates. They have also been identified in farm animals (23), although the genomes of recent isolates from pigs, dogs, and cats proved to be considerably smaller in size than the TTV found in humans and primates (43). The highly conserved noncoding region constitutes about one-third of the genome. The coding region consists of a large open reading frame (ORF), ORF1, coding for the viral capsid protein as well as the smaller ORF2, ORF3, and ORF4. Additional mRNAs result from splicing events (19,40). Many different genotypes have been isolated, and an extremely wide range of DNA sequence divergence has been demonstrated (45). The steadily increasing number of new genotypes and the high sequence variability point to the need for a uniform and defined cla...

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confidence: 75%

“…TT viruses (TTV) are ubiquitous in nature and have been demonstrated in more than 90% of serum samples from healthy individuals where they persist over time (14,16,27,41). Viral particles have been purified from feces (17, 34) and, in addition, are excreted in saliva, breast milk, and bile juice (9,38,47,49).…”

mentioning

confidence: 99%

Isolation of Multiple TT Virus Genotypes from Spleen Biopsy Tissue from a Hodgkin's Disease Patient: Genome Reorganization and Diversity in the Hypervariable Region

Jelčić¹,

Hotz‐Wagenblatt

Hunziker³

et al. 2004

J Virol

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“…Several reports have indicated that TTV is associated with a persistent infection (Nishizawa et al, 1997 ;Simmonds et al, 1998 ;Irving et al, 1999). However, there has been no information regarding the stability of TTV DNA titres during persistent infection.…”

Section: Ttv Populations Within Individualsmentioning

confidence: 99%

“…One possible factor involved in generating such genetic diversity is virus persistence. TTV DNA has been detected in samples obtained from hepatitis C virus co-infected individuals for periods of up to 6 years (Irving et al, 1999), and in a cohort of Scottish haemophiliacs many years after the receipt of the likely contaminated batch of clotting factors .…”

Section: Introductionmentioning

confidence: 99%

TT virus sequence heterogeneity in vivo: evidence for co-infection with multiple genetic types.

Ball¹,

Curran²,

Berridge³

et al. 1999

Journal of General Virology

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TT virus (TTV) is a newly described DNA virus of humans that exhibits an unusually high degree of genetic heterogeneity. We have performed extensive analysis of the TTV populations present in samples, taken over a period of 2 to 6 years, from three individuals with persistent TTV infection. TTV DNA titres estimated for sequential samples were found to be quite stable over the entire study period in two patients, but fluctuated considerably in the third. DNA sequence analysis revealed different genetic diversity among TTV populations from samples from the three patients. In one case, absolute sequence homogeneity was observed among samples over a 3 year period. In a second, a limited amount of heterogeneity was found, including one sequence exhibiting G A hypermutation. TTV DNA sequences from the third patient exhibited quite remarkable genetic heterogeneity : evidence was found of seven distinct infecting viruses, representing four of the six TTV genotypes that have been described. In addition, minor variants of three of these seven sequences were observed. The heterogeneity of the viral population in this individual declined steadily over a 6 year period. This patient infected with a genetically diverse TTV population had the highest viral DNA titre.

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“…They display over 30% nucleotide diversity (19) and are classified into five distantly related groups (13). TTVs are ubiquitous in nature and have been demonstrated in more than 90% of serum samples from healthy individuals, where they persist over time (5,10,12,16). A tissue culture system that supports efficient replication of TTV is not yet available (4, 13), and this has delayed the study of both TTV genome replication and TTV gene expression.…”

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Human Circovirus TT Virus Genotype 6 Expresses Six Proteins following Transfection of a Full-Length Clone

Qiu

Kakkola

Cheng

et al. 2005

J Virol

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The expression profile of the circovirus TTV has not yet been fully characterized. In this paper, we show that following transfection of a full-length viral clone of TTV genotype 6, each of the three virally encoded mRNAs is translated from two initiating AUGs, and therefore, the TTV genome generates at least six proteins. Localization studies of hemagglutinin-tagged versions of these proteins in fixed cells, and green fluorescent protein-tagged versions of these proteins in living cells, expressed following transfection, demonstrated that two were primarily nuclear, two were primarily cytoplasmic, and two were found throughout the cell.TTV is a small, nonenveloped icosahedral virus approximately 30 nm in diameter which contains a circular, singlestranded 3.6-to 3.9-kb DNA genome of the minus sense (11,12,15). At least 39 genotypes of TTV have been identified. They display over 30% nucleotide diversity (19) and are classified into five distantly related groups (13). TTVs are ubiquitous in nature and have been demonstrated in more than 90% of serum samples from healthy individuals, where they persist over time (5,10,12,16). A tissue culture system that supports efficient replication of TTV is not yet available (4, 13), and this has delayed the study of both TTV genome replication and TTV gene expression. To date, characterization of the full spectrum of TTV proteins generated during infection or transfection of a full-length TTV genome has not been completed.Three species of mRNAs (2.8, 1.2, and 1.0 kb) (Fig. 1A) have been detected in infected bone marrow cells (14) and are generated following transfection of a full-length TTV clone into monkey COS cells (7), which support the expression but not the replication of TTV. Antibodies in TTV-infected individuals that react with two proteins encoded by the 2.8-kb mRNA have been detected (2, 17). The first is the large protein encoded by TTV ORF1 (the ORF1 protein [ Fig. 1C]), which is predicted to be 736 amino acids in length and initiate from a methionine at nucleotide (nt) 581 (O1AUG). (All nucleotide numbers refer to GenBank accession number AY666122.) The second protein (the ORF2 protein [ Fig. 1C]) is encoded from the 2.8-kb mRNA in ORF2, initiating at a methionine at nt 354 (O2AUG) and extending for 117 amino acids.Following transfection in COS cells of cDNA constructs driven by the cytomegalovirus promoter, the 1.2-kb TTV mRNA has been shown to express a 281-amino-acid protein that initiates in ORF2 from the O2AUG and remains in ORF2 after the splice (the ORF2/2 protein [ Fig. 1C]) (1). The 1.0-kb mRNA has been predicted to encode a protein of 275 amino acids that initiates in ORF2 from the O2AUG and is fused to ORF3 following splicing (the ORF2/3 protein [ Fig. 1C]) (7). Generation of these proteins directly from the viral genome has not yet been demonstrated following either viral infection or transfection of TTV clones. Although the 1.2-and 1.0-kb mRNAs are presumably competent to also generate proteins initiated at the O1AUG, the production of O1AUG-initiate...

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TT Virus Infection in Patients with Hepatitis C: Frequency, Persistence, and Sequence Heterogeneity

Cited by 45 publications

References 16 publications

Isolation of Multiple TT Virus Genotypes from Spleen Biopsy Tissue from a Hodgkin's Disease Patient: Genome Reorganization and Diversity in the Hypervariable Region

Isolation of Multiple TT Virus Genotypes from Spleen Biopsy Tissue from a Hodgkin's Disease Patient: Genome Reorganization and Diversity in the Hypervariable Region

TT virus sequence heterogeneity in vivo: evidence for co-infection with multiple genetic types.

Human Circovirus TT Virus Genotype 6 Expresses Six Proteins following Transfection of a Full-Length Clone

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