Role of HTLV‐1 proviral DNA load and clonality in the development of adult T‐cell leukemia/lymphoma in asymptomatic carriers

Okayama, Akira; Stuver, Sherri O.; Matsuoka, Masao; Ishizaki, Junzo; Tanaka, Gen-ichi; Kubuki, Yoko; Müeller, Nancy; Hsieh, Chung‐Cheng; Tachibana, Nobuyoshi; Tsubouchi, Hirohito

doi:10.1002/ijc.20144

Cited by 100 publications

(82 citation statements)

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“…The presence of leukemic clones was detected during the carrier state by inverse PCR method. Such clonal proliferation is directly associated with the onset of ATL (Okayama et al, 2004), and these studies clearly illustrate that HTLV-I-infected clones can transform to malignancy during the carrier state.…”

Section: Clonal Proliferation Of Htlv-i-infected Cellsmentioning

confidence: 71%

Natural history of adult T-cell leukemia/lymphoma and approaches to therapy

2005

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After cell-to-cell transmission, HTLV-I increases its viral genome by de novo infection and proliferation of infected cells. Proliferation of infected cells is clonal and persistent in vivo. During the carrier state, infected cells are selected in vivo by the host's immune system, the genetic and epigenetic environment of proviral integration sites, and other factors. In leukemic cells, tax gene expression is frequently impaired by genetic and epigenetic mechanisms. Such loss of Tax expression enables ATL cells to escape the host immune system. On the other hand, ATL cells acquire the ability to proliferate without Tax by intracellular genetic and epigenetic changes. Despite advances in support and the development of novel treatment agents, the prognosis for ATLL remains poor. A number of therapies, however, do appear to improve prognosis compared to CHOP (VEPA). These include interferon-a plus zidovudine (probably after 1-2 cycles of CHOP), intensive chemotherapy as in LSG-15 with G-CSF support and Allo-SCT (which includes the potential for cure). Emerging novel approaches include HDAC inhibitors, monoclonal antibodies, and proteasome inhibitors. Comparison between different therapeutic approaches is complicated by the range of natural history of ATLL, different recruitments of naı¨ve-to-therapy, refractory or relapsed patients, and variations in the reporting of outcome that frequently excludes difficultto-evaluate patients. Moreover, results from relatively small proof-of-principle studies have not been extended with randomized, controlled trials. As a result, currently, there is no clear evidence to support the value of any particular treatment approach over others. To avoid further unnecessary patient suffering and to identify optimal therapy as rapidly as possible, large randomized, controlled trials encompassing multicenter, international collaborations will be necessary.

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Section: Clonal Proliferation Of Htlv-i-infected Cellsmentioning

confidence: 71%

Natural history of adult T-cell leukemia/lymphoma and approaches to therapy

2005

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“…Their common characteristic is the increased number of HTLV-1-infected cells (HTLV-1-infected leukemia cells in ATL). 4,7 Furthermore, the high viral load in ACs increases the risk of developing HAM/TSP or ATL. 4,7 These findings suggest that common mechanisms underlie the insufficient control of HTLV-1 infection in both diseases.…”

Section: Discussionmentioning

confidence: 99%

“…A higher HTLV-1 load increases the risk of HAM/TSP and ATL. 4,7 Therefore, the precise mechanisms controlling HTLV-1-infected cells must be better understood. With regard to the host defense mechanisms involved in HTLV-1 infection, the role of HTLV-1-specific CD8 ϩ cytotoxic T lymphocytes (CTLs) has been studied.…”

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confidence: 99%

Severe loss of invariant NKT cells exhibiting anti–HTLV-1 activity in patients with HTLV-1–associated disorders

Azakami

Sato

Araya

et al. 2009

Blood

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Invariant natural killer T (iNKT) cells are unique T cells that regulate the immune response to microbes, cancers, and autoimmunity. We assessed the characteristics of iNKT cells from persons infected with human T-lymphotropic virus type 1 (HTLV-1). Whereas most infected persons remain asymptomatic carriers (ACs IntroductionHuman T-cell lymphotropic virus type 1 (HTLV-1) causes persistent infection. Whereas most infected persons remain asymptomatic carriers (ACs), 3% to 5% develop a T-cell malignancy termed adult T-cell leukemia (ATL), and another 0.25% to 3% develop a chronic progressive inflammatory neurologic disease known as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/ TSP). [1][2][3] One of the most important pathogenic factors in HAM/ TSP is an increased HTLV-1 load in the peripheral blood mononuclear cells (PBMCs) and cerebrospinal fluid, 4-6 which suggests that in affected persons, virus control is inadequate. A higher HTLV-1 load increases the risk of HAM/TSP and ATL. 4,7 Therefore, the precise mechanisms controlling HTLV-1-infected cells must be better understood. With regard to the host defense mechanisms involved in HTLV-1 infection, the role of HTLV-1-specific CD8 ϩ cytotoxic T lymphocytes (CTLs) has been studied. [8][9][10] The HTLV-1-specific CTL response is critical for a low viral load to be maintained. [9][10][11] Despite the high frequency of HTLV-1-specific CTLs, the number of HTLV-1-infected T cells is surprisingly high in HAM/TSP patients. 5,6 We and others have reported that the maturation and functioning of HTLV-1-specific CTLs are inadequate in HAM/TSP patients, although in vitro studies have shown that these CTLs exert cytolytic activity against HTLV-1-expressing target cells. 12,13 Therefore, we hypothesize that there may be another cell population without CTLs that contributes to the control of HTLV-1-infected T cells.A unique T-cell subpopulation, natural killer T (NKT) cells, constitute a subset of lymphocytes that share the features of both innate and adaptive immune cells. Unlike conventional T cells, NKT cells express a T-cell receptor (TCR) that recognizes glycolipids instead of protein antigens. Moreover, these cells share properties and receptors with NK cells. They rapidly produce granzymes and perforins on stimulation. Among the CD3 ϩ T cells in human blood, 10% to 25% express NK cell-surface molecules, such as CD161, and these can be classified as NKT cells. 14,15 A small population of T cells within this NKT cell subset expresses a highly conserved V␣24J␣18 TCR chain that associates preferentially with V␤11. [16][17][18] These T cells are referred to as invariant NKT (iNKT) cells. Very recently, a novel clonotypic monoclonal antibody 6B11 specific for the V␣24J␣18 TCR chain has been shown to selectively stain human iNKT cells. 18,19 Activation of human iNKT cells requires the presentation of glycolipids, such as ␣-galactosylceramide (␣-GalCer) on the major histocompatibility complex class I-like molecule CD1d. 20 ␣-GalCer stimulation induces rapid cytoki...

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“…El diagnóstico definitivo de leucemia/linfoma de células T del adulto requiere la demostración de la integración monoclonal de HTLV-1 (5); sin embargo, la prueba confirmatoria de clonalidad viral no está disponible en el país y es difícil practicarla en tejido incluido en bloques de parafina; esta prueba en sangre solo se hace con fines de investigación (6). En otros laboratorios de referencia, el diagnóstico hematopatológico de Estados Unidos y Europa, la prueba de clonalidad viral no se practica de forma rutinaria y a pesar de esto se hacen diagnósticos de leucemia/linfoma de células T del adulto, basados usualmente en las características morfológicas y fenotípicas de la enfermedad, y en la presencia de anticuerpos para HTLV-1/2 mediante la técnica ELISA.…”

Section: Figuraunclassified

“…Actualmente, esta enfermedad está bien reconocida por la Organización Mundial de la Salud y existe consenso diagnóstico sobre sus características morfológicas, inmunofenotipo y alteraciones genéticas (5). Se ha establecido la integración monoclonal del HTLV-1 y se han identificado dos proteínas involucradas en la progresión de la enfermedad (6).…”

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