Review Open Access
Copyright ©2006 Baishideng Publishing Group Co., Limited. All rights reserved.
World J Gastroenterol. Aug 28, 2006; 12(32): 5122-5134
Published online Aug 28, 2006. doi: 10.3748/wjg.v12.i32.5122
Transfusion transmitted virus: A review on its molecular characteristics and role in medicine
M Irshad, YK Joshi, Y Sharma, I Dhar
M Irshad, Y Sharma, I Dhar, Clinical Biochemistry Division, Department of Laboratory Medicine, All India Institute of Medical Sciences, New Delhi-110029, India
YK Joshi, Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi-110029, India
Author contributions: All authors contributed equally to the work.
Supported by Indian Council of Medical Research, New Delhi-110049 for financial support
Correspondence to: Dr. M Irshad, Additional Professor, Clinical Biochemistry Division, Department of Laboratory Medicine, PO Box -4938, A.I.I.M.S., New Delhi-110029, India.
Telephone: +91-11-26594764
Received: March 3, 2006
Revised: May 15, 2006
Accepted: May 22, 2006
Published online: August 28, 2006


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. Although 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.

Key Words: Transfusion transmitted virus, DNA, Virus, Hepatitis, Transfusion


Transfusion transmitted virus (TTV) is a recently discovered virus which was suspected to be a causative agent of non-A to non-E hepatitis. TTV was first identified in the serum of a patient who was hospitalized with post transfusion hepatitis of unknown etiology in 1997[1]. Initially, TTV was described as a non-enveloped, 3739 bases long and single stranded DNA virus. Based on its genomic characteristics, it was reported to be a parvovirus-like pathogen. Later, studies on the molecular and biophysical characteristics of TTV demonstrated this novel agent as a non-enveloped virus with a small, covalently closed circular genome of single stranded DNA comprising 3852 bases[2-4]. Its buoyant density is significantly different from that of parvoviruses. Also there was a significant sequence difference between TTV and members of the Circoviridae[5]. It was proposed that TTV belongs to a new virus family that was tentatively designated Circinoviridae[2] paracircoviridae[6] or the TTV family[7] by different research groups. TTV isolates have an extremely wide range of sequence divergence[8-10] and were tentatively classified into 23 genotypes with sequence divergence of > 30% from one another[11] or into four major phylogenetic groups[7,11]. TTV like mini virus (TLMV) with 2.8-3.0 kb genomic length was also identified in humans and chimpanzees[12-14].

Since the discovery of TTV, studies have been published describing the prevalence of TTV infection in people with acute or chronic hepatitis as well as in blood donors and drug users and also in healthy persons[15-17]. It is apparent that currently it is not possible to ascribe TTV to any specific diseases. TTV can be transmitted parenterally and has been found in plasma and peripheral blood mononuclear cells. However, non-parenteral transmission is also possible as TTV can be excreted in feces[10]. Molecular and phylogenetic analysis of polymerase chain reaction (PCR) fragments revealed that TTV could be divided into several genotypes that are found worldwide without any direct correlation with geographical distribution of diseases[2,18-20]. This is an interesting area to investigate different aspects of TTV and several groups are working to extricate many mysteries related to this agent world over. Until now, an abundance of information has been published on TTV in relation to its molecular form and infectious status.

To have a compilation of information and also have a better understanding of TTV, the present article provides a holistic view on various characteristics of this novel agent with particular emphasis on its molecular characteristics, epidemiological features, endemic behavior and pathogenesis as well as prospects of its eradication on the basis of published information.


TTV, a common virus in humans with high prevalence in the general population[21,22] is a single stranded DNA virus. Its the genome was sequenced by Okamoto et al[3] almost entirely on the prototype isolate TA278 encompassing 3739 nucleotides and was temporarily believed to be a linear DNA. However, later studies[2] with the GHI isolate and TA 278 isolate[4] have identified a GC-rich missing link of about 100 nucleotides that complete the TTV genome as a closed circular DNA with a length of 3852 nucleotides (nt) and a particle size of 30-50 nm. Thus, TTV is an unenveloped virus whose genome consists of a circular and single stranded DNA molecule of negative polarity and about 3.8 kb length[2]. TTV has an isopycnic density of 1.31-1.34 g/mL in CsCl[2,4]. The TTV genome has two or three possible open reading frames (ORFs) capable of encoding 770 aa (ORF1), 202 aa (ORF2) and 105 aa (ORF3 ) polypeptides[4]. Analysis of the TTV transcription pattern in COS-1[23] and bone marrow cells[24] has revealed the existence of at least three species of spliced mRNA molecules of 2.9-3, 1.2, and 1.0 kb in length, with common 5′ and 3′ termini, leading to the creation of new reading frames (ORF3 and ORF4) in addition to the previously described ORF1 and ORF2[25].

Many studies have indicated a high degree of genetic diversity of TTV. The entire genome was sequenced for SANBAN and TA 278 isolates[26]. The genetic organization of the genome was similar in two isolates: two open reading frames (ORF1 and ORF2) were sandwiched by the motifs of TATA box and polyadenylation signal, and a GC-rich short stretch resided at the midst of the untranslated region. No other ORFs longer than 300 nt and common to SANBAN and TA278 were found. The overall nucleotide sequence identity between the two isolates was 56.7%, significantly lower than that (93%) between TA278 and GH1[2]. Interestingly, the nucleotide sequence identity was relatively higher in the untranslated region (73.0%) than in the translated region (52.2%). A great degree of genetic diversity for a group of viruses represented by TTV most likely had a long history of evaluation and adaptation to humans. Despite the extensive sequence divergence of TTV and TLMV in coding regions of the genome, three areas of remarkable conservation have been identified in the part of UTR that contains promoters and splice sites[24]. Sequence conservation is found among all known human isolates of TTV and TLMV as well as those recovered from a range of non-human primates.

Based on its physico-chemical and genomic characteristics[2-4], TTV was proposed as a member of new viral family tentatively named the Circinoviridae[3]. Although TTV shares some features, such as a negative-stranded circular DNA genome, with members of the Circoviridae[1], the genetic organization of its genome is distinctly different from that of viruses that belong to this family. Therefore, TTV was tentatively classified into the virus family, Circinoviridae[3].


The TTV genome sequence is extremely heterogeneous. Phylogenetic analysis performed on TTV isolates recovered from several parts of the world revealed the existence of 6 different genotypes[3,27]. The sequence heterogeneity of the TTV genome, however, is more complex. One report described the identification of 16 TTV genotypes[28]. Another study identified 5 additional TTV genetic groups[10]. One of these was found to represent an additional TTV genotype, whereas the other 4 additional genetic groups were significantly distinct from TTV and from one another compared to the original TTV genotypes. This observation suggested that these 4 new genetic groups represent closely related, yet different, TTV-like viral species. The existence of genetic divergence between different TTV isolates beyond genotypes was noted by another group of researchers[8]. It has been hypothesized that a whole “swarm” of numerous TTV-like species circulates in the human population worldwide[29]. Despite this extensive sequence diversity, all variants of TTV share a common genomic organization with three predicted encoded proteins of similar length and likely function.

TTV was originally found in humans; however, recent studies showed that TTV can also be identified in serum specimens obtained from domesticated farm animals[29] and from non-human primates[29,30]. Phylogenetic analysis using the TTV sequence obtained from animals demonstrated that these sequences belong to already known human TTV genotypes[29,30], although some sequences recovered from nonhuman primates remain unclassified[30]. The results of these experiments demonstrated that chimpanzees may be infected with some TTV-related species that have not been found in humans. An additional phylogenetic analysis using all known TTV sequences, some of which were not classified[26,30] or were classified previously as new TTV genotypes[10], suggested the existence of 16 genotypes or 13 different TTV-like species. The prototype TTV-I[8] sequences were classified into eight genotypes found in humans as well as in non-human primates and farm animals. Moreover, genetically distant variants, namely PMV, SANBAN and SEN viruses have been identified. Frequent homologous recombination, which can occur when a subject is co-infected with two or more isolates, is an important multiplier of the TTV genetic diversity. This phylogenetic tree contains 13 major groups. Each major group represents sequences that are more distant from the other major group sequences. This observation is strongly supported by the analysis of frequency distribution of evolutionary distances. Comparison of sequences from one major group of branches to all other branches demonstrates that each of the 13 major groups of branches may represent different viral species. All of these viruses are closely related to the prototype TTV strains tentatively designated TTV-I. The other viral species identified with each major branch were also designated TTV with the addition of Roman numerals (e.g. TTV-II, TTV-III) as proposed previously[8].

All 13 major groups of branches or viral species may be arranged into four groups. Group A contains viral species I and IX; group B contains II, III, X, XI, XII, and XIII; group C contains IV and V; and group D contains VI, VII, and VIII. The TT viruses found in humans belong to groups A, B, and C. Group C is composed exclusively of viruses found in humans and group D of viruses found only in non-human primates. The primate TT viruses can be also found in groups A and B. Group A includes two viral species. One of these viruses is the prototype TTV-I, which was originally identified in a Japanese patient with parenterally transmitted hepatitis of unknown etiology[1]. Previously, seven TTV-I genotypes were identified[27,28]. However, based on phylogenetic analysis, TTV-I genotypes 2 and 3 were suggested to be combined as genotype 2/3[8]. This suggestion reduces the number of TTV-I genotypes to 6. Earlier, several new TTV variants were found in non-human primates[29,30]. The phylogenetic analysis performed in this study confirmed that sequences Bo-Ho and Bo-De identified by Vergchoor et al belonged to genotype 2/3. However, sequences Ch-Pe and Ch-Br2 constituted two new TTV-1 genotypes[29] whose sequences constituted a new major branch in the phylogenetic tree representing TTV-IX, which is different from, but closely related to the prototype TTV-I. TTV-IX detected in chimpanzees is most closely related to the TTV-I genotype 8 found only in non-human primates[30]. Recently, several new TTV variants were identified in serum specimens from healthy Japanese individuals[31]. Group B contains TTV-II, TTV-III, TTV-X, TTV-XI, TTV-XII and TTV-XIII, which can be found in non-human primates as well as in human specimens. TTV-II, TTV-III, TTV-X and TTV-XIII were found only in humans. Group C is composed of two human viruses, TTV-IV and TTV-V. Group D consists of three new chimpanzee viruses, namely TTV-VI, TTV-VII and TTV-VIII.


TTV was first characterized as a blood-borne virus and was thus referred to as a transfusion-transmitted virus (TTV)[3,32]. However, later studies suggested the existence of other routes of transmission also. In fact the mechanism of TTV transmission has not yet been elucidated. The higher prevalence of TTV in persons treated with blood[3] or blood products[32] has suggested parenteral transmission as a frequent route of TTV infection. TTV is common in patients who have an increased risk of infection with blood-borne viruses, such as hemophiliacs (68%), patients on maintenance hemodialysis (46%), and abusers of intravenous drugs (40%)[3]. There is a high prevalence of TTV in blood products. TTV contamination was found in 10 of 18 batches (56%) of factor VIII and IX concentrates manufactured from non-remunerated donors, and in 7 (44%) of 16 batches of commercially available products[32]. These observations suggest that TTV is transmitted by blood and blood products. However, infrequent detection of TTV-DNA in serum samples from prostitutes and homosexual men[17] and the findings of fecal[33] and bile[34] excretion of TTV indicate that TTV may have characteristics different from other blood-borne viruses. The prevalence of TTV in blood donors in different countries varies between 1.9% to 62%[3,22,27,32,35]: 1.9% in England[32], 9.1%-12.8% in United States[27], 12% in Japan[3] , 36% in Thailand[35] and 62% in Brazil[22]. Moreover, the majority of TTV infected people had no history of blood and/or blood products transfusion. The relatively high prevalence of TTV in blood donors and the large proportion of TTV infected patients with no history of transfusion of blood and blood products also suggest that alternative routes of transmission of TTV infection may exist[36]. TTV DNA has also been detected in saliva[36], throat swabs[37], breast milk[38], semen[39] and vaginal fluid[40] thus, supporting routes of transmission other than blood and blood products[33,37].

Excretion of TTV in feces of infected individuals suggests of possible fecal-oral transmission[33]. Some studies have reported placental transmission of TTV[41-43], whereas others have not detected TTV in cord blood and amniotic fluid[44-45]. These studies show the absence of transuterine transmission of TTV. Since children of TTV-infected mothers apparently tend to get infected more often and earlier after birth than children of TTV negative mothers, the role of postnatal transmission of TTV is being considered. Postnatal route of transmission from mother to child and infection via frequent social contacts seem to be very important modes of transmission in children[46-48]. Furthermore, variation in the TTV prevalence in children from 5.1% in Japan[49] to 54% in the Democratic Republic of Congo[50] is also suggestive of the possible involvement of some specific environmental factors in the acquisition of TTV infection. The sexual mode of transmission is likely of low effectiveness[51].


Infection with both TTV and TLMV has been detected in various non-human primates[2,52,53]. At the same time, there are reports showing cross-species transmission of TTV genotypes. Human TTV variants can infect chimpanzees and macaques[13,54]. Beyond primates, host range of TTV and TLMV is uncertain. One study has demonstrated frequent TTV infection of domestic animals such as cows, pigs, sheep and chickens[47]. However, it is not known how these species acquire TTV infection. Recently, highly divergent TTV like viruses were detected in pigs, cats and dogs, distinct from those found using the N22 primers[55] suggesting that this virus family may indeed be widely distributed in the mammalian order. There are reports showing high prevalence of TTV infection in captured chimpanzees and crab eating macaques[56]. These findings suggest that TTV is widespread among wild Chimpanzees living in West Africa. However, this TTV infection was found non pathogenic. Based on analysis of full-length sequence data, this TTV may represent a new TTV-like viral species or genus, although it is closely related to human TTV[56].


Regarding target organs for TTV infection, TTV-DNA has been detected by both PCR and in situ hybridization in liver and peripheral blood mononuclear cells (PBMC)[57,58]. However, these studies have shown that TTV replicates in liver, but not in PBMC. Simultaneously, TTV was detected and found with replicative intermediates in bone marrow cells from TTV infected patients[24]. This finding and few other studies[59] indicate that TTV-DNA in PBMC corresponds to viral particles passively attached to cell membrane and TTV infects hematopoietic cells but only replicate when these cells are activated. Since the percentage of circulating activated cells is very low, this may be the cause for the lack of detection of TTV replicative intermediates in freshly isolated PBMC from TTV infected patients.


The development of sensitive and reliable polymerase chain reaction (PCR) protocols allowed the detection of TTV DNA at a very high prevalence in sera of healthy populations around the world[21,22,29]. Currently, the heteroduplex mobility assay to detect multiple infections with isolates of TTV belonging to different genotypes or subtypes has also been developed. In the simplest application of heteroduplex mobility assay, heteroduplexes are formed by denaturing and reannealing mixtures of PCR amplified DNA fragments from divergent isolates of the same virus. When these products are separated on polyacrylamide gels a homoduplex band plus two slow moving heteroduplex bands are observed. The mobility of heteroduplexes is related to the genetic distance between two strands. This technique was applied earlier to HIV isolates, measles virus, CMV and hepatitis C virus. While detecting TTV DNA by PCR, it was found that repeated freezing and thawing of serum did not have much effect on stability of TTV DNA. Specimens are not required to be aliquoted for repeated testing and retrospective studies[60].

Both TTV and TLMV have sequence heterogeneity. Some TTV subtypes have less than 50% sequence identity. However, there are certain conserved regions. Primers were designed in such a way that most of the subtypes could be detected[61]. Recently, real time PCR based methods with either SYBR Green or TaqMan Probe, designed to quantitate selectively TTV and TLMV, have also been used[61].


Epidemiological studies have shown that TTV is described worldwide in various populations. The prevalence of TTV viremia in healthy adults of developed countries is in the range of 1%-34%. Prevalence reported from third world countries was found to be higher, typically 40%-70%. In people who have received multiple blood transfusions the virus is almost universally present with more than one subtype in each individual. Table 1 demonstrates the countrywide prevalence of TTV infection in different categories of populations including both healthy persons and patients with various types of diseases[62-75].

Table 1 Global prevalence of TTV infection in normal subjects and patient populations.
S.No.CountryGroupNo. testedNo. Positive (%)Reference No.
1ItalyPatients with different clinical diagnosis62
Unselected pathologies221110 (50)
Hemophillia A3324 (73)
Hemodialysis3619 (53)
HCV positive patients
Normal ALT3017 (57)
Abnormal ALT5024 (48)
Cirrhosis309 (30)
HCC138 (62)
HCV negative patients
Non-A non G hepatitis2311 (48)
Autoimmune hepatitis114 (36)
Primary liver diseases1711 (65)
Cryptogenic extrahepatic diseases
Systemic lupus erythematosus (SLE)3419 (56)
Psoriasis10256 (55)
Rheumatoid arthritis6017 (28)
2ItalyHealthy blood donors10022 (22)63
Hemophiliacs178123 (69)
HIV I infected mothers8329 (34.9)
- Intravenous drug users4621 (45.6)
- Non-intravenous drug users378 (21.6)
- Infants born to TTV298 (27.5)
infected mothers
4ItalyHIV Negative65
- Blood donors10491 (87.5)
- Chronic hepatitis C10699 (93.4)
- Hemodialysis patients100100 (100)
- Thalassemic patients3636 (100)
- IVDUs3731 (83.8)
HIV Positive
- IVDUs102102 (100)
- Homosexuals5852 (89.7)
- Heterosexuals5044 (88.0)
5ItalyHaemophiliacs217204 (94)66
6ChinaHealthy persons13629 (21.3)67
Prostitutes14046 (32.9)
7ChinaIntravenous drug users5014 (28)68
- Hemophilics5035 (70)
- Thalassemics4027 (67.5)
- Hemodialysis patients5013 (26)
Household contacts
- Spouse403 (7.5)
- Non spouse577 (12.3)
Acute hepatitis A524 (7.7)
Non A-E hepatitis
- Acute125 (41.6)
- Chronic92 (22.2)
- Fulminant115 (45.4)
Hepatitis B carriers20030 (15)
Hepatitis C carriers10036 (36)
Healthy adults10010 (10)
Healthy children12233 (2.7)
Non A-E hepatitis198 (42.1)
- Acute136 (46.1)
- Chronic31 (33.3)
- Fulminant31 (33.3)
Thalassemic children6447 (73.4)
- Transfused during cardiac surgery8037 (46.3)
- Chronic HBV carrier3010 (33.3)
- Biliary atresia325 (15.6)
9USA (Minnesota)Healthy donors with elevated ALT995 (5)70
Healthy donors with normal ALT1461 (0.7)
10JapanPatients with chronic liver disease of unknown etiology6957 (83)71
Volunteer blood donors5040 (80)
11TanzaniaRural women156115 (74)72
12IndiaSewage water638 (12.7)73
13BrazilPatients sera18448 (26)74
Patients saliva16749 (46)
14NorwayBlood donors201180 (98.6)75

From preliminary reports two characteristics of TTV infection have emerged rendering it as a potential cause of liver disease. First, Okamoto et al[3] demonstrated that TTV-DNA levels in liver tissue were equal to or 10-100 times higher than those in serum, suggesting that this virus replicated in the liver. Second, Nishizawa et al[1] reported the appearance of TTV-DNA in the sera of patients with post transfusion hepatitis of unknown etiology to display close correlation with ALT levels. Neither one of these characteristics, hepatotropism or correlation of viral titres with serum ALT, had previously been demonstrated for HGV. However, most subsequent investigations could not confirm their significance in the development of fulminant hepatitis, cryptogenic chronic liver disease and HCC. In addition, the implications of coinfection with TTV in the natural history of chronic HBV or HCV infection are also far from clear. Although TTV can be transmitted by parenteral route, its role in causing posttransfusion hepatitis has not been established[76-79]. The majority of individuals who become TTV-DNA-positive after blood transfusion usually have normal ALT and do not develop chronic hepatitis, although TTV viremia frequently persists for several years. Patients who develop chronic hepatitis are invariably coinfected with HBV or HCV and chronic hepatitis is closely correlated with HBV or HCV infection. This raises the possibility that TTV is merely an innocent bystander rather than a primary hepatitis virus.

In one of the studies[79], the rate of TTV infections was found to be significantly higher among transfused than among non-transfused patients (26.4% and 4.7%, respectively) and the risk of infection increased with the number of units transfused. The rate of TTV infections with non A-E hepatitis (23.2%) was almost identical to the rate among patients who had been transfused, but did not develop hepatitis (21.8%). Of those patients with acute hepatitis C, 40.0% were simultaneously infected with TTV and TTV did not worsen either biochemical severity or persistence of hepatitis C. In non-A-E cases, the mean ALT was comparable among those positive for TTV and those negative. Neither was there a consistent relationship between ALT and TTV-DNA level among these patients[80].

The role of TTV in acute hepatitis is another unresolved issue. In two Japanese studies[81,82] TTV-DNA was identified in 13.6%-43% of cases of non-A-E community-acquired acute hepatitis. However, these positive rates of TTV do not differ statistically from either those obtained among patients with other types of viral hepatitis or among healthy volunteers. In addition, the ALT levels do not show any difference between TTV-positive and TTV-negative patients. Furthermore, the presence of TTV infection had no apparent effect on the clinical course of patients with hepatitis A, B or C. Thus, according to these studies no correlation appears to exist between TTV infection and the clinical features of sporadic hepatitis. Contrasting another Japanese study[83], TTV-DNA was detected in 2 out of 7 (29%) patients with acute hepatitis of unknown etiology, but in none of the 4 patients with acute HCV-associated hepatitis. At least half of all cases of fulminant hepatitis are seronegative for hepatitis A-E viruses. TTV has been fond in 27%-50% of patients with fulminant hepatitis[3,16,84], but such patients probably received multiple transfusion before testing and recent TTV infection has not always been established. Therefore, it is unclear whether TTV infection is secondary to transfusion or plays an etiologic role in fulminant hepatitis.

Current data suggest that TTV is not the causative agent of chronic liver disease of unknown etiology and neither does it affect the degree of liver damage when present as a coinfection with HBV or HCV[16,77,84-86]. According to our previous study[86], for example, TTV-DNA was detected in 20% of the HBV-positive and 19.5% of the HCV-positive chronic liver disease patients, in 8.3% of seronegative chronic liver disease patients, in 8.3% of seronegative chronic hepatitis/cirrhosis patients and 7% blood donors. Yet, no significant differences between TTV infected and non-infected patients were found as to demographic data, assumed source of infection, biochemical abnormalities, or severity of liver histology. Thus, regarding etiology and progression towards serious chronic liver disease, its contribution seems to be minor if not altogether non-existent. Concerning antiviral therapy, there are no data or treatment of patients who are infected with TTV alone since the role of TTV as a cause of chronic hepatitis has yet to be determined. Studies of patients infected with both HCV and TTV who were treated with interferon showed that the responsiveness to therapy was correlated with HCV alone. In addition, certain genotypes of TTV were quite resistant to interferon although interferon effectively reduced HCV in the same patients[87].

Because the prevalence of TTV is high among patients with chronic viral hepatitis and cryptogenic liver disease, a similar situation has been anticipated to persist among patients with HCC. However, the prevalence of TTV in Thai patients with HCC has shown a wide range of divergence, for example, 6%-60% and 5%-50% in cases with HBV and HCV markers respectively, and 1%-67% in cases without HBV and HCV markers[27,88]. Our study demonstrated the majority of TTV infected HCC to harbor double or triple infections with HBV and/or HCV and the prevalence of TTV infection was comparable to that of healthy volunteers[89]. Contrasting that, another group reported TTV-DNA to occur more frequently in patients with liver cirrhosis and HCC than in those with chronic hepatitis[27]. Using a case-control study to compare the prevalence of 174 Italian patients and matched controls, it was demonstrated that individuals infected with TTV did not exhibit an increased relative risk for developing HCC[90]. Furthermore, it has been demonstrated that the TTV genome is not found integrated into host hepatocyte DNA[91], the one process that might represent a potential risk factor in the development of HCC.


Using the polymerase chain reaction (PCR), epidemiological studies have indicated a worldwide distribution of this virus, with prevalence surveys in the general population reporting values of 12% to 19% in Japan[3,92], 36% in Thailand[27], 2% to 10% in European countries[32,85] and 1% in the USA[16]. In patients on maintenance hemodialysis (HD), who are at an increased risk of parenterally transmitted hepatitis virus infection, a high prevalence (32%-53%) of TTV infection has been reported[93,94]. However, the transmission route of the virus is still unknown and the question of any association between duration of HD or previous transfusion and TTV infection is still a matter of controversy[77,95]. There is also little information about the occupational risk of TTV infection in HD unit workers. By using logistic regression analysis, it was shown that a prior blood transfusion and time on HD were not predictors of the presence of TTV-DNA, so that TTV may have a transmission route not shared by HBV, HCV or HGV. The possibility of TTV transmission, via a nosocomial route in HD units, must be considered[77]. One of the possible routes of transmission in an HD unit is direct from person to person. For this reason, the healthcare staff in the HD unit was suspected as being at high risk for TTV infection. Although a low risk of TTV infection was suggested in hospital staff, there is little information on HD unit workers[96]. TTV infection rate was not influenced by age, sex, or mean duration of dialysis[77,79,97]. Nosocomial transmission may account for TTV infection in some patients on hemodialysis[98].

TTV-DNA genotype 1 (G1) was found to be the main TTV DNA genotype in hemodialysis patients. The fact that hemodialysis patients are polytransfused makes it likely that they are at risk of multiple exposures. Therefore, it was interesting that a significant number of patients were apparently coinfected with different strains of TTV. Sequence analysis of clones from two patients with apparent mixed infections showed that TTV strains belonging to two different major genotypes could coexist in a single patient. It was suggested that infection with one TTV type does not protect against infection with another TTV type[99]. The preliminary data suggested that TTV is transmitted mainly via a parenteral route[3,85]. When TTV infection was studied in hemodialysis patients who were monitored for HCV infection, co-infection was found in 48% at enrollment. The follow-up of the renal transplant patients revealed, that the persistence of single TTV variants over a long period after organ transplant was common. Considering the heterogeneity of TTV isolates, this finding is against frequent infection with different nucleotide sequences and so horizontal spread of certain variants could have been expected. Nevertheless, in the examined patient group, permanent infections, with only single nucleotide changes in the consecutive samples of the same patient could be observed and the TTV variant detected in one patient was usually remotely related to the TTV variants infecting the others with 58%-97% nucleotide sequence identity between the variants. As a highly variable region of the TTV genome, the N22 region is a candidate to carry humoral epitopes on the surface of the virions. Mutations in this region were, however, infrequently detected. The host’s immunity is a plausible evolutionary driving force of the development of TTV genotypes and variants, which process affects most probably the hypervariable genomic regions. If so, the iatrogenic immunosuppression of the transplant recipients can contribute to the long persistence of one variant, while novel infections are infrequent[100].


Accumulating molecular and clinical evidence indicated that the effects of HIV infection can be modified by coinfection with other viruses[101-104]. However, limited information is available about the prevalence and possible pathogenic role of TTV in HIV infected patients with or without AIDS in relation to specific risk factors, and about the viral titres of TTV. Puig-Basagoiti et al[105] reported no influence of TTV infection on CD4 T cell counts and clinical or immune status in HIV-infected patients. In a recent study by Martinez et al[106], no relationship was found between TTV DNA detection and HIV category, CD4 count, HBV and HCV infection or demography features. By contrast, Christensen et al[101] reported correlation between a low CD4 T cell count and high TTV titre in Danish patients with HIV infection as well as a possible prognostic significance of TTV viral load in immunocompromised patients. High TTV viremia levels were found to be associated with decreased survival rates. A significantly higher rate of TTV positivity was noted in HIV-infected patients than in HIV-negative healthy individuals by two distinct PCR methods. Although the detectability of TTV by either of the two PCR features was as in previous studies[105,106], the relative rate of TTV DNA in the patients studied was found to be associated with the HIV viral load and CD4 cell level as well as the development of AIDS.

A series of recent reports has indicated that viral infections can influence the pattern of autoantibody expression in patients with autoimmune diseases. Neidhart and coworkers[107] demonstrated differences in the autoantibody pattern of patients with SSc with antibodies to cytomegalovirus. Other investigations showed a significantly lower prevalence of rheumatoid factors in RA patients infected with TTV, in comparison with non-infected patients. Hajeer et al[108] reported a negative correlation between anti-parvovirus B19 antibodies and rheumatoid factors in patients with RA. In several studies, the autoantibody pattern found in patients with SSc was found to be similar[109-111]. Comparison of the autoantibody patterns in virus infected and non-infected patients with SSc showed that continuing GBV-C or TTV infection or both, have no evident effect on the manifestation of autoantibodies. In conclusion, various reports showed neither a higher prevalence of GBV-C RNA and/or TTV DNA, nor changes in the pattern of expression of autoantibodies in patients with SSc. Therefore, these data provided no evidence for an association between GBV-C and/or TTV infections and SSc.

Not only the clinical significance and the pathogenesis of TTV infection but also the association between TTV infection and raised ALT values have been controversial[1,3,113]. It was found that the raised ALT values were independently related to TTV viraemia among Taiwanese who were not infected with HBV and HCV. TTV infection seemed to be responsible for raised ALT values and to hint positive hepatopathic effects. Tuveri et al suggested that TTV might be implicated in a few cases of acute and chronic non A-non G hepatitis[113]. However, Nakano et al reported that TTV was not the main causative agent of cryptogenic liver disease[114]. Further efforts at confirming the pathogenecity of hepatocyte damage by TTV are necessary. As for direct correlations between TTV and H pylori infection, TTV DNA was detected at a similar rate in patients with and without H pylori infection, and H pylori infection was detected at a similar rate in patients with and without TTV infection. Similarities of prevalence of TTV between patients with and without infection by H pylori, and prevalence of H pylori between patients with and without infection by TTV, as well as the discrepancy in age distributions between prevalence of TTV and H pylori in our patients with peptic ulcer disease indicate that no correlation exists between TTV and H pylori infection, even though the two agents have similar age distributions in the general population and similar routes of transmission have been suggested for the two agents[115]. According to one report, the high prevalence of genogroup 1 TT virus infection in patients with laryngeal cancer and its striking co-prevalence with human papilloma virus infection is biologically important in the progression of squamous cell carcinoma of the larynx[116].

TTV might replicate in the respiratory tract[117]. Also, although we found no evidence that TTV might be the direct cause of ARD, TTV loads in both nasal swabs and plasma samples were substantially higher in subjects with bronchopneumonia (BP) than in the subjects with milder ARD (laryngitis, bronchitis, and bronchiolitis), suggesting among other possibilities that TTV could be locally or systemically immunosuppressive and aggravate disease induced by other agents[117]. However, there is no information on this matter except for recent report showing an inverse relationship between TTV burdens and CD4 cell counts in patients with human immunodeficiency virus type[101,118,119].


Although liver tropism has been suggested, TTV also has been found in other organs including kidneys, prostate, mammary glands, brain, bone marrow cells (BMCs) and peripheral blood mononuclear cells (PBMCs)[3,59,120,121]. Although it is not known precisely in which cell(s) TTV replicates, TTV DNA has been detected frequently in the PBMCs[58,120] and it has also been suggested to infect and replicate in hematopoietic cells in the bone marrow[122,123]. Earlier reports had revealed that there was a higher TTV genome load in the PBMCs of cancer patients than in healthy controls (blood donors)[124]. This could have been related to immune abnormality in cancer patients when compared with the controls, thereby allowing increased TTV replication in the former.

It was demonstrated that TTV is present in the nucleus and cytoplasm of some of the PBMCs. It is possible that infection of immune cells could facilitate escape of the virus from the immune response. Concealed as a “Trojan horse”, TTV in PBMCs might serve as a reservoir of TTV for chronicity of the infection and transmission in some clinical and epidemiological settings. The observation that TTV-negative PBMCs bound considerable virus in vitro suggests that at least some TTV found associated with ex vivo derived PBMCs might be of plasma origin rather than produced by the cells themselves. We have, however, obtained evidence indicating that PHA-stimulated PBMCs support TTV replication in vitro and release substantial titres of virus into the culture fluid. TTV-related single-stranded DNA viruses such as circoviruses and parvoviruses require actively multiplying cells for productive replication[125,126]. That proliferating hematopoietic cells might be an important source for the TTV that circulates in infected individuals is suggested by findings showing that baseline TTV viremia decreased markedly in virus-positive prospective bone marrow transplant recipients after myelosuppression with cyclophosphamide and total body irradiation[122]. Whether TTV is also dependent on cell cycling for active replication remains to be formally established.

It is well known that some viruses can be activated by immune stimulation, most notably HIV, which requires lymphocyte activation for optimum replication[127,128]. In this regard, it has been shown recently that an animal circovirus related to TTV, porcine circovirus type 2 (PCV-2), can replicate to higher levels in piglets as a result of immunization with a bacterial porcine vaccine[129]. One major distinction between PCV-2 stimulated in this study and TTV is that the porcine virus is capable of causing a wasting syndrome and may do so more effectively following immune stimulation. In addition, immune suppression due to drugs or induced stress resulted in a transient increase in TTV titers in humans[130,131]. This indicated that resting PBMCs could not produce TTV, but that mitogen activated cells could be stimulated in vitro to replicate TTV. Thus, there is a suggestion that TTV levels may be related to the state of activation of the host immune system as postulated in an earlier publication[132].

Recently, replicative circular double-stranded intermediates of TTV DNA have been reported in liver and BMC[24,133]. TTV DNA has been detected by in situ hybridization in nuclei of hepatocytes from experimentally infected rhesus monkeys, indicating that TTV truly infects hepatocytes[134]. However, TTV DNA titers in sera of TTV-infected patients decreased to undetectable levels during immunosuppression following bone marrow transplantation[122]. Moreover, liver cells have been found to contain only TTV DNA and not mRNA[123], suggesting that TTV replicates in hematopoietic cells rather than liver. Southern blot analysis argues against integration of the TTV genome into the genomes of human hematopoietic tumor cells, obtained from bone marrow aspirates, lymph nodes, or human hepatocellular carcinoma[91,135]. Although, TTV DNA is frequently detected in PBMC of infected individuals[58,120], double-stranded replicative intermediates have not been detected in PBMC.

TTV, a new member of the Circoviridae family, has not been cultured in vitro and its pathogenic potential is still not clear. A cell line for isolating and cultivating TTV will significantly accelerate the research on TTV. Human lymphoblastoid cells, particularly B cells, transformed with oncovirus such as Epstein-Barr virus, may be useful for culturing TTV. Because DNA viruses are often found integrated into host genomic DNA as has been reported for hepatitis B virus[136-139], the possible integration of TTV DNA into the genome of hepatic cells was investigated. When a 2.2 kb TTV probe was used in a Southern blot analysis of liver genomic DNA, no signal was obtained. Thus, TTV DNA was not found to be integrated into hepatocyte chromosomes, and the liver apparently was not the site of TTV replication for this particular case. Similarly, Yamamoto et al[91] have reported the absence of viral replication in hepatocytes of TTV infected cases of hepatocellular carcinoma. These data, taken together, suggest that the site of TTV replication occurs in the bone marrow rather than in the hepatocytes, and that TTV infection was the cause of the aplastic anemia. Similar findings suggesting TTV replication in bone marrow have been obtained by other researchers[88].


After IFN-alpha administration with a regimen of 6 MU thrice a week for 24 wk followed by 3 MU thrice a week for 12 wk, 24 of 50 (48%) concurrent TTV-infected patients achieved complete clearance of TTV DNA 6 mo after the cessation of therapy, with 7%-8% TTV spontaneous clearance rate reported annually in previous reports[77]. Other studies indicated that IFN-alpha has a potential antiviral effect on TTV. In previous studies, IFN therapy was effective against TTV with an eradication rate of 45%-55%[140,141]. Transient disappearance of TTV viremia during IFN-alpha therapy was observed in some reports, demonstrating the direct antiviral effects of IFN-alpha on the suppression of TTV. Nevertheless, delayed TTV clearance (TTV DNA positive at E/T and negative after cessation of therapy) that had not been reported previously occurred in few patients. Delayed complete virological response was observed in chronic hepatitis B patients after the end of therapy with Thymosin alpha l[142] or IFN[143] that revealed immune modulation effects. Since TTV is a DNA virus as HBV, delayed clearance of TTV after IFN therapy may indicate that immune modulation plays an important role. The findings in the present study implied that both antiviral effects and immunomodulatory actions of IFN-alpha are important on the eradication of TTV. Further studies are needed to investigate and clarify the actual mechanism of responsiveness of TTV to IFN-alpha.

In evaluating the clinical characteristics and virological features related to clearance of TTV after IFN-alpha therapy, the viral clearance at the E/T was the only important factor associated with clearance of TTV viremia. Neither the pretreatment ALT levels nor the histopathology were predictors for TTV clearance. Besides, there was no correlation between response of HCV and TTV. All the results may indicate the difference in virologic kinetics and mechanism of IFN effects between TTV and HCV that influence the response and resistance to IFN-alpha. The ALT levels at E/T or 6 mo after cessation of treatment were not related to TTV but HCV viremia also denied the hepatopathic effects of TTV infection.


From the compilation of published reports on this newly characterized virus and its global status, it is evident that TTV is prevalent in several countries of the world. As such, it is not involved in causation of a serious problem in the body and simply acts as a bystander without much impact of its single or co-infection with other viruses. Of course, attempts are still going on to find out exact clinical implications of TTV infection. Much is already known about the molecular biology of the virus, yet there still remains a need to develop simple techniques based on molecular and immunodiagnostics to diagnose TTV infection in all categories of laboratories. This will facilitate studies on TTV in more detail and at several places to unravel mysteries related to this infection.


S- Editor Pan BR L- Editor Rippe RA E- Editor Bai SH

1.  Nishizawa T, Okamoto H, Konishi K, Yoshizawa H, Miyakawa Y, Mayumi M. A novel DNA virus (TTV) associated with elevated transaminase levels in posttransfusion hepatitis of unknown etiology. Biochem Biophys Res Commun. 1997;241:92-97.  [PubMed]  [DOI]
2.  Mushahwar IK, Erker JC, Muerhoff AS, Leary TP, Simons JN, Birkenmeyer LG, Chalmers ML, Pilot-Matias TJ, Dexai SM. Molecular and biophysical characterization of TT virus: evidence for a new virus family infecting humans. Proc Natl Acad Sci USA. 1999;96:3177-3182.  [PubMed]  [DOI]
3.  Okamoto H, Nishizawa T, Kato N, Ukita M, Ikeda H, Iizuka H, Miyakawa Y, Mayumi M. Molecular cloning and characterization of a novel DNA virus (TTV) associated with posttransfusion hepatitis of unknown etiology. Hepatol Res. 1998;10:1-16.  [PubMed]  [DOI]
4.  Miyata H, Tsunoda H, Kazi A, Yamada A, Khan MA, Murakami J, Kamahora T, Shiraki K, Hino S. Identification of a novel GC-rich 113-nucleotide region to complete the circular, single-stranded DNA genome of TT virus, the first human circovirus. J Virol. 1999;73:3582-3586.  [PubMed]  [DOI]
5.  Pringle CR. Virus taxonomy at the XIth International Congress of Virology, Sydney, Australia, 1999. Arch Virol. 1999;144:2065-2070.  [PubMed]  [DOI]
6.  Takahashi K, Iwasa Y, Hijikata M, Mishiro S. Identification of a new human DNA virus (TTV-like mini virus, TLMV) intermediately related to TT virus and chicken anemia virus. Arch Virol. 2000;145:979-993.  [PubMed]  [DOI]
7.  Tanaka Y, Primi D, Wang RY, Umemura T, Yeo AE, Mizokami M, Alter HJ, Shih JW. Genomic and molecular evolutionary analysis of a newly identified infectious agent (SEN virus) and its relationship to the TT virus family. J Infect Dis. 2001;183:359-367.  [PubMed]  [DOI]
8.  Khudyakov YE, Cong ME, Nichols B, Reed D, Dou XG, Viazov SO, Chang J, Fried MW, Williams I, Bower W. Sequence heterogeneity of TT virus and closely related viruses. J Virol. 2000;74:2990-3000.  [PubMed]  [DOI]
9.  Mushahwar IK. Recently discovered blood-borne viruses: are they hepatitis viruses or merely endosymbionts. J Med Virol. 2000;62:399-404.  [PubMed]  [DOI]
10.  Okamoto H, Takahashi M, Nishizawa T, Ukita M, Fukuda M, Tsuda F, Miyakawa Y, Mayumi M. Marked genomic heterogeneity and frequent mixed infection of TT virus demonstrated by PCR with primers from coding and noncoding regions. Virology. 1999;259:428-436.  [PubMed]  [DOI]
11.  Muljono DH, Nishizawa T, Tsuda F, Takahashi M, Okamoto H. Molecular epidemiology of TT virus (TTV) and characterization of two novel TTV genotypes in Indonesia. Arch Virol. 2001;146:1249-1266.  [PubMed]  [DOI]
12.  Okamoto H, Nishizawa T, Tawara A, Peng Y, Takahashi M, Kishimoto J, Tanaka T, Miyakawa Y, Mayumi M. Species-specific TT viruses in humans and nonhuman primates and their phylogenetic relatedness. Virology. 2000;277:368-378.  [PubMed]  [DOI]
13.  Takahashi K, Hijikata M, Samokhvalov EI, Mishiro S. Full or near full length nucleotide sequences of TT virus variants (Types SANBAN and YONBAN) and the TT virus-like mini virus. Intervirology. 2000;43:119-123.  [PubMed]  [DOI]
14.  Biagini P, Gallian P, Attoui H, Touinssi M, Cantaloube J, de Micco P, de Lamballerie X. Genetic analysis of full-length genomes and subgenomic sequences of TT virus-like mini virus human isolates. J Gen Virol. 2001;82:379-383.  [PubMed]  [DOI]
15.  Biagini P, Gallian P, Cantaloube JF, De Micco P, de Lamballerie X. Presence of TT virus in French blood donors and intravenous drug users. J Hepatol. 1998;29:684-685.  [PubMed]  [DOI]
16.  Charlton M, Adjei P, Poterucha J, Zein N, Moore B, Therneau T, Krom R, Wiesner R. TT-virus infection in North American blood donors, patients with fulminant hepatic failure, and cryptogenic cirrhosis. Hepatology. 1998;28:839-842.  [PubMed]  [DOI]
17.  MacDonald DM, Scott GR, Clutterbuck D, Simmonds P. Infrequent detection of TT virus infection in intravenous drug users, prostitutes, and homosexual men. J Infect Dis. 1999;179:686-689.  [PubMed]  [DOI]
18.  Biagini P, Gallian P, Attoui H, Cantaloube JF, de Micco P, de Lamballerie X. Determination and phylogenetic analysis of partial sequences from TT virus isolates. J Gen Virol. 1999;80:419-424.  [PubMed]  [DOI]
19.  Tanaka Y, Mizokami M, Orito E, Ohno T, Nakano T, Kato T, Kato H, Mukaide M, Park YM, Kim BS. New genotypes of TT virus (TTV) and a genotyping assay based on restriction fragment length polymorphism. FEBS Lett. 1998;437:201-206.  [PubMed]  [DOI]
20.  Viazov S, Ross RS, Niel C, de Oliveira JM, Varenholz C, Da Villa G, Roggendorf M. Sequence variability in the putative coding region of TT virus: evidence for two rather than several major types. J Gen Virol. 1998;79:3085-3089.  [PubMed]  [DOI]
21.  Takahashi K, Hoshino H, Ohta Y, Yoshida N, Mishiro S. Very high prevalence of TT virus (TTV) infection in general population of Japan revealed by a new set of PCR primers. Hepatol Res. 1998;12:233-239.  [PubMed]  [DOI]
22.  Niel C, de Oliveira JM, Ross RS, Gomes SA, Roggendorf M, Viazov S. High prevalence of TT virus infection in Brazilian blood donors. J Med Virol. 1999;57:259-263.  [PubMed]  [DOI]
23.  Kamahora T, Hino S, Miyata H. Three spliced mRNAs of TT virus transcribed from a plasmid containing the entire genome in COS1 cells. J Virol. 2000;74:9980-9986.  [PubMed]  [DOI]
24.  Okamoto H, Takahashi M, Nishizawa T, Tawara A, Sugai Y, Sai T, Tanaka T, Tsuda F. Replicative forms of TT virus DNA in bone marrow cells. Biochem Biophys Res Commun. 2000;270:657-662.  [PubMed]  [DOI]
25.  Takahashi K, Ohta Y, Mishiro S. Partial 2.4-kb sequences of TT virus (TTV) genome from eight Japanese isolates: diagnostic and phylogenetic implications. Hepatol Res. 1998;12:111-120.  [PubMed]  [DOI]
26.  Hijikata M, Takahashi K, Mishiro S. Complete circular DNA genome of a TT virus variant (isolate name SANBAN) and 44 partial ORF2 sequences implicating a great degree of diversity beyond genotypes. Virology. 1999;260:17-22.  [PubMed]  [DOI]
27.  Tanaka H, Okamoto H, Luengrojanakul P, Chainuvati T, Tsuda F, Tanaka T, Miyakawa Y, Mayumi M. Infection with an unenveloped DNA virus (TTV) associated with posttransfusion non-A to G hepatitis in hepatitis patients and healthy blood donors in Thailand. J Med Virol. 1998;56:234-238.  [PubMed]  [DOI]
28.  Takayama S, Yamazaki S, Matsuo S, Sugii S. Multiple infection of TT virus (TTV) with different genotypes in Japanese hemophiliacs. Biochem Biophys Res Commun. 1999;256:208-211.  [PubMed]  [DOI]
29.  Leary TP, Erker JC, Chalmers ML, Desai SM, Mushahwar IK. Improved detection systems for TT virus reveal high prevalence in humans, non-human primates and farm animals. J Gen Virol. 1999;80:2115-2120.  [PubMed]  [DOI]
30.  Verschoor EJ, Langenhuijzen S, Heeney JL. TT viruses (TTV) of non-human primates and their relationship to the human TTV genotypes. J Gen Virol. 1999;80:2491-2499.  [PubMed]  [DOI]
31.  Okamoto H, Nishizawa T, Ukita M, Takahashi M, Fukuda M, Iizuka H, Miyakawa Y, Mayumi M. The entire nucleotide sequence of a TT virus isolate from the United States (TUS01): comparison with reported isolates and phylogenetic analysis. Virology. 1999;259:437-448.  [PubMed]  [DOI]
32.  Simmonds P, Davidson F, Lycett C, Prescott LE, MacDonald DM, Ellender J, Yap PL, Ludlam CA, Haydon GH, Gillon J. Detection of a novel DNA virus (TTV) in blood donors and blood products. Lancet. 1998;352:191-195.  [PubMed]  [DOI]
33.  Okamoto H, Akahane Y, Ukita M, Fukuda M, Tsuda F, Miyakawa Y, Mayumi M. Fecal excretion of a nonenveloped DNA virus (TTV) associated with posttransfusion non-A-G hepatitis. J Med Virol. 1998;56:128-132.  [PubMed]  [DOI]
34.  Ukita M, Okamoto H, Kato N, Miyakawa Y, Mayumi M. Excretion into bile of a novel unenveloped DNA virus (TT virus) associated with acute and chronic non-A-G hepatitis. J Infect Dis. 1999;179:1245-1248.  [PubMed]  [DOI]
35.  Desai SM, Muerhoff AS, Leary TP, Erker JC, Simons JN, Chalmers ML, Birkenmeyer LG, Pilot-Matias TJ, Mushahwar IK. Prevalence of TT virus infection in US blood donors and populations at risk for acquiring parenterally transmitted viruses. J Infect Dis. 1999;179:1242-1244.  [PubMed]  [DOI]
36.  Ross RS, Viazov S, Runde V, Schaefer UW, Roggendorf M. Detection of TT virus DNA in specimens other than blood. J Clin Virol. 1999;13:181-184.  [PubMed]  [DOI]
37.  Ishikawa T, Hamano Y, Okamoto H. Frequent detection of TT virus in throat swabs of pediatric patients. Infection. 1999;27:298.  [PubMed]  [DOI]
38.  Schröter M, Polywka S, Zöllner B, Schäfer P, Laufs R, Feucht HH. Detection of TT virus DNA and GB virus type C/Hepatitis G virus RNA in serum and breast milk: determination of mother-to-child transmission. J Clin Microbiol. 2000;38:745-747.  [PubMed]  [DOI]
39.  Inami T, Konomi N, Arakawa Y, Abe K. High prevalence of TT virus DNA in human saliva and semen. J Clin Microbiol. 2000;38:2407-2408.  [PubMed]  [DOI]
40.  Fornai C, Maggi F, Vatteroni ML, Pistello M, Bendinelli M. High prevalence of TT virus (TTV) and TTV-like minivirus in cervical swabs. J Clin Microbiol. 2001;39:2022-2024.  [PubMed]  [DOI]
41.  Gerner P, Oettinger R, Gerner W, Falbrede J, Wirth S. Mother-to-infant transmission of TT virus: prevalence, extent and mechanism of vertical transmission. Pediatr Infect Dis J. 2000;19:1074-1077.  [PubMed]  [DOI]
42.  Goto K, Sugiyama K, Ando T, Mizutani F, Terabe K, Tanaka K, Nishiyama M, Wada Y. Detection rates of TT virus DNA in serum of umbilical cord blood, breast milk and saliva. Tohoku J Exp Med. 2000;191:203-207.  [PubMed]  [DOI]
43.  Morrica A, Maggi F, Vatteroni ML, Fornai C, Pistello M, Ciccorossi P, Grassi E, Gennazzani A, Bendinelli M. TT virus: evidence for transplacental transmission. J Infect Dis. 2000;181:803-804.  [PubMed]  [DOI]
44.  Iso K, Suzuki Y, Takayama M. Mother-to-infant transmission of TT virus in Japan. Int J Gynaecol Obstet. 2001;75:11-19.  [PubMed]  [DOI]
45.  Ohto H, Ujiie N, Takeuchi C, Sato A, Hayashi A, Ishiko H, Nishizawa T, Okamoto H. TT virus infection during childhood. Transfusion. 2002;42:892-898.  [PubMed]  [DOI]
46.  Hsieh SY, Wu YH, Ho YP, Tsao KC, Yeh CT, Liaw YF. High prevalence of TT virus infection in healthy children and adults and in patients with liver disease in Taiwan. J Clin Microbiol. 1999;37:1829-1831.  [PubMed]  [DOI]
47.  Simmonds P, Prescott LE, Logue C, Davidson F, Thomas AE, Ludlam CA. TT virus--part of the normal human flora. J Infect Dis. 1999;180:1748-1750.  [PubMed]  [DOI]
48.  Saback FL, Gomes SA, de Paula VS, da Silva RR, Lewis-Ximenez LL, Niel C. Age-specific prevalence and transmission of TT virus. J Med Virol. 1999;59:318-322.  [PubMed]  [DOI]
49.  Goto K, Sugiyama K, Terabe K, Mizutani F, Wada Y. Detection rates of TT virus among children who visited a general hospital in Japan. J Med Virol. 1999;57:405-407.  [PubMed]  [DOI]
50.  Davidson F, MacDonald D, Mokili JL, Prescott LE, Graham S, Simmonds P. Early acquisition of TT virus (TTV) in an area endemic for TTV infection. J Infect Dis. 1999;179:1070-1076.  [PubMed]  [DOI]
51.  Saláková M, Nemecek V, König J, Tachezy R. Age-specific prevalence, transmission and phylogeny of TT virus in the Czech Republic. BMC Infect Dis. 2004;4:56.  [PubMed]  [DOI]
52.  Abe K, Inami T, Ishikawa K, Nakamura S, Goto S. TT virus infection in nonhuman primates and characterization of the viral genome: identification of simian TT virus isolates. J Virol. 2000;74:1549-1553.  [PubMed]  [DOI]
53.  Okamoto H, Nishizawa T, Takahashi M, Tawara A, Peng Y, Kishimoto J, Wang Y. Genomic and evolutionary characterization of TT virus (TTV) in tupaias and comparison with species-specific TTVs in humans and non-human primates. J Gen Virol. 2001;82:2041-2050.  [PubMed]  [DOI]
54.  Tawara A, Akahane Y, Takahashi M, Nishizawa T, Ishikawa T, Okamoto H. Transmission of human TT virus of genotype 1a to chimpanzees with fecal supernatant or serum from patients with acute TTV infection. Biochem Biophys Res Commun. 2000;278:470-476.  [PubMed]  [DOI]
55.  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.  [PubMed]  [DOI]
56.  Inami T, Obara T, Moriyama M, Arakawa Y, Abe K. Full-length nucleotide sequence of a simian TT virus isolate obtained from a chimpanzee: evidence for a new TT virus-like species. Virology. 2000;277:330-335.  [PubMed]  [DOI]
57.  López-Alcorocho JM, Mariscal LF, de Lucas S, Rodríguez-Iñigo E, Casqueiro M, Castillo I, Bartolomé J, Herrero M, Manzano ML, Pardo M. Presence of TTV DNA in serum, liver and peripheral blood mononuclear cells from patients with chronic hepatitis. J Viral Hepat. 2000;7:440-447.  [PubMed]  [DOI]
58.  Okamura A, Yoshioka M, Kubota M, Kikuta H, Ishiko H, Kobayashi K. Detection of a novel DNA virus (TTV) sequence in peripheral blood mononuclear cells. J Med Virol. 1999;58:174-177.  [PubMed]  [DOI]
59.  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;301:121-129.  [PubMed]  [DOI]
60.  Durmaz R, Otlu B, Direkel S. Effect of multiple freezing and thawing of serum on TT virus and hepatitis B virus DNA positivity. Arch Virol. 2002;147:515-518.  [PubMed]  [DOI]
61.  Maggi F, Fornai C, Morrica A, Casula F, Vatteroni ML, Marchi S, Ciccorossi P, Riente L, Pistello M, Bendinelli M. High prevalence of TT virus viremia in italian patients, regardless of age, clinical diagnosis, and previous interferon treatment. J Infect Dis. 1999;180:838-842.  [PubMed]  [DOI]
62.  Chen BP, Rumi MG, Colombo M, Lin YH, Ramaswamy L, Luna J, Liu JK, Prati D, Mannucci PM. TT virus is present in a high frequency of Italian hemophilic patients transfused with plasma-derived clotting factor concentrates. Blood. 1999;94:4333-4336.  [PubMed]  [DOI]
63.  de Martino M, Moriondo M, Azzari C, Resti M, Galli L, Vierucci A. TT virus infection in human immunodeficiency virus type 1 infected mothers and their infants. J Med Virol. 2000;61:347-351.  [PubMed]  [DOI]
64.  Zehender G, Manzin A, De Maddalena C, Colasante C, Solforosi L, Corsi F, Bianchi-Bosisio A, Girotto M, Schirru I, Russo U. Molecular epidemiology of TT virus in Italy and phylogenesis of viral isolates from subjects at different risk for parenteral exposure. J Med Virol. 2001;63:76-84.  [PubMed]  [DOI]
65.  Pistello M, Morrica A, Maggi F, Vatteroni ML, Freer G, Fornai C, Casula F, Marchi S, Ciccorossi P, Rovero P. TT virus levels in the plasma of infected individuals with different hepatic and extrahepatic pathology. J Med Virol. 2001;63:189-195.  [PubMed]  [DOI]
66.  Huang YH, Wu JC, Lin CC, Sheng WY, Lee PC, Wang YJ, Chang FY, Lee SD. Prevalence and risk factor analysis of TTV infection in prostitutes. J Med Virol. 2000;60:393-395.  [PubMed]  [DOI]
67.  Kao JH, Chen W, Hsiang SC, Chen PJ, Lai MY, Chen DS. Prevalence and implication of TT virus infection: minimal role in patients with non-A-E hepatitis in Taiwan. J Med Virol. 1999;59:307-312.  [PubMed]  [DOI]
68.  Hsu HY, Ni YH, Chen HL, Kao JH, Chang MH. TT virus infection in healthy children, children after blood transfusion, and children with non-A to E hepatitis or other liver diseases in Taiwan. J Med Virol. 2003;69:66-71.  [PubMed]  [DOI]
69.  Cleavinger PJ, Persing DH, Li H, Moore SB, Charlton MR, Sievers C, Therneau TM, Zein NN. Prevalence of TT virus infection in blood donors with elevated ALT in the absence of known hepatitis markers. Am J Gastroenterol. 2000;95:772-776.  [PubMed]  [DOI]
70.  Nishiguchi S, Enomoto M, Shiomi S, Tanaka M, Fukuda K, Tamori A, Tanaka T, Takeda T, Seki S, Yano Y. TT virus infection in patients with chronic liver disease of unknown etiology. J Med Virol. 2000;62:392-398.  [PubMed]  [DOI]
71.  Stark K, Poggensee G, Höhne M, Bienzle U, Kiwelu I, Schreier E. Seroepidemiology of TT virus, GBC-C/HGV, and hepatitis viruses B, C, and E among women in a rural area of Tanzania. J Med Virol. 2000;62:524-530.  [PubMed]  [DOI]
72.  Vaidya SR, Chitambar SD, Arankalle VA. Polymerase chain reaction-based prevalence of hepatitis A, hepatitis E and TT viruses in sewage from an endemic area. J Hepatol. 2002;37:131-136.  [PubMed]  [DOI]
73.  Vasconcelos HC, Gomes SA, Cataldo M, Niel C. Prevalence and genetic diversity of TT virus genotype 21 (YONBAN virus) in Brazil. Arch Virol. 2003;148:517-529.  [PubMed]  [DOI]
74.  Moen EM, Huang L, Grinde B. Molecular epidemiology of TTV-like mini virus in Norway. Arch Virol. 2002;147:181-185.  [PubMed]  [DOI]
75.  Moen EM, Sleboda J, Grinde B. Real-time PCR methods for independent quantitation of TTV and TLMV. J Virol Methods. 2002;104:59-67.  [PubMed]  [DOI]
76.  Prati D, Lin YH, De Mattei C, Liu JK, Farma E, Ramaswamy L, Zanella A, Lee H, Rebulla P, Allain JP. A prospective study on TT virus infection in transfusion-dependent patients with beta-thalassemia. Blood. 1999;93:1502-1505.  [PubMed]  [DOI]
77.  Oguchi T, Tanaka E, Orii K, Kobayashi M, Hora K, Kiyosawa K. Transmission of and liver injury by TT virus in patients on maintenance hemodialysis. J Gastroenterol. 1999;34:234-240.  [PubMed]  [DOI]
78.  Kobayashi M, Chayama K, Arase Y, Kobayashi M, Tsubota A, Suzuki Y, Koida I, Saitoh S, Murashima N, Ikeda K. Prevalence of TT virus before and after blood transfusion in patients with chronic liver disease treated surgically for hepatocellular carcinoma. J Gastroenterol Hepatol. 1999;14:358-363.  [PubMed]  [DOI]
79.  Matsumoto A, Yeo AE, Shih JW, Tanaka E, Kiyosawa K, Alter HJ. Transfusion-associated TT virus infection and its relationship to liver disease. Hepatology. 1999;30:283-288.  [PubMed]  [DOI]
80.  Vimolket T, Theamboonlers A, Jantaradsamee P, Seksarn P, Hirsch P, Poovorawan Y. Clearance of hepatitis TT virus infection among thalassemia children and IVDU. Southeast Asian J Trop Med Public Health. 1999;30:269-272.  [PubMed]  [DOI]
81.  Fukuda Y, Nakano I, Katano Y, Kumada T, Hayashi K, Nakano S, Hayakawa T. TT virus (TTV) is not associated with acute sporadic hepatitis. Infection. 1999;27:125-127.  [PubMed]  [DOI]
82.  Kanda T, Yokosuka O, Ikeuchi T, Seta T, Kawai S, Imazeki F, Saisho H. The role of TT virus infection in acute viral hepatitis. Hepatology. 1999;29:1905-1908.  [PubMed]  [DOI]
83.  Ikeda H, Takasu M, Inoue K, Okamoto H, Miyakawa Y, Mayumi M. Infection with an unenveloped DNA virus (TTV) in patients with acute or chronic liver disease of unknown etiology and in those positive for hepatitis C virus RNA. J Hepatol. 1999;30:205-212.  [PubMed]  [DOI]
84.  Giménez-Barcons M, Forns X, Ampurdanés S, Guilera M, Soler M, Soguero C, Sánchez-Fueyo A, Mas A, Bruix J, Sánchez-Tapias JM. Infection with a novel human DNA virus (TTV) has no pathogenic significance in patients with liver diseases. J Hepatol. 1999;30:1028-1034.  [PubMed]  [DOI]
85.  Naoumov NV, Petrova EP, Thomas MG, Williams R. Presence of a newly described human DNA virus (TTV) in patients with liver disease. Lancet. 1998;352:195-197.  [PubMed]  [DOI]
86.  Viazov S, Ross RS, Varenholz C, Lange R, Holtmann M, Niel C, Roggendorf M. Lack of evidence for an association between TTV infection and severe liver disease. J Clin Virol. 1998;11:183-187.  [PubMed]  [DOI]
87.  Tangkijvanich P, Theamboonlers A, Hirsch P, Kullavanijaya P, Suwangool P, Poovorawan Y. TT virus infection in chronic liver disease. Hepatogastroenterology. 1999;46:1053-1058.  [PubMed]  [DOI]
88.  Chayama K, Kobayashi M, Tsubota A, Kobayashi M, Arase Y, Suzuki Y, Saitoh S, Murashima N, Ikeda K, Okamoto K. Susceptibility of TT virus to interferon therapy. J Gen Virol. 1999;80:631-634.  [PubMed]  [DOI]
89.  Tangkijvanich P, Hirsch P, Theamboonlers A, Nuchprayoon I, Poovorawan Y. Association of hepatitis viruses with hepatocellular carcinoma in Thailand. J Gastroenterol. 1999;34:227-233.  [PubMed]  [DOI]
90.  Tagger A, Donato F, Ribero ML, Binelli G, Gelatti U, Portera G, Albertini A, Fasola M, Chiesa R, Nardi G. A case-control study on a novel DNA virus (TT virus) infection and hepatocellular carcinoma. The Brescia HCC Study. Hepatology. 1999;30:294-299.  [PubMed]  [DOI]
91.  Yamamoto T, Kajino K, Ogawa M, Gotoh I, Matsuoka S, Suzuki K, Moriyama M, Okubo H, Kudo M, Arakawa Y. Hepatocellular carcinomas infected with the novel TT DNA virus lack viral integration. Biochem Biophys Res Commun. 1998;251:339-343.  [PubMed]  [DOI]
92.  Nagano K, Fukuda Y, Yokozaki S, Okada K, Tanaka K, Funahashi K, Hayakawa T. Low risk of TT virus (TTV) infection in medical workers. J Hosp Infect. 1999;42:243-246.  [PubMed]  [DOI]
93.  Gallian P, Berland Y, Olmer M, Raccah D, de Micco P, Biagini P, Simon S, Bouchouareb D, Mourey C, Roubicek C. TT virus infection in French hemodialysis patients: study of prevalence and risk factors. J Clin Microbiol. 1999;37:2538-2542.  [PubMed]  [DOI]
94.  Forns X, Hegerich P, Darnell A, Emerson SU, Purcell RH, Bukh J. High prevalence of TT virus (TTV) infection in patients on maintenance hemodialysis: frequent mixed infections with different genotypes and lack of evidence of associated liver disease. J Med Virol. 1999;59:313-317.  [PubMed]  [DOI]
95.  Ikeuchi T, Okuda K, Yokosuka O, Kanda T, Kobayashi S, Murata M, Hayashi H, Yokozeki K, Ohtake Y, Kashima T. Superinfection of TT virus and hepatitis C virus among chronic haemodialysis patients. J Gastroenterol Hepatol. 1999;14:796-800.  [PubMed]  [DOI]
96.  Shibuya A, Satomichi A, Takeuchi A, Saigenji K, Sakurai K, Kobayashi N, Yoshida A. Transfusion transmitted virus infection in patients on maintenance haemodialysis and in hospital workers. J Hosp Infect. 2001;47:277-281.  [PubMed]  [DOI]
97.  Utsunomiya S, Yoshioka K, Wakita T, Seno H, Takagi K, Ishigami M, Yano M, Watanabe K, Kobayashi M, Watanabe K. TT virus infection in hemodialysis patients. Am J Gastroenterol. 1999;94:3567-3570.  [PubMed]  [DOI]
98.  Kanamoto-Tanaka Y, Furusyo N, Nakashima H, Etoh Y, Kashiwagi S, Hayashi J. TT-virus infection in Japanese general population and in hemodialysis patients. Dig Dis Sci. 2002;47:1915-1920.  [PubMed]  [DOI]
99.  Yuki N, Kato M, Masuzawa M, Ishida H, Inoue T, Tabata T, Matsushita Y, Kishimoto H, Sasaki Y, Hayashi N. Clinical implications of coinfection with a novel DNA virus (TTV) in hepatitis C virus carriers on maintenance hemodialysis. J Med Virol. 1999;59:431-436.  [PubMed]  [DOI]
100.  Szládek G, Juhász A, Asztalos L, Szöke K, Murvai M, Szarka K, Veress G, Gergely L, Kónya J. Persisting TT virus (TTV) genogroup 1 variants in renal transplant recipients. Arch Virol. 2003;148:841-851.  [PubMed]  [DOI]
101.  Christensen JK, Eugen-Olsen J, SŁrensen M, Ullum H, Gjedde SB, Pedersen BK, Nielsen JO, Krogsgaard K. Prevalence and prognostic significance of infection with TT virus in patients infected with human immunodeficiency virus. J Infect Dis. 2000;181:1796-1799.  [PubMed]  [DOI]
102.  Cribier B, Schmitt C, Rey D, Uhl G, Lang JM, Vetter D, Kirn A, Stoll-Keller F. HIV increases hepatitis C viraemia irrespective of the hepatitis C virus genotype. Res Virol. 1997;148:267-271.  [PubMed]  [DOI]
103.  Ockenga J, Tillmann HL, Trautwein C, Stoll M, Manns MP, Schmidt RE. Hepatitis B and C in HIV-infected patients. Prevalence and prognostic value. J Hepatol. 1997;27:18-24.  [PubMed]  [DOI]
104.  Woitas RP, Rockstroh JK, Beier I, Jung G, Kochan B, Matz B, Brackmann HH, Sauerbruch T, Spengler U. Antigen-specific cytokine response to hepatitis C virus core epitopes in HIV/hepatitis C virus-coinfected patients. AIDS. 1999;13:1313-1322.  [PubMed]  [DOI]
105.  Puig-Basagoiti F, Cabana M, Guilera M, Giménez-Barcons M, Sirera G, Tural C, Clotet B, Sánchez-Tapias JM, Rodés J, Saiz JC. Prevalence and route of transmission of infection with a novel DNA virus (TTV), hepatitis C virus, and hepatitis G virus in patients infected with HIV. J Acquir Immune Defic Syndr. 2000;23:89-94.  [PubMed]  [DOI]
106.  Martínez NM, García F, García F, Alvarez M, Bernal MC, Piédrola G, Hernández J, Maroto MC. TT virus DNA in serum, peripheral blood mononuclear cells and semen of patients infected by HIV. AIDS. 2000;14:1464-1466.  [PubMed]  [DOI]
107.  Neidhart M, Kuchen S, Distler O, Brühlmann P, Michel BA, Gay RE, Gay S. Increased serum levels of antibodies against human cytomegalovirus and prevalence of autoantibodies in systemic sclerosis. Arthritis Rheum. 1999;42:389-392.  [PubMed]  [DOI]
108.  Hajeer AH, MacGregor AJ, Rigby AS, Ollier WE, Carthy D, Silman AJ. Influence of previous exposure to human parvovirus B19 infection in explaining susceptibility to rheumatoid arthritis: an analysis of disease discordant twin pairs. Ann Rheum Dis. 1994;53:137-139.  [PubMed]  [DOI]
109.  Genth E, Mierau R. [Diagnostic significance of scleroderma and myositis-associated autoantibodies]. Z Rheumatol. 1995;54:39-49.  [PubMed]  [DOI]
110.  Spencer-Green G, Alter D, Welch HG. Test performance in systemic sclerosis: anti-centromere and anti-Scl-70 antibodies. Am J Med. 1997;103:242-248.  [PubMed]  [DOI]
111.  Font J, Tàssies D, García-Carrasco M, Ramos-Casals M, Cervera R, Reverter JC, Sánchez-Tapias JM, Mazzara R, Ingelmo M. Hepatitis G virus infection in primary Sjögren's syndrome: analysis in a series of 100 patients. Ann Rheum Dis. 1998;57:42-44.  [PubMed]  [DOI]
112.  Takayama S, Miura T, Matsuo S, Taki M, Sugii S. Prevalence and persistence of a novel DNA TT virus (TTV) infection in Japanese haemophiliacs. Br J Haematol. 1999;104:626-629.  [PubMed]  [DOI]
113.  Tuveri R, Jaffredo F, Lunel F, Nalpa B, Pol S, Feray C, Marcellin P, Thibault V, Delagneau JF, Opolon P. Impact of TT virus infection in acute and chronic, viral- and non viral-related liver diseases. J Hepatol. 2000;33:121-127.  [PubMed]  [DOI]
114.  Nakano T, Park YM, Mizokami M, Choi JY, Orito E, Ohno T, Kato T, Kondo Y, Tanaka Y, Kato H. TT virus infection among blood donors and patients with non-B, non-C liver diseases in Korea. J Hepatol. 1999;30:389-393.  [PubMed]  [DOI]
115.  Toyoda H, Nomura C, Watanabe M, Takahama K, Hobara R, Yokozaki S, Fukuda Y, Nakano H. Investigation of the association between infection with Helicobacter pylori and with TT virus, a novel DNA virus, in patients with gastroduodenal ulcer or ulcer scar. Eur J Gastroenterol Hepatol. 2000;12:1289-1293.  [PubMed]  [DOI]
116.  Szládek G, Juhász A, Kardos G, Szoke K, Major T, Sziklai I, Tar I, Márton I, Kónya J, Gergely L. High co-prevalence of genogroup 1 TT virus and human papillomavirus is associated with poor clinical outcome of laryngeal carcinoma. J Clin Pathol. 2005;58:402-405.  [PubMed]  [DOI]
117.  Maggi F, Pifferi M, Fornai C, Andreoli E, Tempestini E, Vatteroni M, Presciuttini S, Marchi S, Pietrobelli A, Boner A. TT virus in the nasal secretions of children with acute respiratory diseases: relations to viremia and disease severity. J Virol. 2003;77:2418-2425.  [PubMed]  [DOI]
118.  Shibayama T, Masuda G, Ajisawa A, Takahashi M, Nishizawa T, Tsuda F, Okamoto H. Inverse relationship between the titre of TT virus DNA and the CD4 cell count in patients infected with HIV. AIDS. 2001;15:563-570.  [PubMed]  [DOI]
119.  Touinssi M, Gallian P, Biagini P, Attoui H, Vialettes B, Berland Y, Tamalet C, Dhiver C, Ravaux I, De Micco P. TT virus infection: prevalence of elevated viraemia and arguments for the immune control of viral load. J Clin Virol. 2001;21:135-141.  [PubMed]  [DOI]
120.  Okamoto H, Kato N, Iizuka H, Tsuda F, Miyakawa Y, Mayumi M. Distinct genotypes of a nonenveloped DNA virus associated with posttransfusion non-A to G hepatitis (TT virus) in plasma and peripheral blood mononuclear cells. J Med Virol. 1999;57:252-258.  [PubMed]  [DOI]
121.  Pineau P, Meddeb M, Raselli R, Qin LX, Terris B, Tang ZY, Tiollais P, Mazzaferro V, Dejean A. Effect of TT virus infection on hepatocellular carcinoma development: results of a Euro-Asian survey. J Infect Dis. 2000;181:1138-1142.  [PubMed]  [DOI]
122.  Kanda Y, Tanaka Y, Kami M, Saito T, Asai T, Izutsu K, Yuji K, Ogawa S, Honda H, Mitani K. TT virus in bone marrow transplant recipients. Blood. 1999;93:2485-2490.  [PubMed]  [DOI]
123.  Kikuchi K, Miyakawa H, Abe K, Kako M, Katayama K, Fukushi S, Mishiro S. Indirect evidence of TTV replication in bone marrow cells, but not in hepatocytes, of a subacute hepatitis/aplastic anemia patient. J Med Virol. 2000;61:165-170.  [PubMed]  [DOI]
124.  Zhong S, Chan JY, Yeo W, Tam JS, Johnson PJ. Hepatitis B envelope protein mutants in human hepatocellular carcinoma tissues. J Viral Hepat. 1999;6:195-202.  [PubMed]  [DOI]
125.  Allan GM, McNeilly F, Foster JC, Adair BM. Infection of leucocyte cell cultures derived from different species with pig circovirus. Vet Microbiol. 1994;41:267-279.  [PubMed]  [DOI]
126.  Berns KI. Parvovirus replication. Microbiol Rev. 1990;54:316-329.  [PubMed]  [DOI]
127.  Fauci AS. Multifactorial nature of human immunodeficiency virus disease: implications for therapy. Science. 1993;262:1011-1018.  [PubMed]  [DOI]
128.  Bentwich Z, Kalinkovich A, Weisman Z. Immune activation is a dominant factor in the pathogenesis of African AIDS. Immunol Today. 1995;16:187-191.  [PubMed]  [DOI]
129.  Kyriakis SC, Saoulidis K, Lekkas S, Miliotis ChC, Papoutsis PA, Kennedy S. The effects of immuno-modulation on the clinical and pathological expression of postweaning multisystemic wasting syndrome. J Comp Pathol. 2002;126:38-46.  [PubMed]  [DOI]
130.  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;70:177-182.  [PubMed]  [DOI]
131.  Maggi F, Fornai C, Zaccaro L, Morrica A, Vatteroni ML, Isola P, Marchi S, Ricchiuti A, Pistello M, Bendinelli M. TT virus (TTV) loads associated with different peripheral blood cell types and evidence for TTV replication in activated mononuclear cells. J Med Virol. 2001;64:190-194.  [PubMed]  [DOI]
132.  Maggi F, Marchi S, Fornai C, Tempestini E, Andreoli E, Lanini L, Vatteroni ML, Bellini M, De Bortoli N, Costa F. Relationship of TT virus and Helicobacter pylori infections in gastric tissues of patients with gastritis. J Med Virol. 2003;71:160-165.  [PubMed]  [DOI]
133.  Okamoto H, Ukita M, Nishizawa T, Kishimoto J, Hoshi Y, Mizuo H, Tanaka T, Miyakawa Y, Mayumi M. Circular double-stranded forms of TT virus DNA in the liver. J Virol. 2000;74:5161-5167.  [PubMed]  [DOI]
134.  Luo K, Liang W, He H, Yang S, Wang Y, Xiao H, Liu D, Zhang L. Experimental infection of nonenveloped DNA virus (TTV) in rhesus monkey. J Med Virol. 2000;61:159-164.  [PubMed]  [DOI]
135.  Tanaka Y, Mizokami M, Orito E, Ohno T, Nakano T, Kato T, Iida S, Ueda R. Lack of integrated TT virus (TTV) genomes in cellular DNA in infected human hematopoietic cells. Leuk Lymphoma. 2000;38:411-417.  [PubMed]  [DOI]
136.  Brechot C, Pourcel C, Louise A, Rain B, Tiollais P. Presence of integrated hepatitis B virus DNA sequences in cellular DNA of human hepatocellular carcinoma. Nature. 1980;286:533-535.  [PubMed]  [DOI]
137.  Chakraborty PR, Ruiz-Opazo N, Shouval D, Shafritz DA. Identification of integrated hepatitis B virus DNA and expression of viral RNA in an HBsAg-producing human hepatocellular carcinoma cell line. Nature. 1980;286:531-533.  [PubMed]  [DOI]
138.  Edman JC, Gray P, Valenzuela P, Rall LB, Rutter WJ. Integration of hepatitis B virus sequences and their expression in a human hepatoma cell. Nature. 1980;286:535-538.  [PubMed]  [DOI]
139.  Shafritz DA, Shouval D, Sherman HI, Hadziyannis SJ, Kew MC. Integration of hepatitis B virus DNA into the genome of liver cells in chronic liver disease and hepatocellular carcinoma. Studies in percutaneous liver biopsies and post-mortem tissue specimens. N Engl J Med. 1981;305:1067-1073.  [PubMed]  [DOI]
140.  Akahane Y, Sakamoto M, Miyazaki Y, Okada S, Inoue T, Ukita M, Okamoto H, Miyakawa Y, Mayumi M. Effect of interferon on a nonenveloped DNA virus (TT virus) associated with acute and chronic hepatitis of unknown etiology. J Med Virol. 1999;58:196-200.  [PubMed]  [DOI]
141.  Hagiwara H, Hayashi N, Mita E, Oshita M, Kobayashi I, Iio S, Hiramatsu N, Sasaki Y, Kasahara A, Kakinuma K. Influence of transfusion-transmitted virus infection on the clinical features and response to interferon therapy in Japanese patients with chronic hepatitis C. J Viral Hepat. 1999;6:463-469.  [PubMed]  [DOI]
142.  Chien RN, Liaw YF, Chen TC, Yeh CT, Sheen IS. Efficacy of thymosin alpha1 in patients with chronic hepatitis B: a randomized, controlled trial. Hepatology. 1998;27:1383-1387.  [PubMed]  [DOI]
143.  Lin SM, Sheen IS, Chien RN, Chu CM, Liaw YF. Long-term beneficial effect of interferon therapy in patients with chronic hepatitis B virus infection. Hepatology. 1999;29:971-975.  [PubMed]  [DOI]