Human T-cell lymphotropic virus IIIB glycoprotein (gp120) bound to CD4 determinants on normal lymphocytes and expressed by infected cells serves as target for immune attack.

This study aimed to describe comorbidities and symptoms of asymptomatic HTLV-1-infected patients according to the proviral load. Medical records were revised and patients categorized in high and low proviral load groups: >5% and <5% -infected cells, respectively. Frequency of symptoms was quantified. A total of 64 patients were evaluated. Twenty three (36%) patients had high proviral load. All patients had clinical abnormalities reported in the medical records. The most frequently comorbidities were hypertension (37.5%) and depression (25%) and the most frequent symptoms were neurological (82.8%) and ophthalmologic (65.6%). There were no differences in the frequencies of clinical manifestations in patients with low and high proviral load, except for urinary retention, that was more prevalent in the group with high proviral (34.8%). In summary, patients infected with HTLV-1 asymptomatic have a wide spectrum of clinical abnormalities and should be closely followed in order to identify the development of HTLV-1-associated diseases.

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Epstein–Barr Virus Permissively Infects Human Syncytiotrophoblastsin Vitroand Induces Replication of Human T Cell Leukemia-Lymphoma Virus Type I in Dually Infected Cells

Virology ◽

10.1006/viro.1997.8449 ◽

1997 ◽

Vol 229 (2) ◽

pp. 400-414 ◽

Cited By ~ 14

Author(s):

Ferenc D. Tóth ◽

George Aboagye-Mathiesen ◽

József Nemes ◽

Xiangdong Liu ◽

István Andirkó ◽

...

Keyword(s):

T Cell ◽

Virus Type ◽

Epstein Barr Virus ◽

Type I ◽

T Cell Leukemia ◽

Cell Leukemia ◽

Barr Virus ◽

Human T Cell ◽

Infected Cells ◽

Epstein Barr

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Pentosan Polysulfate Demonstrates Anti-human T-Cell Leukemia Virus Type 1 ActivitiesIn VitroandIn Vivo

Journal of Virology ◽

10.1128/jvi.00413-19 ◽

2019 ◽

Vol 93 (16) ◽

Cited By ~ 1

Author(s):

Guangyong Ma ◽

Jun-ichirou Yasunaga ◽

Koichi Ohshima ◽

Tadashi Matsumoto ◽

Masao Matsuoka

Keyword(s):

T Cell ◽

Leukemia Virus ◽

Spastic Paraparesis ◽

T Cell Leukemia ◽

Pentosan Polysulfate ◽

Cell Leukemia ◽

Cell Leukemia Virus Type ◽

Human T Cell ◽

Infected Cells

ABSTRACTHuman T-cell leukemia virus type 1 (HTLV-1) infection causes T-cell leukemia and inflammatory diseases, most notably including HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The underlying mechanism for the pathogenesis of HAM/TSP remains unclear. According to a recent clinical trial, a humanized antibody that targets CCR4+cells ameliorates inflammation by reducing the number of infected cells in the central nervous system; this result suggests that the transmigration of HTLV-1-infected cells plays a crucial role in HAM/TSP. Partly due to the blood-brain barrier, current treatments for HAM/TSP are mostly palliative. Pentosan polysulfate (PPS), a semisynthetic glycosaminoglycan, has recently been used to treat HAM/TSP and was found to alleviate the symptoms. In this study, we investigated the effect of PPS on HTLV-1-infected cells and provide evidence for its efficacy in HAM/TSP. PPS was cytotoxic to certain HTLV-1-infected cells and significantly suppressed HTLV-1 virion production. PPS also efficiently inhibited HTLV-1 cell-cell transmission in T cells. In addition, PPS blocked HTLV-1 infection of primary endothelial cells (human umbilical vascular endothelial cells) and suppressed the subsequent induction of proinflammatory cytokine expression. Furthermore, PPS was found to inhibit the adhesion and transmigration of HTLV-1-infected cells. We also confirmed the anti-HTLV-1 effect of PPSin vivousing two mouse models. PPS blocked HTLV-1 infection in a mouse model with peripheral blood mononuclear cell (PBMC)-humanized NOD-scid IL2Rgammanull(huPBMC NSG) mice. PPS was also found to suppress the development of dermatitis and lung damage in HTLV-1 bZIP factor (HBZ)-transgenic (HBZ-Tg) mice, an HTLV-1 transgenic mouse model in which the mice develop systemic inflammation.IMPORTANCEHTLV-1 is the first human retrovirus to have been identified and is endemic in certain areas worldwide. HTLV-1 infection leads to the development of an inflammatory disease called HAM/TSP, a myelopathy characterized by slowly progressive spastic paraparesis. There have been no effective therapeutics available for HAM/TSP, but recently, a semisynthetic glycosaminoglycan, named pentosan polysulfate (PPS), has been found to alleviate the symptoms of HAM/TSP. Here we conducted a comprehensive study on the effect of PPS bothin vitroandin vivo. PPS demonstrated anti-HTLV-1 potential in infected cell lines, as shown by its suppressive effects on HTLV-1 replication and transmission and on the transmigration of infected T cells. Moreover, results obtained from two HTLV-1 mouse models demonstrate that PPS inhibits HTLV-1 infection and inflammation developmentin vivo. Our work offers insights into the treatment of HAM/TSP by PPS and also suggests its possible use for treating other HTLV-1-induced inflammatory diseases.

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Repression of Tax Expression Is Associated both with Resistance of Human T-Cell Leukemia Virus Type 1-Infected T Cells to Killing by Tax-Specific Cytotoxic T Lymphocytes and with Impaired Tumorigenicity in a Rat Model

Journal of Virology ◽

10.1128/jvi.78.8.3827-3836.2004 ◽

2004 ◽

Vol 78 (8) ◽

pp. 3827-3836 ◽

Cited By ~ 17

Author(s):

Machiko Nomura ◽

Takashi Ohashi ◽

Keiko Nishikawa ◽

Hironori Nishitsuji ◽

Kiyoshi Kurihara ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Leukemia Virus ◽

T Cell Leukemia ◽

Cell Leukemia ◽

Cell Leukemia Virus Type ◽

Human T Cell ◽

T Cell Leukemia Virus ◽

Infected Cells

ABSTRACT Human T-cell leukemia virus type 1 (HTLV-1) causes adult T-cell leukemia (ATL). Although the viral transactivation factor, Tax, has been known to have apparent transforming ability, the exact function of Tax in ATL development is still not clear. To understand the role of Tax in ATL development, we introduced short-interfering RNAs (siRNAs) against Tax in a rat HTLV-1-infected T-cell line. Our results demonstrated that expression of siRNA targeting Tax successfully downregulated Tax expression. Repression of Tax expression was associated with resistance of the HTLV-1-infected T cells to Tax-specific cytotoxic-T-lymphocyte killing. This may be due to the direct effect of decreased Tax expression, because the Tax siRNA did not alter the expression of MHC-I, CD80, or CD86. Furthermore, T cells with Tax downregulation appeared to lose the ability to develop tumors in T-cell-deficient nude rats, in which the parental HTLV-1-infected cells induce ATL-like lymphoproliferative disease. These results indicated the importance of Tax both for activating host immune response against the virus and for maintaining the growth ability of infected cells in vivo. Our results provide insights into the mechanisms how the host immune system can survey and inhibit the growth of HTLV-1-infected cells during the long latent period before the onset of ATL.

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Central role of PI3K in transcriptional activation of hTERT in HTLV-I–infected cells

Blood ◽

10.1182/blood-2008-01-134692 ◽

2008 ◽

Vol 112 (7) ◽

pp. 2946-2955 ◽

Cited By ~ 34

Author(s):

Marcia Bellon ◽

Christophe Nicot

Keyword(s):

T Cell ◽

Wilms Tumor ◽

Telomerase Activity ◽

Pi3k Pathway ◽

T Cell Leukemia ◽

Htert Promoter ◽

Cell Leukemia ◽

Human T Cell ◽

Infected Cells ◽

I Cells

Abstract The persistence of human T-cell leukemia/lymphoma virus-I (HTLV-I)–infected cells is dependent upon clonal expansion and up-regulation of telomerase (hTERT). We have previously found that in interleukin (IL)–2–independent transformed HTLV-I cells, Tax strongly activates the hTERT promoter through nuclear factor-κB (NF-κB)–mediated Sp1 and c-Myc activation. In IL-2–dependent cells and adult T-cell leukemia/lymphoma (ATLL) patient samples, however, Tax expression is very low to undetectable, yet these cells retain strong telomerase activity. This suggests the existence of compensatory mechanisms in IL-2–dependent cells and ATLL patients. In this study, we demonstrate that telomerase activity is significantly decreased upon IL-2 withdrawal in immortalized HTLV-I cell lines. Inhibition of PI3K or AKT signaling pathways reduced telomerase activity in HTLV-I cells. We found that IL-2/IL-2R signaling was associated with a PI3K-dependent/AKT-independent transcriptional up-regulation of the endogenous hTERT promoter. We found that activation of the PI3K pathway mediated cytoplasmic retention of the Wilms tumor (WTI) protein, which strongly suppressed the hTERT promoter. The importance of this regulatory pathway for telomerase expression is underscored by findings that the PI3K pathway is commonly found activated in cancer cells.

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Human T-cell lymphotropic virus type 1 (HTLV-1) infected cells identified by flow cytometry and HTLV-1 proviral load

Journal of the American Academy of Dermatology ◽

10.1016/j.jaad.2015.02.658 ◽

2015 ◽

Vol 72 (5) ◽

pp. AB160

Keyword(s):

Flow Cytometry ◽

T Cell ◽

Virus Type ◽

Proviral Load ◽

Human T Cell ◽

Infected Cells

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Human T-cell leukaemia virus type 1: parasitism and pathogenesis

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2016.0272 ◽

2017 ◽

Vol 372 (1732) ◽

pp. 20160272 ◽

Cited By ~ 25

Author(s):

Charles R. M. Bangham ◽

Masao Matsuoka

Keyword(s):

T Cell ◽

Virus Type ◽

Inflammatory Diseases ◽

Spastic Paraparesis ◽

Cell Leukaemia ◽

Cell Contact ◽

Leukaemia Virus ◽

Human T Cell ◽

Infected Cells

Human T-cell leukaemia virus type 1 (HTLV-1) causes not only adult T-cell leukaemia-lymphoma (ATL), but also inflammatory diseases including HTLV-1-associated myelopathy/tropical spastic paraparesis. HTLV-1 transmits primarily through cell-to-cell contact, and generates abundant infected cells in the host in order to survive and transmit to a new host. The resulting high proviral load is closely associated with the development of ATL and inflammatory diseases. To increase the number of infected cells, HTLV-1 changes the immunophenotype of infected cells, induces proliferation and inhibits apoptosis through the cooperative actions of two viral genes, tax and HTLV-1 bZIP factor ( HBZ ). As a result, infected cells survive, proliferate and infiltrate into the tissues, which is critical for transmission of the virus. Thus, the strategy of this virus is indivisibly linked with its pathogenesis, providing a clue for prevention and treatment of HTLV-1-induced diseases. This article is part of the themed issue ‘Human oncogenic viruses’.

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De Novo Human T-Cell Leukemia Virus Type 1 Infection of Human Lymphocytes in NOD-SCID, Common γ-Chain Knockout Mice

Journal of Virology ◽

10.1128/jvi.01009-06 ◽

2006 ◽

Vol 80 (21) ◽

pp. 10683-10691 ◽

Cited By ~ 37

Author(s):

Paola Miyazato ◽

Jun-ichirou Yasunaga ◽

Yuko Taniguchi ◽

Yoshio Koyanagi ◽

Hiroaki Mitsuya ◽

...

Keyword(s):

T Cell ◽

De Novo ◽

Leukemia Virus ◽

T Cell Leukemia ◽

Cell Leukemia ◽

Cell Leukemia Virus Type ◽

Human Pbmc ◽

Human T Cell ◽

Infected Cells ◽

Nog Mice

ABSTRACT Human T-cell leukemia virus type 1 (HTLV-1) is the etiologic agent of adult T-cell leukemia, a disease that is triggered after a long latency period. HTLV-1 is known to spread through cell-to-cell contact. In an attempt to study the events in early stages of HTLV-1 infection, we inoculated uninfected human peripheral blood mononuclear cells and the HTLV-1-producing cell line MT-2 into NOD-SCID, common γ-chain knockout mice (human PBMC-NOG mice). HTLV-1 infection was confirmed with the detection of proviral DNA in recovered samples. Both CD4+ and CD8+ T cells were found to harbor the provirus, although the latter population harbored provirus to a lesser extent. Proviral loads increased with time, and inverse PCR analysis revealed the oligoclonal proliferation of infected cells. Although tax gene transcription was suppressed in human PBMC-NOG mice, it increased after in vitro culture. This is similar to the phenotype of HTLV-1-infected cells isolated from HTLV-1 carriers. Furthermore, the reverse transcriptase inhibitors azidothymidine and tenofovir blocked primary infection in human PBMC-NOG mice. However, when tenofovir was administered 1 week after infection, the proviral loads did not differ from those of untreated mice, indicating that after initial infection, clonal proliferation of infected cells was predominant over de novo infection of previously uninfected cells. In this study, we demonstrated that the human PBMC-NOG mouse model should be a useful tool in studying the early stages of primary HTLV-1 infection.

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