In recent years, the continuous development of metagenomics has revealed that in addition to the digestive tract, some viruses are also common in mammalian blood. To explore and monitor potential novel viruses, in April 2015, a blood sample was collected from a healthy captive giant panda at the Chengdu Research Base of Giant Panda Breeding in Sichuan Province, China. The genomes of 25 different anelloviruses containing the complete ORF1 region have been identified. The BLASTp results showed that the amino acid sequence identity of these viruses with the best match in GenBank ranged from 27.15% to 41.29%. Based on phylogenetic analysis and SDT (Species Demarcation Tool) analysis of the complete ORF1 regions of these 25 viruses, these sequences were deduced to represent one or several novel virus genera or species. This virological study has increased our understanding of the diversity of anelloviruses in the blood of giant pandas, but further laboratory analysis is needed to verify its possible pathogenicity.

Torque Teno Virus (TTV), member of Anelloviridae family, is considered a worldwide distributed emergent virus and is currently classified into seven genogroups. Interestingly, the pathogenicity of TTV remains unclear. However, it has been constantly associated to hepatitis cases of unknown etiology (HUE) as well as extensively studied in concurrent infections with Hepatitis B Virus (HBV), Hepatitis C Virus (HCV) and Human Immunodeficiency Virus type 1 (HIV-1). In South America, TTV epidemiological data is scant, involving some studies from Brazil, Venezuela, Colombia and Bolivia. The aim of this work was to investigate for the first time in Uruguay the presence of TTV by a nested-PCR system in 85 human serum samples infected with HBV and/or HCV and/or HIV-1 and in HUE cases. Overall, our results reported a TTV infection rate of 79% (67/85). Furthermore, the molecular characterization of Uruguayan strains revealed that one of them clustered in genogroup 1, while the remaining ones formed separate clusters closely related to genogroup 3, which should be confirmed by complete genome sequencing. Further investigation about TTV circulation in Uruguayan population is needed in order to provide additional information about the genetic variability and TTV epidemiology in South America.

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.

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.

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.

The aim of the present study was to describe the clinicopathological characteristics and the natural history of acute non-(A-E) hepatitis and to assess the possible role of hepatitis G virus (HGV), TT virus (TTV) and mainly SEN virus (SENV).

A cohort of 55 patients with sporadic acute non-(A-E) hepatitis with a mean follow up of 31 (6-55) months was studied.

The clinical presentation was fulminant in one (1.8%), protracted with impaired regeneration in seven (12.7%) and benign in the remaining 47 (85.5%) cases. Progression to chronic hepatitis was observed in 15 (27.3%) patients; it was more frequent in clinically severe than in non-severe cases (five of eight patients or 62.5% vs 10 of 47 patients or 21.3%, P = 0.028). Six of 10 biopsied chronic non-(A-E) cases developed cirrhosis within 10-33 months. Serum HGV-RNA was detected in 16 of 55 (29.1%) patients, TTV in 20 of 38 (52.6%) patients and SENV-D/H DNA in 20 of 55 (36.4%) cases. HGV-RNA was detected more frequently in clinically severe than in non-severe cases (five of eight or 62.5% vs 11 of 47 or 23.4%, P = 0.038). There was no other association between the presence of HGV, TTV, or SENV infection and patient characteristics or severity and outcome of disease.

HGV, TTV, and SENV do not seem to be responsible for the majority of sporadic acute non-(A-E) hepatitis cases. Our cohort further supports the existence of new, unknown hepatitis agent(s) with uncertain mode of transmission. The non-(A-E) agent(s) can also cause chronic hepatitis, which often has an aggressive course with rapid development of cirrhosis.

A novel human DNA virus was isolated from the serum of a patient with posttransfusion hepatitis; it was named transfusion transmitted virus (TTV).

To ascertain the influence of TTV (detected by polymerase chain reaction amplification of a conserved region of the viral genome) coinfection in individuals infected with hepatitis viruses (A, B, and C) and to investigate the putative role played by TTV in hepatic dysfunction in individuals with acute non-A-E hepatitis.

Sixty-two patients with viral hepatitis were included in the study in addition to 18 blood donors. Viral study of 4 hepatotropic viruses (A, B, C, and E) was carried out. Study for TTV DNA was performed by nested polymerase chain reaction.

The prevalence of TTV was not statistically different between hepatitis patients and blood donors, and it was not correlated to the levels of the hepatic aspartate aminotransferase and alanine aminotransferase between individuals evidencing dual infection with hepatitis B and C viruses and healthy blood donors. However, in the group of patients with viral hepatitis of unknown etiology (non-A-E), those evidencing TTV viremia had statistically significant lower levels of alanine aminotransferase (P = .03) and aspartate aminotransferase (P = .04) than those who were TTV negative.

We can conclude that TTV is a frequent virus isolated from patients with various types of viral hepatitis, from cases of hepatitis without obvious viral agent, and from the healthy population. TTV has no effect on biochemical markers of associated viral hepatitis. It may be associated with a mild form of non-A-E hepatitis.

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.

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.

This study was aimed at obtaining data on the epidemiology and clinical course of TT virus (TTV) infections among Indian subjects.

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.

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.

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.

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.

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.

The aim of this study was to evaluate the transfusional transmitted virus (TTV) seroprevalence in asymptomatic HBsAg (+) patients and to assess the influence of TTV on the course of these patients.

Sixty asymptomatic HBV carriers were included and 31 healthy volunteers served as controls. Cases were followed at 6-month intervals for a total duration of 4 years.

In the asymptomatic carrier group, 31 patients (51.7%) had a history of surgery and 10 (16.7%) had a history of blood transfusions. TTV-DNA was detected in 45 of these patients (75%). In the control group, 12 patients (38.7%) had a history of surgery and 2 had (6.5%) a history of blood transfusions. TTV-DNA was found in 20 (64.5%) of these subjects. The incidence of TTV-DNA positivity was not significantly different between the two groups (P > 0.05).

In spite of the common occurrence of HBV and TTV, TTV-DNA was also detected in 64.5% of healthy controls. Furthermore, during 4 years of follow up, TTV had no detrimental effects on the course of asymptomatic HBV carriers. These results suggest that the hepatic injury due to TTV is insignificant in this group of patients.

Although transfusion-transmitted infections are rare, non-infectious complications occur relatively frequently. Solvent/detergent-treated fresh-frozen plasma (SD-FFP) has been shown to reduce the frequency of both types of complication, although previous economic evaluations failed to consider non-infective events and subsequently underestimated the benefits of SD-FFP.

A time-series analytical model was used to estimate the incremental cost/life year saved for SD-FFP compared with untreated FFP, having controlled for post-transfusion mortality and patient age. Various infective and non-infective transfusion-related complications were considered.

The discounted cost/life year saved for SD-FFP use in the UK was pound sterling 22,728 [95% confidence interval (95% CI): pound sterling 22,604-22,853] for neonates and pound sterling 98,465 (95% CI: pound sterling 97,924-99,005) for patients aged 70. The cost-effectiveness ratio was below pound sterling 50,000/life year saved for patients < or = 48 years of age, and below pound sterling 30,000/life year saved for those < or = 21 years of age. In transfusion recipients with no significant morbidity, the cost-effectiveness ratio was pound sterling 12,335 for neonates and pound sterling 61,692 for 70-year olds. The most important driver of cost-effectiveness was transfusion-related acute lung injury (TRALI), on account of its relatively high incidence and mortality rate.

Previous analyses greatly underestimated the cost-effectiveness of SD-FFP. Inclusion of non-infectious complications suggests that SD-FFP is cost-effective in patients < or = 48 years of age and in older patients with good clinical prognosis, which may justify the wider use of this technology.

To determine the prevalence and clinical impact of transfusion-transmitted virus (TTV) DNA in patients with chronic liver diseases in the Southeast Anatolia region of Turkey where hepatitis B and C viral infections are endemic.

Patients diagnosed with chronic liver disease by clinical, biochemical and histologic means were enrolled in the study. Serum samples of 60 patients (19 males, 41 females) with chronic liver diseases, and of 45 healthy volunteer blood donors as a control group were collected. The chronic liver disease group consisted of 11 patients with hepatitis B, 44 with hepatitis C and 5 with chronic liver disease of unknown etiology. Presence of TTV DNA was investigated by the polymerase chain reaction. Using a scoring system histological grading of inflammation and staging of fibrosis were performed only in the chronic hepatitis C group.

TTV DNA was detected in 47 (78%) patients with chronic liver disease and 5 (11%) volunteers in the control group. The difference was statistically significant (p < 0.001). Ten of the 11 (91%) patients with hepatitis B, 32 of 44 (73%) of those with hepatitis C-related chronic liver disease, and 5 of 5 (100%) of the patients with cryptogenic liver disease were positive for TTV DNA.

TTV is highly prevalent in patients with chronic liver diseases in Southeast Anatolia, Turkey but no pathogenic effect attributable to TTV infection was detected.

TT virus (TTV) is widespread in the general population, however, the mode of its transmission and the mechanism of maintaining it in the general population are unclear.

To determine the possible mother-to-infant route of transmission, 54 infants bom to 50 anti-HCV-positive mothers were assessed longitudinally. Nucleotide sequences amplified by seminested PCR with primers targeting the N22 variable coding region of genotypes 1 through 6 were compared in mothers and their infants.

The prevalence of TTV DNA was 30 percent (15/50; 95% CI, 18-45) in mothers and 44 percent (24/54; 95% CI, 31-59) in their infants. TTV DNA was detected during a follow-up period in 13 (87%; 95% CI, 60-98) of 15 infants born to infected mothers and in 11 (28%; 95% CI, 15-45) of 39 infants bom to DNA-negative mothers. None of 38 cord blood samples, but one of 14 blood samples, obtained at 1 month of age had detectable TTV DNA. The lowest infection rate at the earliest ages and the subsequent increasing prevalence of infection (22% at 6 months and 33% [43% cumulative rate] at 2 years) is consistent with an age-dependent acquisition of TTV by nonparenteral routes. In 13-mother-infant pairs positive for TTV DNA, six showed a high degree of nucleotide sequence similarity (99.1-100%), whereas the remaining seven pairs differed more than 10 percent from each other (46.8-89.2%). The viral load of matemal blood was not a plausible risk factor for transmission. Genotype 1, of which pathogenicity failed to be shown by measurement of hepatic enzymes, was more rapidly cleared (88 vs. 8% other genotypes, p < 0.001) among infants.

These observations strongly suggest that the main factor for TTV acquisition in children involves their age-associated increase in environmental interactions with infectious materials. Genotype 1 might be involved in a weak or a limited pathologic role, which can possibly be diluted by other harmless genotypes.

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.

TT virus (TTV) was first described in 1997 by representational difference analysis of sera from non-A to non-G posttransfusion hepatitis patients and hence intensively investigated as a possible addition to the list of hepatitis-inducing viruses. The TTV genome is a covalently closed single-stranded DNA of approximately 3.8 kb with a number of characteristics typical of animal circoviruses, especially the chicken anemia virus. TTV is genetically highly heterogeneous, which has led investigators to group isolates into numerous genotypes and subtypes and has limited the sensitivity of many PCR assays used for virus detection. The most remarkable feature of TTV is the extraordinarily high prevalence of chronic viremia in apparently healthy people, up to nearly 100% in some countries. The original hypothesis that it might be an important cause of cryptogenic hepatitis has not been borne out, although the possibility that it may produce liver damage under specific circumstances has not been excluded. The virus has not yet been etiologically linked to any other human disease. Thus, TTV should be considered an orphan virus.