Rapid isolation of viral integration site reveals frequent integration of HTLV-1 into expressed loci

Ozawa, Tatsuhiko; Itoyama, Takahiro; Sadamori, Naoki; Yamada, Yasuaki; Hata, Tomoko; Tomonaga, Masao; Isobe, Masaharu

doi:10.1007/s10038-004-0126-7

Cited by 24 publications

(26 citation statements)

References 44 publications

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“…21,22 HTLV-1 integration was found to favor genes, transcriptional start sites, and CpG islands both in vitro and in vivo. 18,[23][24][25][26] We hypothesize that the genomic integration site of the provirus determines the level of proviral expression: in turn, the proviral For personal use only. on May 12, 2018. by guest www.bloodjournal.org From gene products determine both the proliferation rate and the susceptibility to CTL-mediated lysis of that infected T-cell clone.…”

mentioning

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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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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“…Although the viral Tax protein is clearly involved in oncogenic transformation, it is still unclear whether HTLV-1 integration sites influence the expression of cellular or viral genes that relate to the development of disease. There have been several studies of HTLV-1 integration sites in the human genome (19,24,31,32,44), but the number of sites examined in the majority of these studies was small and the integration sites were cloned from chronically infected patients. In one study, Doi et al characterized 56 HTLV-1 integration sites from carrier cells and 59 sites from leukemia cells (19) and found that in carrier cells, HTLV-1 integration tended to occur in heterochromatin alphoid repeated regions, whereas in leukemia cells, HTLV-1 integration favored actively transcribed genes.…”

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confidence: 99%

Human T-Cell Leukemia Virus Type 1 Integration Target Sites in the Human Genome: Comparison with Those of Other Retroviruses

Derse

Crise

et al. 2007

J Virol

154

153

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Retroviral integration into the host genome is not entirely random, and integration site preferences vary among different retroviruses. Human immunodeficiency virus (HIV) prefers to integrate within active genes, whereas murine leukemia virus (MLV) prefers to integrate near transcription start sites and CpG islands. On the other hand, integration of avian sarcoma-leukosis virus (ASLV) shows little preference either for genes, transcription start sites, or CpG islands. While host cellular factors play important roles in target site selection, the viral integrase is probably the major viral determinant. It is reasonable to hypothesize that retroviruses with similar integrases have similar preferences for target site selection. Although integration profiles are well defined for members of the lentivirus, spumaretrovirus, alpharetrovirus, and gammaretrovirus genera, no members of the deltaretroviruses, for example, human T-cell leukemia virus type 1 (HTLV-1), have been evaluated. We have mapped 541 HTLV-1 integration sites in human HeLa cells and show that HTLV-1, like ASLV, does not specifically target transcription units and transcription start sites. Comparing the integration sites of HTLV-1 with those of ASLV, HIV, simian immunodeficiency virus, MLV, and foamy virus, we show that global and local integration site preferences correlate with the sequence/structure of virus-encoded integrases, supporting the idea that integrase is the major determinant of retroviral integration site selection. Our results suggest that the global integration profiles of other retroviruses could be predicted from phylogenetic comparisons of the integrase proteins. Our results show that retroviruses that engender different insertional mutagenesis risks can have similar integration profiles.

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“…A similar mechanism was recently proposed for ATL (17,18). Therefore we analyzed the HTLV-1 integration sites in the clonal cell populations from spleens of infected C3H/HeJ mice (Table II).…”

Section: Proviral Integration Sitesmentioning

confidence: 68%

Clonal proliferation of HTLV-1-infected cells is associated with spontaneous malignant tumor formation in mice

Tanaka

Nitta²,

Yoshida³

et al. 2009

Int J Oncol

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Abstract. Adult T-cell leukemia/lymphoma (ATL) is characterized by monoclonal proliferation of tumor cells that harbor integrated human T-cell leukemia virus type-1 (HTLV-1). These malignant cells accumulate in various organs including the liver, spleen and skin in addition to blood and lymph nodes. Although there have been several reports of animal models of HTLV-1 infection in which proviral distribution has been examined, clonal expansion of the experimentally infected host cells has not been extensively analyzed. Here we provide experimental evidence that clonal proliferation of the infected host cells occurs in the spleen for more than one year. During a 15 month period of persistent infection, two out of ten mice developed spontaneous tumors. Although the tumors were not ATL-like, cells exhibiting mono-or oligoclonal proliferation and having the same site of HTLV-1 integration were identified in tumor tissues as well as in the spleen. Quantitative analysis of the cells belonging to each cell clone suggested that these proliferating cell clones were associated with the tumors and that spontaneous tumor tissues might provide a suitable microenvironment for proliferation and accumulation of infected cell clones at the late stage of infection.

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Rapid isolation of viral integration site reveals frequent integration of HTLV-1 into expressed loci

Cited by 24 publications

References 44 publications

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

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

Human T-Cell Leukemia Virus Type 1 Integration Target Sites in the Human Genome: Comparison with Those of Other Retroviruses

Clonal proliferation of HTLV-1-infected cells is associated with spontaneous malignant tumor formation in mice

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