TCF1 and LEF1 act as T-cell intrinsic HTLV-1 antagonists by targeting Tax

Human T-cell leukemia virus type 1 (HTLV-1) is a delta-type retrovirus that induces malignant and inflammatory diseases during its long persistence in vivo. HTLV-1 can infect various kinds of cells; however, HTLV-1 provirus is predominantly found in peripheral CD4 T cells in vivo. Here we find that TCF1 and LEF1, two Wnt transcription factors that are specifically expressed in T cells, inhibit viral replication through antagonizing Tax functions. TCF1 and LEF1 can each interact with Tax and inhibit Tax-dependent viral expression and activation of NF-κB and AP-1. As a result, HTLV-1 replication is suppressed in the presence of either TCF1 or LEF1. On the other hand, T-cell activation suppresses the expression of both TCF1 and LEF1, and this suppression enables Tax to function as an activator. We analyzed the thymus of a simian T-cell leukemia virus type 1 (STLV-1) infected Japanese macaque, and found a negative correlation between proviral load and TCF1/LEF1 expression in various T-cell subsets, supporting the idea that TCF1 and LEF1 negatively regulate HTLV-1 replication and the proliferation of infected cells. Thus, this study identified TCF1 and LEF1 as Tax antagonistic factors in vivo, a fact which may critically influence the peripheral T-cell tropism of this virus.

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In vivo dynamics and adaptation of HTLV-1-infected clones under different clinical conditions

PLoS Pathogens ◽

10.1371/journal.ppat.1009271 ◽

2021 ◽

Vol 17 (2) ◽

pp. e1009271

Author(s):

Mikiko Izaki ◽

Jun-ichirou Yasunaga ◽

Kisato Nosaka ◽

Kenji Sugata ◽

Hayato Utsunomiya ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Virus Type ◽

Leukemia Virus ◽

Cell Leukemia ◽

Cell Leukemia Virus Type ◽

T Cell Leukemia Virus ◽

Infected Cells

Human T-cell leukemia virus type 1 (HTLV-1) spreads through cell contact. Therefore, this virus persists and propagates within the host by two routes: clonal proliferation of infected cells and de novo infection. The proliferation is influenced by the host immune responses and expression of viral genes. However, the detailed mechanisms that control clonal expansion of infected cells remain to be elucidated. In this study, we show that newly infected clones were strongly suppressed, and then stable clones were selected, in a patient who was infected by live liver transplantation from a seropositive donor. Conversely, most HTLV-1+ clones persisted in patients who received hematopoietic stem cell transplantation from seropositive donors. To clarify the role of cell-mediated immunity in this clonal selection, we suppressed CD8+ or CD16+ cells in simian T-cell leukemia virus type 1 (STLV-1)-infected Japanese macaques. Decreasing CD8+ T cells had marginal effects on proviral load (PVL). However, the clonality of infected cells changed after depletion of CD8+ T cells. Consistent with this, PVL at 24 hours in vitro culture increased, suggesting that infected cells with higher proliferative ability increased. Analyses of provirus in a patient who received Tax-peptide pulsed dendritic cells indicate that enhanced anti-Tax immunity did not result in a decreased PVL although it inhibited recurrence of ATL. We postulate that in vivo selection, due to the immune response, cytopathic effects of HTLV-1 and intrinsic attributes of infected cells, results in the emergence of clones of HTLV-1-infected T cells that proliferate with minimized HTLV-1 antigen expression.

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In vivo antagonistic role of the Human T-Cell Leukemia Virus Type 1 regulatory proteins Tax and HBZ

PLoS Pathogens ◽

10.1371/journal.ppat.1009219 ◽

2021 ◽

Vol 17 (1) ◽

pp. e1009219

Author(s):

Abdou Akkouche ◽

Sara Moodad ◽

Rita Hleihel ◽

Hala Skayneh ◽

Séverine Chambeyron ◽

...

Keyword(s):

T Cell ◽

Virus Type ◽

Leukemia Virus ◽

T Cell Leukemia ◽

Cell Leukemia ◽

Cell Leukemia Virus Type ◽

Human T Cell ◽

T Cell Leukemia Virus

Adult T cell leukemia (ATL) is an aggressive malignancy secondary to chronic infection by the human T-cell leukemia virus type 1 (HTLV-1) infection. Two viral proteins, Tax and HBZ, play central roles in ATL leukemogenesis. Tax expression transforms T cells in vitro and induces ATL-like disease in mice. Tax also induces a rough eye phenotype and increases hemocyte count in Drosophila melanogaster, indicative of transformation. Among multiple functions, Tax modulates the expression of the enhancer of zeste homolog 2 (EZH2), a methyltransferase of the Polycomb Repressive Complex 2 (PRC2), leading to H3K27me3-dependent reprogramming of around half of cellular genes. HBZ is a negative regulator of Tax-mediated viral transcription. HBZ effects on epigenetic signatures are underexplored. Here, we established an hbz transgenic fly model, and demonstrated that, unlike Tax, which induces NF-κB activation and enhanced PRC2 activity creating an activation loop, HBZ neither induces transformation nor NF-κB activation in vivo. However, overexpression of Tax or HBZ increases the PRC2 activity and both proteins directly interact with PRC2 complex core components. Importantly, overexpression of HBZ in tax transgenic flies prevents Tax-induced NF-κB or PRC2 activation and totally rescues Tax-induced transformation and senescence. Our results establish the in vivo antagonistic effect of HBZ on Tax-induced transformation and cellular effects. This study helps understanding long-term HTLV-1 persistence and cellular transformation and opens perspectives for new therapeutic strategies targeting the epigenetic machinery in ATL.

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Human T-Cell Leukemia Virus Type 1 Expressing Nonoverlapping Tax and Rex Genes Replicates and Immortalizes Primary Human T Lymphocytes but Fails To Replicate and Persist In Vivo

Journal of Virology ◽

10.1128/jvi.79.23.14473-14481.2005 ◽

2005 ◽

Vol 79 (23) ◽

pp. 14473-14481 ◽

Cited By ~ 8

Author(s):

Ihab Younis ◽

Brenda Yamamoto ◽

Andrew Phipps ◽

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) is an oncogenic retrovirus associated primarily with adult T-cell leukemia and neurological disease. HTLV-1 encodes the positive trans-regulatory proteins Tax and Rex, both of which are essential for viral replication. Tax activates transcription initiation from the viral long terminal repeat and modulates the transcription or activity of a number of cellular genes. Rex regulates gene expression posttranscriptionally by facilitating the cytoplasmic expression of incompletely spliced viral mRNAs. Tax and Rex mutants have been identified that have defective activities or impaired biochemical properties associated with their function. To ultimately determine the contribution of specific protein activities on viral replication and cellular transformation of primary T cells, mutants need to be characterized in the context of an infectious molecular clone. Since the tax and rex genes are in partially overlapping reading frames, mutation in one gene frequently disrupts the other, confounding interpretation of mutational analyses in the context of the virus. Here we generated and characterized a unique proviral clone (H1IT) in which the tax and rex genes were separated by expressing Tax from an internal ribosome entry site. We showed that H1IT expresses both functional Tax and Rex. In short- and long-term coculture assays, H1IT was competent to infect and immortalize primary human T cells similar to wild-type HTLV-1. In contrast, H1IT failed to efficiently replicate and persist in inoculated rabbits, thus emphasizing the importance of temporal and quantitative regulation of specific mRNA for viral survival in vivo.

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Human T-Cell Leukemia Virus Type 1 Envelope Protein: Post-Entry Roles in Viral Pathogenesis

Viruses ◽

10.3390/v14010138 ◽

2022 ◽

Vol 14 (1) ◽

pp. 138

Author(s):

Victoria Maksimova ◽

Amanda R. Panfil

Keyword(s):

T Cells ◽

T Cell ◽

Virus Type ◽

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) is an oncogenic retrovirus that is the causative infectious agent of adult T-cell leukemia/lymphoma (ATL), an aggressive and fatal CD4+ T-cell malignancy, and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), a chronic neurological disease. Disease progression in infected individuals is the result of HTLV-1-driven clonal expansion of CD4+ T-cells and is generally associated with the activities of the viral oncoproteins Tax and Hbz. A closely related virus, HTLV-2, exhibits similar genomic features and the capacity to transform T-cells, but is non-pathogenic. In vitro, HTLV-1 primarily immortalizes or transforms CD4+ T-cells, while HTLV-2 displays a transformation tropism for CD8+ T-cells. This distinct tropism is recapitulated in infected people. Through comparative studies, the genetic determinant for this divergent tropism of HTLV-1/2 has been mapped to the viral envelope (Env). In this review, we explore the emerging roles for Env beyond initial viral entry and examine current perspectives on its contributions to HTLV-1-mediated disease development.

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

Journal of Clinical Microbiology ◽

10.1128/jcm.00659-17 ◽

2017 ◽

Vol 55 (9) ◽

pp. 2838-2849 ◽

Cited By ~ 12

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.

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Human T Cell Leukemia Virus Type 1 Tax Inhibits Innate Antiviral Signaling via NF- B-Dependent Induction of SOCS1

Journal of Virology ◽

10.1128/jvi.00007-11 ◽

2011 ◽

Vol 85 (14) ◽

pp. 6955-6962 ◽

Cited By ~ 45

Author(s):

S. Charoenthongtrakul ◽

Q. Zhou ◽

N. Shembade ◽

N. S. Harhaj ◽

E. W. Harhaj

Keyword(s):

T Cell ◽

Virus Type ◽

Leukemia Virus ◽

T Cell Leukemia ◽

Cell Leukemia ◽

Antiviral Signaling ◽

Cell Leukemia Virus Type ◽

Human T Cell ◽

T Cell Leukemia Virus

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

Journal of Virology ◽

10.1128/jvi.03113-15 ◽

2016 ◽

Vol 90 (7) ◽

pp. 3760-3772 ◽

Cited By ~ 21

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.

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