Random integration of HTLV-I provirus; increasing chromosomal instability

Ohshima, Koichi; Ohgami, Akiko; Matsuoka, Masao; Etoh, Ken‐ichiro; Utsunomiya, Atae; Makino, Tomoki; Ishiguro, Masako; Suzumiya, Junji; Kikuchi, Masahiro

doi:10.1016/s0304-3835(98)00188-8

Cited by 25 publications

(26 citation statements)

References 20 publications

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“…The 5Ј LTR causes transcriptional interference (9) and is deleted in tumors induced by ALV. In contrast to ALV, HTLV-1 provirus integration sites are random in ATL cells (12,40,45), indicating that the 3Ј LTR does not activate the transcription of specific cellular genes. By contrast, we have reported that the HBZ gene, which is transcribed from the 3Ј LTR, is required for the proliferation of ATL cells (44).…”

Section: Discussionmentioning

confidence: 95%

“…First, genomic DNA from a single ATL sample with one type 2 defective provirus was mixed in various proportions (5,10,20,40, and 100%) with DNA from an ATL cell line harboring a complete provirus (TL-Om1). Then we used real-time PCR to quantify provirus loads at three different regions of the provirus: (i) 5Ј LTR-gag (deleted only in type 2 defective provirus), (ii) gag (deleted in both type 1 and type 2 defective proviruses), and (iii) pX (conserved in all proviruses).…”

Section: Methodsmentioning

confidence: 99%

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Preferential Selection of Human T-Cell Leukemia Virus Type 1 Provirus Lacking the 5′ Long Terminal Repeat during Oncogenesis

Miyazaki

Yasunaga

Taniguchi

et al. 2007

J Virol

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104

118

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In adult T-cell leukemia (ATL) cells, a defective human T-cell leukemia virus type 1 (HTLV-1) provirus lacking the 5 long terminal repeat (LTR), designated type 2 defective provirus, is frequently observed. To investigate the mechanism underlying the generation of the defective provirus, we sequenced HTLV-1 provirus integration sites from cases of ATL. In HTLV-1 proviruses retaining both LTRs, 6-bp repeat sequences were adjacent to the 5 and 3 LTRs. In 8 of 12 cases with type 2 defective provirus, 6-bp repeats were identified at both ends. In five of these cases, a short repeat was bound to CA dinucleotides of the pol and env genes at the 5 end, suggesting that these type 2 defective proviruses were formed before integration. In four cases lacking the 6-bp repeat, short (6-to 26-bp) deletions in the host genome were identified, indicating that these defective proviruses were generated after integration. Quantification indicated frequencies of type 2 defective provirus of less than 3.9% for two carriers, which are much lower than those seen for ATL cases (27.8%). In type 2 defective proviruses, the second exons of the tax, rex, and p30 genes were frequently deleted, leaving Tax unable to activate NF-B and CREB pathways. The HTLV-1 bZIP factor gene, located on the minus strand, is expressed in ATL cells with this defective provirus, and its coding sequences are intact, suggesting its significance in oncogenesis.

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Section: Discussionmentioning

confidence: 95%

Section: Methodsmentioning

confidence: 99%

Preferential Selection of Human T-Cell Leukemia Virus Type 1 Provirus Lacking the 5′ Long Terminal Repeat during Oncogenesis

Miyazaki

Yasunaga

Taniguchi

et al. 2007

J Virol

Self Cite

104

118

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“…The specific mechanism by which proviral integration influences chromosomal abnormalities remains to be determined. Since HTLV-I integrates randomly into host cell chromosomes (Seiki et al, 1984;Ohshima et al, 1998), the chromosomal abnormalities induced by HTLV-I infection are predicted to be random events and only those abnormalities that conveyed a growth advantage would be observed in expanded transformed cell populations.…”

Section: Genome Instability and Htlv-i Infectionmentioning

confidence: 99%

Impact of HTLV-I Tax on cell cycle progression and the cellular DNA damage repair response

2005

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“…7,8 The leukemic clones carry generally one (complete or defective) provirus per cell. [12][13][14] There has been a longstanding debate on the question of whether HTLV-1 is latent or persistently expressed in vivo. Persistent expression is strongly suggested by the extensive evidence that the strong, chronically activated cytotoxic T lymphocyte (CTL) response to HTLV-1 limits the proviral load and reduces the risk of HAM/TSP.…”

Section: Introductionmentioning

confidence: 99%

The host genomic environment of the provirus determines the abundance of HTLV-1–infected T-cell clones

Gillet

Malani

Melamed

et al. 2011

Blood

271

467

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Human T-lymphotropic virus type 1 (HTLV-1) persists by driving clonal proliferation of infected T lymphocytes. A high proviral load predisposes to HTLV-1-associated diseases. Yet the reasons for the variation within and between persons in the abundance of HTLV-1-infected clones remain unknown. We devised a highthroughput protocol to map the genomic location and quantify the abundance of > 91 000 unique insertion sites of the provirus from 61 HTLV-1 ؉ persons and > 2100 sites from in vitro infection. We show that a typical HTLV-1-infected host carries between 500 and 5000 unique insertion sites. We demonstrate that negative selection dominates during chronic infection, favoring establishment of proviruses integrated in transcriptionally silenced DNA: this selection is significantly stronger in asymptomatic carriers. We define a parameter, the oligoclonality index, to quantify clonality. The high proviral load characteristic of HTLV-1- IntroductionHuman T-lymphotropic virus type 1 (HTLV-1) causes adult T-cell leukemia-lymphoma (ATLL), HTLV-1-associated myelopathy/ tropical spastic paraparesis (HAM/TSP), uveitis, and infective dermatitis. It is estimated that 15 to 20 million persons live with HTLV-1 infection worldwide. A small proportion (up to 7%, depending on the area) of HTLV-1-infected persons develop disease, whereas the majority remain asymptomatic carriers (ACs). Infection occurs via breastfeeding, transfusion of infected cellular blood products, or sexual intercourse. Symptoms appear after a long period (years or decades) of clinical latency. 1 The HTLV-1 proviral load (PVL) remains stable within each infected person and correlates with the outcome of infection. However, the PVL varies widely among infected people, even within a particular diagnostic group. [2][3][4] The sequence of HTLV-1 is also stable within a person, 5,6 indicating that the PVL is maintained in vivo mainly by mitosis of infected cells during the chronic phase of the infection. This interpretation is supported by the observation that individual clones of infected cells can persist in patients for several years. 7-9 Thus, it has been hypothesized that infectious transmission of HTLV-1 is important early in infection across the virologic synapse, 10 whereas mitotic replication is responsible for maintaining proviral load once a persistent infection has been established and reached an equilibrium with the immune response. 11 In approximately 5% of infected people, persistent clonal proliferation culminates in malignant transformation in the disease ATLL. 7,8 The leukemic clones carry generally one (complete or defective) provirus per cell. [12][13][14] There has been a longstanding debate on the question of whether HTLV-1 is latent or persistently expressed in vivo. Persistent expression is strongly suggested by the extensive evidence that the strong, chronically activated cytotoxic T lymphocyte (CTL) response to HTLV-1 limits the proviral load and reduces the risk of HAM/TSP. 11 Furthermore, there is both experimental evidence 15 and th...

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Random integration of HTLV-I provirus; increasing chromosomal instability

Cited by 25 publications

References 20 publications

Preferential Selection of Human T-Cell Leukemia Virus Type 1 Provirus Lacking the 5′ Long Terminal Repeat during Oncogenesis

Preferential Selection of Human T-Cell Leukemia Virus Type 1 Provirus Lacking the 5′ Long Terminal Repeat during Oncogenesis

Impact of HTLV-I Tax on cell cycle progression and the cellular DNA damage repair response

The host genomic environment of the provirus determines the abundance of HTLV-1–infected T-cell clones

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