Distinct genotypes of a nonenveloped DNA virus associated with posttransfusion non-A to G hepatitis (TT virus) in plasma and peripheral blood mononuclear cells

TT virus (TTV) is a recently identified widespread DNA virus of humans that produces persistent viremia in the absence of overt clinical manifestations. In an attempt to shed light on the dynamics of chronic infection, we measured the levels of TTV in the plasma of 25 persistently infected patients during the first 3 months of alpha interferon (IFN-␣) treatment for concomitant hepatitis C virus (HCV) infection. The first significant decline of TTV loads was observed at day 3 versus day 1 for HCV. Subsequently, the loads of TTV became progressively lower in most patients, but some initial responders relapsed before the end of the follow-up, suggesting that at least in some subjects the effects of IFN on TTV can be very short-lived. No correlation between the responses of TTV and HCV to therapy was found. Fitting the viremia data obtained during the first week of treatment into previously developed mathematical models showed that TTV sustains very active chronic infections, with over 90% of the virions in plasma cleared and replenished daily and a minimum of approximately 3.8 ؋ 10 10 virions generated per day. Low levels of TTV were occasionally detected in the peripheral blood mononuclear cells of patients who had cleared plasma viremia, thus corroborating previous results showing that these cells may support TTV replication and/or persistence.

“…TTV has previously been shown to circulate in blood closely associated with PBMC as well as free virions (13,25,28). In eight patients of Fig.…”

Section: Resultsmentioning

confidence: 98%

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confidence: 99%

Dynamics of Persistent TT Virus Infection, as Determined in Patients Treated with Alpha Interferon for Concomitant Hepatitis C Virus Infection

Maggi¹,

Pistello²,

Vatteroni³

et al. 2001

“…The other important factor regarding TTV evolution is the capability of multiple genotypes and genetic variants (see above) to persist for a long period in one infected person (3,21,29,31). One study, for example, showed that the nucleotide sequence of TTV genotypes 1 and 2 could be detected over a 15-month follow-up period without any alterations (3).…”

Section: Vol 74 2000mentioning

confidence: 99%

Sequence Heterogeneity of TT Virus and Closely Related Viruses

Khudyakov

Cong

Nichols

et al. 2000

TT virus (TTV) is a recently discovered infectious agent originally obtained from transfusion-related hepatitis. However, the causative link between the TTV infection and liver disease remains uncertain. Recent studies demonstrated that genome sequences of different TTV strains are significantly divergent. To assess genetic heterogeneity of the TTV genome in more detail, a sequence analysis of PCR fragments (271 bp) amplified from open reading frame 1 (ORF1) was performed. PCR fragments were amplified from 5 to 40% of serum specimens obtained from patients with different forms of hepatitis who reside in different countries (e.g., China, Egypt, Vietnam, and the United States) and from normal human specimens obtained from U.S. residents. A total of 170 PCR fragments were sequenced and compared to sequences derived from the corresponding TTV genome region deposited in GenBank. Genotypes 2 and 3 were found to be significantly more genetically related than any other TTV genotype. Moreover, three sequences were shown to be almost equally related to both genotypes 2 and 3. These observations suggest a merger of genotypes 2 and 3 into one genotype, 2/3. Additionally, five new groups of TTV sequences were identified. One group represents a new genotype, whereas the other four groups were shown to be more evolutionary distant from all known TTV sequences. The evolutionary distances between these four groups were also shown to be greater than between TTV genotypes. The phylogenetic analysis suggested that these four new genetic groups represent closely related yet different viral species. Thus, TTV exists as a "swarm" of at least five closely related but different viruses. These observations suggest a high degree of genetic complexity within the TTV population. The finding of the additional TTV-related species should be taken into consideration when the association between TTV infections and human diseases of unknown etiology is studied.A new TT virus (TTV) was recently discovered in a serum specimen obtained from a Japanese patient with posttransfusion hepatitis of unknown etiology (16,20). In the same study, TTV DNA was detected by PCR in serum specimens from three of five patients with posttransfusion non-A through non-G hepatitis. It was shown that TTV DNA titers closely correlated with the level of aminotransferase in these three patients (16). Additionally, TTV DNA was found in liver tissues in titers that are equal to or 10 to 100 times greater than those in the corresponding serum specimens (20). In combination with these findings, the identification of TTV DNA in 47% of patients with fulminant hepatitis and 46% of patients with chronic liver disease of unknown etiology (20) was used to hypothesize that TTV may be responsible for at least a part of acute and chronic liver disease of unknown etiology (16,20). However, the detection of TTV DNA in 12% of normal blood donors in Japan (20) indicates that this hypothesis should be thoroughly tested before a final conclusion is drawn regarding an association between TTV a...

“…To date, more than 16 genotypes separated by more than 30% divergence at the nucleotide level have been described (6,7,14,16,18,22), incorporating three hypervariable regions (13). Understanding the origins of such diversity is a fundamental problem in virology.…”

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confidence: 99%

Extensive Homologous Recombination among Widely Divergent TT Viruses

Worobey

2000

Analyses of a collection of full-length TT virus genomes showed nearly half of them to be recombinant. The results were highly significant and revealed homologous recombination both within and among genotypes, often involving extremely divergent lineages. Recombination breakpoints were significantly more common in the noncoding region of the TT virus genome than in the coding region.TT virus (TTV) is a newly discovered nonenveloped DNA virus that was initially considered to be a possible agent of viral hepatitis, since it was first recovered from a patient with posttransfusion hepatitis of unknown etiology (12,15). Subsequent studies, however, have shown it to be very widespread and to occur at an extremely high prevalence even in healthy populations (1,9,18,20), casting doubt on its causal role in human disease. Its circular, single-stranded, negative-sense DNA genome, approximately 3,850 nucleotides in length (10, 11), bears little or no identifiable similarity to other known viruses, and TTV appears to represent a new virus family, tentatively designated Circinoviridae (11).For a DNA virus, TTV exhibits an astonishingly large amount of genetic diversity. To date, more than 16 genotypes separated by more than 30% divergence at the nucleotide level have been described (6,7,14,16,18,22), incorporating three hypervariable regions (13). Understanding the origins of such diversity is a fundamental problem in virology. While the role played by mutation has long been considered, it is becoming increasingly apparent that recombination also plays a key role in the evolution of many virus groups (19,24). The recent availability of several full-length TTV sequences (3,6,10,11,16), along with evidence for mixed infection by multiple genetic types (2,4,17,21), prompted this investigation into whether recombination might also play a role in the evolution of TTV.A total of 15 full-length or near-full-length TTV genomes with the following isolate names (accession numbers) were collected from GenBank: TA278 (AB017610) (16); GH1 (AF122913) (11); TUS01 (AB017613) (16); SAN-BAN (AB025946) (6); JA20 (AF122914), JA9 (AF122915), JA10 (AF122919), JA4 (AF122917), JA1 (AF122916), JA2B (AF122918), US32 (AF122921), and US35 (AF122920) (3); and BDH1 (AF116842), TTVCHN1 (AF079173), and TTVCHN2 (AF129887). The sequences were aligned using CLUSTAL W (23) and adjusted by hand. The resulting 3,853-nucleotide fulllength TTV alignment is available from the author on request.The aligned data set was analyzed by various methods to identify possible recombinant isolates, to characterize their putative recombination breakpoints, and to test results suggestive of recombination for statistical significance. First, an exploratory tree analysis (5) was performed by sliding a 400-nucleotide window down the sequence alignment in 200-nucleotide increments, generating a series of trees for the different regions. All trees were reconstructed with the PAUP* program (version 4; Sinauer Associates, Sunderland, Mass.) using the neighbor-joining algorithm with di...