scholarly journals Kinetic Analysis of Human T-Cell Leukemia Virus Type 1 Gene Expression in Cell Culture and Infected Animals

2009 ◽  
Vol 83 (8) ◽  
pp. 3788-3797 ◽  
Author(s):  
Min Li ◽  
Matthew Kesic ◽  
Han Yin ◽  
Lianbo Yu ◽  
Patrick L. Green
Keyword(s):  
Gene Expression ◽  
T Cell ◽  
Proviral Load ◽  
Leukemia Virus ◽  
Viral Gene ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Cell Leukemia Virus Type ◽  
Human T Cell

ABSTRACT Human T-cell leukemia virus type 1 (HTLV-1) infection causes adult T-cell leukemia and is associated with a variety of lymphocyte-mediated disorders. It has been hypothesized that a highly regulated pattern of HTLV-1 gene expression is critical for virus survival and disease pathogenesis. In this study, real-time reverse transcriptase PCR was used to determine the kinetics of viral gene expression in cells transiently transfected with an HTLV-1 proviral plasmid, in newly infected human peripheral blood mononuclear cells (PBMCs), and in PBMCs from newly infected rabbits. The HTLV-1 gene expression profiles in transiently transfected and infected cells were similar; over time, all transcripts increased and then maintained stable levels. gag/pol, tax/rex, and env mRNA were detected first and at the highest levels, whereas the expression levels of the accessory genes, including the antisense Hbz, were significantly lower than the tax/rex levels (ranging from 1 to 4 logs depending on the specific mRNA). In infected rabbits, tax/rex and gag/pol mRNA levels peaked early after inoculation and progressively decreased, which correlated inversely with the proviral load and host antibody response against viral proteins. Interestingly, Hbz mRNA was detectable at 1 week postinfection and increased and stabilized. The expression levels of all other HTLV-1 genes in infected rabbit PBMCs were at or below our limit of detection. This analysis provides insight into viral gene expression under various in vitro and in vivo experimental conditions. Our in vivo data indicate that in infected rabbits, Hbz mRNA expression over time directly correlates with the proviral load, which provides the first evidence linking Hbz expression to proviral load and the survival of the virus-infected cell in the host.

scholarly journals 5′-Long Terminal Repeat-Selective CpG Methylation of Latent Human T-Cell Leukemia Virus Type 1 Provirus In Vitro and In Vivo

2002 ◽  
Vol 76 (18) ◽  
pp. 9389-9397 ◽  
Author(s):  
Tsukasa Koiwa ◽  
Akiko Hamano-Usami ◽  
Takaomi Ishida ◽  
Akihiko Okayama ◽  
Kazunari Yamaguchi ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cell ◽  
Leukemia Virus ◽  
Cpg Methylation ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Cell Leukemia Virus Type ◽  
Human T Cell

ABSTRACT CpG methylation of the human T-cell leukemia virus type 1 (HTLV-1) long terminal repeat (LTR) has been implicated in proviral latency, but there is presently little information available regarding the pattern of LTR methylation and its effect on viral gene expression. To gain insight into the mechanisms of HTLV-1 latency, we have studied methylation of individual CpG sites in the U3-R region of the integrated proviral LTR by using bisulfite genomic sequencing methods. Surprisingly, our results reveal selective hypermethylation of the 5′ LTR and accompanying hypomethylation of the 3′ LTR in both latently infected cell lines and adult T-cell leukemia (ATL) cells having a complete provirus. Moreover, we observed a lack of CpG methylation in the LTRs of 5′-defective proviruses recovered from ATL samples, which is consistent with the selective hypomethylation of the 3′ LTR. Thus, the integrated HTLV-1 provirus in these carriers appears to be hypermethylated in the 5′ LTR and hypomethylated in the 3′ LTR. These results, together with the observation that proviral gene expression is reactivated by 5-azacytidine in latently infected cell lines, indicate that selective hypermethylation of the HTLV-1 5′ LTR is common both in vivo and in vitro. Thus, hypermethylation of the 5′ LTR appears to be an important mechanism by which HTLV-1 gene expression is repressed during viral latency.

scholarly journals Proviral Features of Human T Cell Leukemia Virus Type 1 in Carriers with Indeterminate Western Blot Analysis Results

2017 ◽  
Vol 55 (9) ◽  
pp. 2838-2849 ◽  
Author(s):  
Madoka Kuramitsu ◽  
Tsuyoshi Sekizuka ◽  
Tadanori Yamochi ◽  
Sanaz Firouzi ◽  
Tomoo Sato ◽  
...  
Keyword(s):  
T Cell ◽  
Virus Type ◽  
Proviral Load ◽  
Leukemia Virus ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Cell Leukemia Virus Type ◽  
Human T Cell ◽  
T Cell Leukemia Virus

ABSTRACTWestern blotting (WB) for human T cell leukemia virus type 1 (HTLV-1) is performed to confirm anti-HTLV-1 antibodies detected at the initial screening of blood donors and in pregnant women. However, the frequent occurrence of indeterminate results is a problem with this test. We therefore assessed the cause of indeterminate WB results by analyzing HTLV-1 provirus genomic sequences. A quantitative PCR assay measuring HTLV-1 provirus in WB-indeterminate samples revealed that the median proviral load was approximately 100-fold lower than that of WB-positive samples (0.01 versus 0.71 copy/100 cells). Phylogenic analysis of the complete HTLV-1 genomes of WB-indeterminate samples did not identify any specific phylogenetic groups. When we analyzed the nucleotide changes in 19 HTLV-1 isolates from WB-indeterminate samples, we identified 135 single nucleotide substitutions, composed of four types, G to A (29%), C to T (19%), T to C (19%), and A to G (16%). In the most frequent G-to-A substitution, 64% occurred at GG dinucleotides, indicating that APOBEC3G is responsible for mutagenesis in WB-indeterminate samples. Moreover, interestingly, five WB-indeterminate isolates had nonsense mutations in Pol and/or Tax, Env, p12, and p30. These findings suggest that WB-indeterminate carriers have low production of viral antigens because of a combination of a low proviral load and mutations in the provirus, which may interfere with host recognition of HTLV-1 antigens.

scholarly journals Functional Comparison of HBZ and the Related APH-2 Protein Provides Insight into Human T-Cell Leukemia Virus Type 1 Pathogenesis

2016 ◽  
Vol 90 (7) ◽  
pp. 3760-3772 ◽  
Author(s):  
Amanda R. Panfil ◽  
Nathan J. Dissinger ◽  
Cory M. Howard ◽  
Brandon M. Murphy ◽  
Kristina Landes ◽  
...  
Keyword(s):  
T Cell ◽  
Leukemia Virus ◽  
Antisense Strand ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Cell Leukemia Virus Type ◽  
Human T Cell ◽  
T Cell Leukemia Virus

ABSTRACTHuman T-cell leukemia virus type 1 (HTLV-1) and type 2 (HTLV-2) are highly related retroviruses that transform T cellsin vitrobut have distinct pathological outcomesin vivo. HTLV-1 encodes a protein from the antisense strand of its proviral genome, the HTLV-1 basic leucine zipper factor (HBZ), which inhibits Tax-1-mediated viral transcription and promotes cell proliferation, a high proviral load, and persistencein vivo. In adult T-cell leukemia/lymphoma (ATL) cell lines and patient T cells,hbzis often the only viral gene expressed. The antisense strand of the HTLV-2 proviral genome also encodes a protein termed APH-2. Like HBZ, APH-2 is able to inhibit Tax-2-mediated viral transcription and is detectable in most primary lymphocytes from HTLV-2-infected patients. However, unlike HBZ, the loss of APH-2in vivoresults in increased viral replication and proviral loads, suggesting that HBZ and APH-2 modulate the virus and cellular pathways differently. Herein, we examined the effect of APH-2 on several known HBZ-modulated pathways: NF-κB (p65) transactivation, transforming growth factor β (TGF-β) signaling, and interferon regulatory factor 1 (IRF-1) transactivation. Like HBZ, APH-2 has the ability to inhibit p65 transactivation. Conversely, HBZ and APH-2 have divergent effects on TGF-β signaling and IRF-1 transactivation. Quantitative PCR and protein half-life experiments revealed a substantial disparity between HBZ and APH-2 transcript levels and protein stability, respectively. Taken together, our data further elucidate the functional differences between HBZ and APH-2 and how these differences can have profound effects on the survival of infected cells and, ultimately, pathogenesis.IMPORTANCEHuman T-cell leukemia virus type 1 (HTLV-1) and type 2 (HTLV-2) are highly related retroviruses that have distinct pathological outcomes in infected hosts. Functional comparisons of HTLV-1 and HTLV-2 proteins provide a better understanding about how HTLV-1 infection is associated with disease and HTLV-2 infection is not. The HTLV genome antisense-strand geneshbzandaph-2are often the only viral genes expressed in HTLV-infected T cells. Previously, our group found that HTLV-1 HBZ and HTLV-2 APH-2 had distinct effectsin vivoand hypothesized that the differences in the interactions of HBZ and APH-2 with important cell signaling pathways dictate whether cells undergo proliferation, apoptosis, or senescence. Ultimately, these functional differences may affect how HTLV-1 causes disease but HTLV-2 generally does not. In the current study, we compared the effects of HBZ and APH-2 on several HTLV-relevant cellular pathways, including the TGF-β signaling, NF-κB activation, and IRF-1 transactivation pathways.

scholarly journals Tax and Overlapping Rex Sequences Do Not Confer the Distinct Transformation Tropisms of Human T-Cell Leukemia Virus Types 1 and 2

2003 ◽  
Vol 77 (14) ◽  
pp. 7728-7735 ◽  
Author(s):  
Jianxin Ye ◽  
Li Xie ◽  
Patrick L. Green
Keyword(s):  
T Cells ◽  
T Cell ◽  
Leukemia Virus ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Cell Leukemia Virus Type ◽  
Human T Cell ◽  
T Cell Leukemia Virus

ABSTRACT Human T-cell leukemia virus type 1 (HTLV-1) and HTLV-2 are distinct oncogenic retroviruses that infect several cell types but display their biological and pathogenic activity only in T cells. Previous studies have indicated that in vivo HTLV-1 has a preferential tropism for CD4+ T cells, whereas HTLV-2 in vivo tropism is less clear but appears to favor CD8+ T cells. Both CD4+ and CD8+ T cells are susceptible to HTLV-1 and HTLV-2 infection in vitro, and HTLV-1 has a preferential immortalization and transformation tropism of CD4+ T cells, whereas HTLV-2 immortalizes and transforms primarily CD8+ T cells. The molecular mechanism that determines this tropism of HTLV-1 and HTLV-2 has not been determined. HTLV-1 and HTLV-2 carry the tax and rex transregulatory genes in separate but partially overlapping reading frames. Since Tax has been shown to be critical for cellular transformation in vitro and interacts with numerous cellular processes, we hypothesized that the viral determinant of transformation tropism is encoded by tax. Using molecular clones of HTLV-1 (Ach) and HTLV-2 (pH6neo), we constructed recombinants in which tax and overlapping rex genes of the two viruses were exchanged. p19 Gag expression from proviral clones transfected into 293T cells indicated that both recombinants contained functional Tax and Rex but with significantly altered activity compared to the wild-type clones. Stable transfectants expressing recombinant viruses were established, irradiated, and cocultured with peripheral blood mononuclear cells. Both recombinants were competent to transform T lymphocytes with an efficiency similar to that of the parental viruses. Flow cytometry analysis indicated that HTLV-1 and HTLV-1/TR2 had a preferential tropism for CD4+ T cells and that HTLV-2 and HTLV-2/TR1 had a preferential tropism for CD8+ T cells. Our results indicate that tax/rex in different genetic backgrounds display altered functional activity but ultimately do not contribute to the different in vitro transformation tropisms. This first study with recombinants between HTLV-1 and HTLV-2 is the initial step in elucidating the different pathobiologies of HTLV-1 and HTLV-2.

scholarly journals Essential Role of Human T Cell Leukemia Virus Type 1orf-Iin Lethal Proliferation of CD4+Cells in Humanized Mice

2019 ◽  
Vol 93 (19) ◽  
Author(s):  
Veronica Galli ◽  
Christopher C. Nixon ◽  
Natasa Strbo ◽  
Maria Artesi ◽  
Maria F. de Castro-Amarante ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Leukemia Virus ◽  
Humanized Mice ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Cell Leukemia Virus Type ◽  
Human T Cell ◽  
T Cell Leukemia Virus

ABSTRACTHuman T cell leukemia virus type 1 (HTLV-1) is the ethological agent of adult T cell leukemia/lymphoma (ATLL) and a number of lymphocyte-mediated inflammatory conditions, including HTLV-1-associated myelopathy/tropical spastic paraparesis. HTLV-1orf-Iencodes two proteins, p8 and p12, whose functions in humans are to counteract innate and adaptive responses and to support viral transmission. However, thein vivorequirements fororf-Iexpression vary in different animal models. In macaques, the ablation oforf-Iexpression by mutation of its ATG initiation codon abolishes the infectivity of the molecular clone HTLV-1p12KO. In rabbits, HTLV-1p12KOis infective and persists efficiently. We used humanized mouse models to assess the infectivity of both wild-type HTLV-1 (HTLV-1WT) and HTLV-1p12KO. We found that NOD/SCID/γC−/−c-kit+mice engrafted with human tissues 1 day after birth (designated NSG-1d mice) were highly susceptible to infection by HTLV-1WT, with a syndrome characterized by the rapid polyclonal proliferation and infiltration of CD4+CD25+T cells into vital organs, weight loss, and death. HTLV-1 clonality studies revealed the presence of multiple clones of low abundance, confirming the polyclonal expansion of HTLV-1-infected cellsin vivo. HTLV-1p12KOinfection in a bone marrow-liver-thymus (BLT) mouse model prone to graft-versus-host disease occurred only following reversion of theorf-Iinitiation codon mutation within weeks after exposure and was associated with high levels of HTLV-1 DNA in blood and the expansion of CD4+CD25+T cells. Thus, the incomplete reconstitution of the human immune system in BLT mice may provide a window of opportunity for HTLV-1 replication and the selection of viral variants with greater fitness.IMPORTANCEHumanized mice constitute a useful model for studying the HTLV-1-associated polyclonal proliferation of CD4+T cells and viral integration sites in the human genome. The rapid death of infected animals, however, appears to preclude the clonal selection typically observed in human ATLL, which normally develops in 2 to 5% of individuals infected with HTLV-1. Nevertheless, the expansion of multiple clones of low abundance in these humanized mice mirrors the early phase of HTLV-1 infection in humans, providing a useful model to investigate approaches to inhibit virus-induced CD4+T cell proliferation.

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

2019 ◽  
Vol 93 (16) ◽  
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.

scholarly journals Human T-Cell Leukemia Virus Type 1 Tax Enhances Serum Response Factor DNA Binding and Alters Site Selection

2007 ◽  
Vol 81 (11) ◽  
pp. 6089-6098 ◽  
Author(s):  
Heather Y. Winter ◽  
Susan J. Marriott
Keyword(s):  
Gene Expression ◽  
T Cell ◽  
Serum Response Factor ◽  
Leukemia Virus ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Cell Leukemia Virus Type ◽  
Human T Cell ◽  
T Cell Leukemia Virus ◽  
Serum Response

ABSTRACT Human T-cell leukemia virus type I (HTLV-1) is the etiological agent of adult T-cell leukemia. The viral transforming protein Tax regulates the transcription of viral and cellular genes by interacting with cellular transcription factors and coactivators. The effects of Tax on cellular gene expression have an important impact on HTLV-1-mediated cellular transformation. Expression of the c-fos cellular oncogene is regulated by serum response factor (SRF), and Tax is known to induce c-fos gene expression by activating SRF-responsive transcription. SRF activates cellular gene expression by binding to a consensus DNA sequence (CArG box) located within a serum response element (SRE). Since SRF activates transcription of many growth regulatory genes, this pathway is likely to have a significant impact on Tax-mediated transformation. Here we demonstrate that Tax interacts with SRF and enhances the binding of SRF to SREs located in the c-fos, Nur77, and viral promoters. Also, we establish that in the presence of Tax, SRF selects more divergent CArG box sequences than in the absence of Tax, revealing a novel mechanism for regulating SRF-responsive gene expression. Finally, increased association of SRF with chromatin and specific promoters was observed in Tax-expressing cells, correlating with increased c-fos and Nur77 mRNA levels in Tax-expressing cells. These results suggest that Tax activates SRF-responsive transcription by enhancing its binding affinity to multiple different SRE sequences.

scholarly journals Hyperediting of human T-cell leukemia virus type 2 and simian T-cell leukemia virus type 3 by the dsRNA adenosine deaminase ADAR-1

2012 ◽  
Vol 93 (12) ◽  
pp. 2646-2651 ◽  
Author(s):  
Nga Ling Ko ◽  
Emmanuel Birlouez ◽  
Simon Wain-Hobson ◽  
Renaud Mahieux ◽  
Jean-Pierre Vartanian
Keyword(s):  
T Cell ◽  
Virus Type ◽  
Leukemia Virus ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Cell Leukemia Virus Type ◽  
Human T Cell ◽  
T Cell Leukemia Virus ◽  
Type 3

RNA editing mediated by adenosine deaminases acting on RNA (ADARs) converts adenosine (A) to inosine (I) residues in dsRNA templates. While ADAR-1-mediated editing was essentially described for RNA viruses, the present work addresses the issue for two δ-retroviruses, human T-cell leukemia virus type 2 and simian T-cell leukemia virus type 3 (HTLV-2 and STLV-3). We examined whether ADAR-1 could edit HTLV-2 and STLV-3 virus genomes in cell culture and in vivo. Using a highly sensitive PCR-based method, referred to as 3DI-PCR, we showed that ADAR-1 could hypermutate adenosine residues in HTLV-2. STLV-3 hypermutation was obtained without using 3DI-PCR, suggesting a higher mutation frequency for this virus. Detailed analysis of the dinucleotide editing context showed preferences for 5′ ArA and 5′ UrA. In conclusion, the present observations demonstrate that ADAR-1 massively edits HTLV-2 and STLV-3 retroviruses in vitro, but probably remains a rare phenomenon in vivo.

Preferential selection of human T-cell leukemia virus type I provirus integration sites in leukemic versus carrier states

Blood ◽  
2005 ◽  
Vol 106 (3) ◽  
pp. 1048-1053 ◽  
Author(s):  
Keitarou Doi ◽  
Xiaolin Wu ◽  
Yuko Taniguchi ◽  
Jun-ichirou Yasunaga ◽  
Yorifumi Satou ◽  
...  
Keyword(s):  
T Cell ◽  
Leukemia Virus ◽  
Leukemic Cells ◽  
Viral Gene ◽  
Type I ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Cell Leukemia Virus Type ◽  
Human T Cell ◽  
Integration Sites

Abstract Human T-cell leukemia virus type I (HTLV-I) is a causative agent of neoplastic disease, adult T-cell leukemia (ATL). Although the encoding viral proteins play an important role in oncogenesis, the role of the HTLV-I proviral integration site remains unsolved. We determined the integration sites of HTLV-I proviruses in ATL cells and HTLV-I–infected cells in asymptomatic carriers. In carrier and ATL cells, HTLV-I provirus was integrated into the transcriptional unit at frequencies of 26.8% (15/56) and 33.9% (20/59), respectively, which were equivalent to the frequency calculated based on random integration (33.2%). In addition, HTLV-I provirus was prone to integration near the transcriptional start sites in leukemic cells (P = .006), and the transcriptional direction of the provirus was in accordance with that of integrated cellular genes in 70% of cases. More importantly, the integration sites in the carrier cells favored the alphoid repetitive sequences (11/56; 20%) whereas in leukemic cells they disfavored these sequences (2/59; 3.4%). Taken together, during natural course from carrier to onset of ATL, HTLV-I–infected cells with integration sites favorable for viral gene transcription are susceptible to malignant transformation due to increased viral gene expression.

scholarly journals Prevention of Adult T-Cell Leukemia-Like Lymphoproliferative Disease in Rats by Adoptively Transferred T Cells from a Donor Immunized with Human T-Cell Leukemia Virus Type 1 Tax-Coding DNA Vaccine

2000 ◽  
Vol 74 (20) ◽  
pp. 9610-9616 ◽  
Author(s):  
Takashi Ohashi ◽  
Shino Hanabuchi ◽  
Hirotomo Kato ◽  
Hiromi Tateno ◽  
Fumiyo Takemura ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Dna Vaccine ◽  
Leukemia Virus ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Cell Leukemia Virus Type ◽  
Adult T Cell Leukemia ◽  
Human T Cell

ABSTRACT Human T-cell leukemia virus type 1 (HTLV-1) causes adult T-cell leukemia (ATL) in infected individuals after a long incubation period. To dissect the mechanisms of the development of the disease, we have previously established a rat model of ATL-like disease which allows examination of the growth and spread of HTLV-1 infected tumor cells, as well assessment of the effects of immune T cells on the development of the disease. In the present study, we induced HTLV-1 Tax-specific cytotoxic T lymphocyte (CTL) immunity by vaccination with Tax-coding DNA and examined the effects of the DNA vaccine in our rat ATL-like disease model. Our results demonstrated that DNA vaccine with Tax effectively induced Tax-specific CTL activity in F344/N Jcl-rnu/+ (nu/+) rats and that these CTLs were able to lyse HTLV-1 infected syngeneic T cells in vitro. Adoptive transfer of these immune T cells effectively inhibited the in vivo growth of HTLV-1-transformed tumor in F344/N Jcl-rnu/rnu (nu/nu) rats inoculated with a rat HTLV-1 infected T cell line. Vaccination with mutant Tax DNA lacking transforming ability also induced efficient anti-tumor immunity in this model. Our results indicated a promising effect for DNA vaccine with HTLV-1 Tax against HTLV-1 tumor development in vivo.

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