scholarly journals Immune activation induces immortalization of HTLV-1 LTR-Tax transgenic CD4+ T cells

Blood ◽  
2010 ◽  
Vol 116 (16) ◽  
pp. 2994-3003 ◽  
Author(s):  
Alison Y. Swaims ◽  
Francesca Khani ◽  
Yingyu Zhang ◽  
Arthur I. Roberts ◽  
Satish Devadas ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Activation ◽  
Cd4 T Cells ◽  
Leukemia Virus ◽  
Host Immune System ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Immune System Activation ◽  
Human T Cell

AbstractInfection with the human T-cell leukemia virus-1 (HTLV-1) results in a variety of diseases including adult T-cell leukemia/lymphoma (ATL). Although the pathogenesis of these disorders is poorly understood, it involves complex interactions with the host immune system. Activation of infected T cells may play an important role in disease pathogenesis through induction of the oncogenic HTLV-1 Tax transactivator protein. To test this hypothesis, we employed transgenic mice in which Tax is regulated by the HTLV-1 LTR. T-cell receptor stimulation of LTR-Tax CD4+ T cells induced Tax expression, hyper-proliferation, and immortalization in culture. The transition to cellular immortalization was accompanied by markedly increased expression of the antiapoptotic gene, mcl-1, previously implicated as important in T-cell survival. Immortalized cells exhibited a CD4+CD25+CD3− phenotype commonly observed in ATL. Engraftment of activated LTR-Tax CD4+ T cells into NOD/Shi-scid/IL-2Rγ null mice resulted in a leukemia-like phenotype with expansion and tissue infiltration of Tax+, CD4+ lymphocytes. We suggest that immune activation of infected CD4+ T cells plays an important role in the induction of Tax expression, T-cell proliferation, and pathogenesis of ATL in HTLV-1–infected individuals.

The tumor marker Fascin is strongly induced by the Tax oncoprotein of HTLV-1 through NF-κB signals

Blood ◽  
2011 ◽  
Vol 117 (13) ◽  
pp. 3609-3612 ◽  
Author(s):  
Andrea K. Kress ◽  
Martina Kalmer ◽  
Aileen G. Rowan ◽  
Ralph Grassmann ◽  
Bernhard Fleckenstein
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Marker ◽  
Cd4 T Cells ◽  
Initial Step ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Viral Oncoprotein ◽  
Adult T Cell Leukemia ◽  
Human T Cell

AbstractOncogenic transformation of CD4+ T cells by human T-cell lymphotropic virus type 1 (HTLV-1) is understood as the initial step to adult T-cell leukemia/lymphoma, a process that is mainly initiated by perturbation of cellular signaling by the viral Tax oncoprotein, a potent transcriptional regulator. In search of novel biomarkers with relevance to oncogenesis, we identified the tumor marker and actin-bundling protein Fascin (FSCN1) to be specifically and strongly up-regulated in both HTLV-1–transformed and adult T-cell leukemia/lymphoma patient-derived CD4+ T cells. Fascin is important for migration and metastasis in various types of cancer. Here we report that a direct link can exist between a single viral oncoprotein and Fascin expression, as the viral oncoprotein Tax was sufficient to induce high levels of Fascin. Nuclear factor-κB signals were important for Tax-mediated transcriptional regulation of Fascin in T cells. This suggests that Fascin up-regulation by Tax contributes to the development of HTLV-1–associated pathogenesis.

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 Human T-Cell Leukemia Virus Type 1 Infection Leads to Arrest in the G1 Phase of the Cell Cycle

2008 ◽  
Vol 82 (17) ◽  
pp. 8442-8455 ◽  
Author(s):  
Meihong Liu ◽  
Liangpeng Yang ◽  
Ling Zhang ◽  
Baoying Liu ◽  
Randall Merling ◽  
...  
Keyword(s):  
Cell Cycle ◽  
T Cells ◽  
T Cell ◽  
Leukemia Virus ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Cell Leukemia Virus Type ◽  
Human T Cell ◽  
T Cell Leukemia Virus

ABSTRACT Infection by the human T-cell leukemia virus type 1 (HTLV-1) is thought to cause dysregulated T-cell proliferation, which in turn leads to adult T-cell leukemia/lymphoma. Early cellular changes after HTLV-1 infection have been difficult to study due to the poorly infectious nature of HTLV-1 and the need for cell-to-cell contact for HTLV-1 transmission. Using a series of reporter systems, we show that HeLa cells cease proliferation within one or two division cycles after infection by HTLV-1 or transduction of the HTLV-1 tax gene. HTLV-1-infected HeLa cells, like their tax-transduced counterparts, expressed high levels of p21 CIP1/WAF1 and p27 KIP1 , developed mitotic abnormalities, and became arrested in G1 in senescence. In contrast, cells of a human osteosarcoma lineage (HOS) continued to divide after HTLV-1 infection or Tax expression, albeit at a reduced growth rate and with mitotic aberrations. Unique to HOS cells is the dramatic reduction of p21 CIP1/WAF1 and p27 KIP1 expression, which is in part associated with the constitutive activation of the phosphatidylinositol-3-kinase (PI3K)-protein kinase B (Akt) pathway. The loss of p21 CIP1/WAF1 and p27 KIP1 in HOS cells apparently allows HTLV-1- and Tax-induced G1 arrest to be bypassed. Finally, HTLV-1 infection and Tax expression also cause human SupT1 T cells to arrest in the G1 phase of the cell cycle. These results suggest that productive HTLV-1 infection ordinarily leads to Tax-mediated G1 arrest. However, T cells containing somatic mutations that inactivate p21 CIP1/WAF1 and p27 KIP1 may continue to proliferate after HTLV-1 infection and Tax expression. These infected cells can expand clonally, accumulate additional chromosomal abnormalities, and progress to cancer.

scholarly journals 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

2004 ◽  
Vol 78 (8) ◽  
pp. 3827-3836 ◽  
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.

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.

scholarly journals Human T-cell leukemia virus type-1 antisense-encoded gene, Hbz, promotes T-lymphocyte proliferation

Blood ◽  
2008 ◽  
Vol 112 (9) ◽  
pp. 3788-3797 ◽  
Author(s):  
Joshua Arnold ◽  
Bevin Zimmerman ◽  
Min Li ◽  
Michael D. Lairmore ◽  
Patrick L. Green
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Survival ◽  
Leukemia Virus ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Cell Leukemia Virus Type ◽  
Human T Cell ◽  
T Cell Leukemia Virus

Human T-cell leukemia virus type 1 (HTLV-1) basic leucine zipper factor (HBZ) is dispensable for HTLV-1–mediated cellular transformation in cell culture, but is required for efficient viral infectivity and persistence in rabbits. In most adult T-cell leukemia (ATL) cells, Tax oncoprotein expression is typically low or undetectable, whereas Hbz gene expression is maintained, suggesting that Hbz expression may support infected cell survival and, ultimately, leukemogenesis. Emerging data indicate that HBZ protein can interact with cAMP response element binding protein (CREB) and Jun family members, altering transcription factor binding and transactivation of both viral and cellular promoters. Herein, lentiviral vectors that express Hbz-specific short hairpin (sh)–RNA effectively decreased both Hbz mRNA and HBZ protein expression in transduced HTLV-1–transformed SLB-1 T cells. Hbz knockdown correlated with a significant decrease in T-cell proliferation in culture. Both SLB-1 and SLB-1-Hbz knockdown cells engrafted into inoculated NOD/SCIDγchain−/− mice to form solid tumors that also infiltrated multiple tissues. However, tumor formation and organ infiltration were significantly decreased in animals challenged with SLB-1-Hbz knockdown cells. Our data indicate that Hbz expression enhances the proliferative capacity of HTLV-1–infected T cells, playing a critical role in cell survival and ultimately HTLV-1 tumorigenesis in the infected host.

scholarly journals Human T-cell leukemia virus type-1 (HTLV-1) Tax is expressed at the same level in infected cells of HTLV-1-associated myelopathy or tropical spastic paraparesis patients as in asymptomatic carriers but at a lower level in adult T-cell leukemia cells

Blood ◽  
1995 ◽  
Vol 85 (7) ◽  
pp. 1865-1870 ◽  
Author(s):  
Y Furukawa ◽  
M Osame ◽  
R Kubota ◽  
M Tara ◽  
M Yoshida
Keyword(s):  
T Cells ◽  
T Cell ◽  
Leukemia Virus ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Cell Leukemia Virus Type ◽  
Asymptomatic Carriers ◽  
Adult T Cell Leukemia ◽  
Human T Cell ◽  
T Cell Leukemia Virus

Patients with human T-cell leukemia virus type-1 (HTLV-1)-associated myelopathy (HAM/TSP) generally harbor a much greater population of HTLV-1-infected T cells in peripheral blood mononuclear cells (PBMCs) than asymptomatic carriers. These cells are not malignant but frequently proliferate clonally. To investigate the possibility that higher expression of the viral activator Tax induces preferential proliferation of infected nonmalignant T cells in HAM/TSP patients, the expression of Tax mRNA in fresh PBMCs was analyzed by reverse transcriptase-mediated polymerase chain reaction. Total amount of Tax mRNA was higher in HAM/TSP patients than in carriers, but the expression level was almost the same as that in asymptomatic carriers when compared per infected cell. The expression levels in adult T-cell leukemia patients were significantly lower than those in HAM/TSP patients and asymptomatic carriers. These results indicate that tax gene is not expressed at a continuously high level in HAM/TSP patients who carry a high population of infected T cells, even in those with clonally proliferated infected T cells.

Frequent expression of CCR4 in adult T-cell leukemia and human T-cell leukemia virus type 1–transformed T cells

Blood ◽  
2002 ◽  
Vol 99 (5) ◽  
pp. 1505-1511 ◽  
Author(s):  
Osamu Yoshie ◽  
Ryuichi Fujisawa ◽  
Takashi Nakayama ◽  
Hitomi Harasawa ◽  
Hideaki Tago ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Leukemia Virus ◽  
Flow Cytometric Analysis ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Cell Leukemia Virus Type ◽  
Adult T Cell Leukemia ◽  
Human T Cell ◽  
T Cell Leukemia Virus

Chemokines and chemokine receptors play important roles in migration and tissue localization of various lymphocyte subsets. Here, we report the highly frequent expression of CCR4 in adult T-cell leukemia (ATL) and human T-cell leukemia virus type 1 (HTLV-1)–immortalized T cells. Flow cytometric analysis revealed that ATL and HTLV-1–immortalized T-cell lines consistently expressed CCR4. Inducible expression of HTLV-1 transcriptional activator tax in a human T-cell line Jurkat did not, however, up-regulate CCR4 mRNA. In vitro immortalization of peripheral blood T cells led to preferential outgrowth of CD4+ T cells expressing CCR4. We further demonstrated highly frequent expression of CCR4 in fresh ATL cells by (1) reverse transcriptase–polymerase chain reaction (RT-PCR) analysis of CCR4 expression in peripheral blood mononuclear cells (PBMCs) from patients with ATL and healthy controls; (2) flow cytometric analysis of CCR4-expressing cells in PBMCs from patients with ATL and healthy controls; (3) CCR4 staining of routine blood smears from patients with ATL; and (4) an efficient migration of fresh ATL cells to the CCR4 ligands, TARC/CCL17 and MDC/CCL22, in chemotaxis assays. Furthermore, we detected strong signals for CCR4, TARC, and MDC in ATL skin lesions by RT-PCR. Collectively, most ATL cases have apparently derived from CD4+ T cells expressing CCR4. It is now known that circulating CCR4+ T cells are mostly polarized to Th2 and also contain essentially all skin-seeking memory T cells. Thus, HTLV-1–infected CCR4+ T cells may have growth advantages by deviating host immune responses to Th2. CCR4 expression may also account for frequent infiltration of ATL into tissues such as skin and lymph nodes.

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