Version May 2024
INTRODUCTION — Torque teno virus (TTV) was initially detected in patients who developed elevated serum aminotransferase (ALT) concentrations following transfusion and tested negative for all known hepatitis viruses [1-3]. Contrary to what was initially believed, TTV does not represent a cause of liver disease or contribute appreciably to the clinical course of patients with existing liver disease. This topic will review the virology, epidemiology, clinical associations, detection, and natural history of TTV and other anelloviruses.
VIROLOGY
Classification — Torque teno virus (TTV) is classified in the genus Alfatorquevirus within the family Anelloviridae [4]. Torque teno mini virus (TTMV) and Torque teno midi virus (TTMDV), thus named because of their smaller genomes (approximately 2.8 and 3.2 kb) relative to TTV (approximately 3.8 kb), and a large number of related viruses that have been found in a variety of animals and appear to be host species-specific.
Structure and replication of TTV — Virions are roughly spherical, approximately 30 nm in diameter, and non-enveloped. The genome is a circular molecule of single-stranded, negative-sense DNA of approximately 3.8 kb and consists of a coding and a noncoding region. The nucleotide (nt) sequence of the coding region has indicated the presence of several open reading frames (ORFs), which overlap extensively, and five to seven virus-encoded proteins (possibly also resulting from different splicing) have been documented in cells transfected with TTV DNA. The mechanisms of TTV genome expression and replication are poorly understood. However, a specific amino acid sequence within the product of ORF1 (which also encodes the putative capsid protein) suggests that replication occurs via a rolling circle mechanism [4].
Genetic variants — Although the genetic organization of different TTV isolates is well conserved, their genomes display a very high level of sequence diversity. Only the noncoding region contains a domain of about 130 nt, which is relatively well conserved among the different isolates. The extremely high degree of DNA polymorphism represents the basis for the subdivision of TTV isolates into a large number of genotypes or species (>10 percent nt divergence), a number that has been increasing with the introduction of new molecular techniques of increasing sensitivity [5]. The different genotypes are classified into five distinct phylogenetic groups designated 1 to 5 (>40 nt divergence), which differ markedly in prevalence. For example, genogroups 1 and 3 are most common, while genogroup 2 is generally rarely detected. Coinfection by multiple TTV genotypes and genogroups is very common [6-8]. There are suggestions that the different genetic variants are antigenically distinct [9]. Whether there are also biological or pathogenic differences between them is essentially unknown.
Characterization of some TTV genotypes is ongoing [10-12]. Among the most investigated are the ones also known as SEN virus (SENV). Described at first as an independent virus with several variants (designated A to I), SENV was later found to represent a number of genotypes within genogroup 3 TTV [13]. Studies that have tried to elucidate the clinical significance of the SENV have demonstrated its high prevalence, but have not consistently demonstrated any deleterious effect [14-22]. In one study, SENV DNA (types D and H) was detected in 30 percent of 286 patients with a history of transfusion compared with 3 percent of 97 nontransfused controls [22]. The risk of infection increased in proportion to the number of units transfused. SENV DNA was detected in 11 of 12 patients with transfusion-associated non-A to E hepatitis compared with 55 of 225 who did not develop hepatitis. SENV DNA persisted for more than one year in 45 percent of patients and up to 12 years in 13 percent of patients. The vast majority of SENV-infected recipients did not develop hepatitis.
EPIDEMIOLOGY — Anelloviruses represent a conspicuous, essentially constant component of the (normal) human virome. Few studies have investigated Torque teno mini virus (TTMV) and Torque teno midi virus (TTMDV), but their general and epidemiologic features do not seem to differ substantially from those of TTV [23,24].
Prevalence — TTV is highly prevalent worldwide, with prevalence rates of over 80 to 90 percent among healthy adults [1,6,25-42]. Anellovirus infections are acquired early in life [37-39]. TTV has been detected in the great majority of plasma or other body fluids from children aged two years or less [9,43]. As TTV is blood-borne, rates are higher in individuals who receive blood transfusions [34-36].
Transmission — TTV has been detected in nearly all tissues of the body and in biological fluids, except the intact central nervous system (CNS) [44]. It is excreted with stool, urine, saliva, and nasal fluid [6]. Since TTV appears to be highly resistant in the environment, it has the potential to be transmitted through many routes and serves as an indicator of general viral contamination of the environment [45]. Evidence of vertical transmission between mothers and their infants has been demonstrated in some studies [39]. Indirect evidence has suggested that hematopoietic cells, possibly T lymphocytes, are an important source of the virus found in plasma; however, the full range of cell types that support TTV replication within the body is unknown [46,47].
CLINICAL IMPLICATIONS — The clinical significance of TTV infections remains uncertain.
Lack of association with acute or chronic liver disease — Contrary to what was initially proposed, it is now well established that TTV infections are not a cause of liver disease. It has been suggested that TTV may represent part of the normal human virome [48].
●Acute hepatitis — Several observations have led to the conclusion that TTV is not a cause of acute hepatitis [49-53]. In a study involving healthy blood donors and patients who received a blood transfusion in a variety of settings, new TTV infection was observed in 26 percent of 182 transfused patients of whom 23 percent developed non-A to E hepatitis [49]. However, this rate was not significantly different when compared with patients who developed non-A to E hepatitis without new TTV infection, suggesting that TTV was not the cause of the unknown hepatitis. Similarly, the acquisition of TTV following liver or bone marrow transplantation has not been associated with clinical or biochemical evidence of hepatitis [51].
●Chronic liver disease — Most studies have found no association between TTV infection and biochemical or histologic evidence of liver damage in patients with chronic hepatic disease of unknown cause [34,36,49,54,55].
Studies have not consistently demonstrated an increase in prevalence of TTV in patients with chronic liver disease [54,55]. However, even in those that have demonstrated an increase in prevalence of TTV in patients with liver disease, TTV did not appear to contribute to liver injury [34,54,56]. These reports of increased prevalence of TTV among patients with chronic liver disease may be explained on the basis of shared risk factors for infection rather than TTV being the cause or an aggravating factor of the liver disease [57-59].
TTV DNA has been sought in a number of other settings related to liver disease. TTV does not appear to serve as a trigger for autoimmune hepatitis [60] and has not been associated with cryoglobulinemia [61]. TTV does not appear to interfere with treatment of hepatitis C virus with interferon; discrepant reports have been published as to whether it may be cleared during interferon treatment [3,42,62]. Other studies have found no association between TTV and increased risk of hepatocellular carcinoma in patients with a variety of other predisposing conditions. [63,64].
Other disease associations of unclear significance — TTV has been associated with several disease conditions, but confirmatory studies are needed, and a causal association has not been established. Determining if associations with any other diseases are causal is challenging because of the wide prevalence of the infection in the general population, the presence of the virions in many tissues, the existence of numerous genetic variants of the viruses, the frequent occurrence of coinfections by two or more such variants, and the wide range of viral loads that can be present in individual patients. In fact, these characteristics also challenge the adequacy of traditional approaches for establishing a causal relationship between an infectious agent and a disease [65].
TTV has been associated with systemic lupus erythematosus [62], pancreatic cancer [66], diabetes mellitus [61], poor outcomes in patients with laryngeal cancer [67], periodontal disease [68], multiple sclerosis [69], cryptogenic fever of children [70], and endophthalmitis [71]. TTV may possibly be a cause of acute respiratory diseases in children [72,73] and an aggravating factor in patients with asthma [74], bronchiectasis [75], and chronic obstructive pulmonary disease [76]. Changes in TTV plasma loads have been proposed as an indicator of immune function in immunosuppressed individuals and TTV patterns may be a marker of disease [47,77-82]. (See 'Viral load' below.)
DIAGNOSIS
Viral load — The diagnosis of infection relies solely upon detection of TTV DNA by polymerase chain reaction (PCR) assay [44]. However, there are no commercially available assays. Plasma loads of TTV vary widely in individual patients. For example, in a study of healthy subjects they ranged between 103 and 108 DNA copy numbers per mL [83]. These variations reflect the replicating activity of TTV in the body as well as the number of genetic variants of the virus carried at the time of testing, and the immunological status of the host [42,84]. It appears that immunosuppression may be associated with increasing levels of TTV replication, suggesting a role for the immune system in controlling TTV infection [85]. A variable fraction of the TTV virions found in plasma is bound to presumably virus-specific immunoglobulin G (IgG) or IgM. Whether these immunocomplexes remain infectious is unknown [23].
Other — There are no easy-to-perform tissue culture methods for growing TTV, and reliable serological methods for studying the antiviral antibody responses are lacking [9,24,86]. Anti-TTV IgM antibodies appear in blood 10 to 21 weeks after TTV infection and gradually decrease 5 to 11 weeks after their initial appearance [87]. Anti-TTV IgG antibodies emerge around 16 weeks of infection, reach maximum concentrations at 5 months, and are detectable for four or more years.
NATURAL HISTORY
Viral clearance — Many aspects of the natural history of TTV, including the frequency with which acute infection leads to viral clearance, remain poorly defined. It has been demonstrated that TTV is shed into and removed from the bloodstream at rates comparable to other chronic viremia-inducing viruses such as the hepatitis viruses B and C [42]. In one study that included 48 patients with TTV, chronic infection was observed in 31 cases (86 percent) with TTV persistence for a mean duration of three years [88]. These reports suggest an annual clearance of viral persistence of approximately 1 to 7 percent [35,88]. In another study that included 21 viremic subjects, 14 (67 percent) cleared TTV within five years, but 7 (33 percent) were viremic during 22 years of follow-up [49]. However, these studies were performed using virus detection assays that, due to limitations in sensitivity, were incapable of discriminating between true virus eradications and fluctuations of virus replication that brought the viral burden under the lower limit of detection of the specific assay used.
SUMMARY
●Torque teno virus (TTV) is a non-enveloped single-stranded circular DNA virus classified in the genus Alfatorquevirus within the family Anelloviridae. This family also includes two additional pervasive human viruses, Torque teno mini virus (TTMV) and Torque teno midi virus (TTMDV). (See 'Introduction' above.)
●Anelloviral infections are acquired early in life and represent a large part of the human virome. TTV has been detected in nearly all tissues of the body except the intact central nervous system and in biological fluids. It is excreted in stool, urine, saliva, and nasal fluid. Since TTV appears to be highly resistant in the environment, it has the potential to be transmitted through many routes and serves as an indicator of general viral contamination of the environment. Evidence of vertical transmission between mothers and their infants has been demonstrated in some studies. Few studies have investigated TTMV and TTMDV, but their general and epidemiologic features do not seem to differ substantially from those of TTV. (See 'Epidemiology' above.)
●The mechanisms of TTV genome expression and replication are poorly understood. However, a specific amino acid sequence within the product of open reading frame, ORF1, which also encodes the putative capsid protein, suggests that replication occurs via a rolling circle mechanism. (See 'Structure and replication of TTV' above.)
●The extremely high degree of DNA polymorphism represents the basis for the subdivision of TTV isolates into a large number of genotypes or species (>10 percent nt divergence). The different genotypes are classified into five distinct phylogenetic groups designated 1 to 5 (>40 nt divergence), which differ markedly in prevalence. (See 'Genetic variants' above.)
●The clinical significance of TTV infections remains uncertain. However, contrary to what was initially proposed, it is now well established that TTV infections are not significant causes of liver disease. It has been suggested that TT virus may represent part of the normal human virome. (See 'Clinical implications' above.)
●Many aspects of the natural history of TTV, including the frequency with which acute infection leads to viral clearance, remain poorly defined. (See 'Viral clearance' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Mauro Bendinelli, MD, who contributed to an earlier version of this topic review.
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