Sequence Heterogeneity of TT Virus and Closely Related Viruses

Abstract

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...

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

“…It is also of interest that the ORF1 of certain species contains as many as 14 individual start sites, which when used, will all result in proteins larger than 100 aa. The possible existence of interrupted ORF1s has previously been reported (7,21,26). Other known TTV with an interrupted ORF1 are l03 (AF371370) (25), senv-b (AX025677) (55), tchn-a (AF345526), tchn-c1 (AF345523), tchn-d2 (AF345525) (26), us32 (AF122921) (7), and tt32b8 (AX781361) (6; unpublished data).…”

“…The ORF1 of isolate tth22g4 was interrupted by 2 stop codons, resulting in 3 putative ORFs: ORF1a (75 aa, nt 599 to 824, 225 bp), ORF1b (117 aa, nt 935 to 1286, 351 bp), and ORF1c (499 aa, nt 1331 to 2828, 1,497 bp). An alternative start codon (21) for ORF1 of isolate tth13 was GTG at nt 599, resulting in a putative protein of 743 aa. Single nucleotide changes occurred scattered throughout the rest of the genomes not leading to any obvious modifications.…”

Phylogenetic Evidence for the Rapid Evolution of Human B19 Erythrovirus

“…While B19 virus and the carnivore parvoviruses share a genome structure, they exhibit low levels of sequence similarity, infect different hosts, and have unique routes of infection. For the future it will be important to determine whether this elevated rate is restricted to the Parvoviridae or is characteristic of all ssDNA viruses, as suggested by the high levels of diversity found among these viruses, including members of the Geminiviridae and the Circoviridae, most notably human TT virus (6,9,11,12,15).…”

Clinicopathological study on TTV infection in hepatitis of unknown etiology

“…TTV is an unenveloped, single-stranded and circular DNA virus, which consists of 3852 nucleotides and most closely resembles the members of the Circoviridae family [1][2][3] . Meanwhile, different studies suggested that TTV genotypes were so much and could vary frequently [4][5][6][7][8] . It is believed that TTV belongs to hepadnavirus and replicates chiefly in the liver [9][10][11] , however, some researchers think that the replication site is in the bone marrows rather than in the livers [12] .…”