scholarly journals Human T-Lymphotropic Virus Type 1 Tax Protein Complexes with P-TEFb and Competes for Brd4 and 7SK snRNP/HEXIM1 Binding

2010 ◽  
Vol 84 (24) ◽  
pp. 12801-12809 ◽  
Author(s):  
Won-Kyung Cho ◽  
Moon Kyoo Jang ◽  
Keven Huang ◽  
Cynthia A. Pise-Masison ◽  
John N. Brady
Keyword(s):  
Molecular Weight ◽  
Rna Polymerase Ii ◽  
Virus Type ◽  
T Lymphotropic Virus ◽  
Cyclin T1 ◽  
Tax Protein ◽  
In Cells

ABSTRACT Positive transcription elongation factor b (P-TEFb) plays an important role in stimulating RNA polymerase II elongation for viral and cellular gene expression. P-TEFb is found in cells in either an active, low-molecular-weight (LMW) form or an inactive, high-molecular-weight (HMW) form. We report here that human T-lymphotropic virus type 1 (HTLV-1) Tax interacts with the cyclin T1 subunit of P-TEFb, forming a distinct Tax/P-TEFb LMW complex. We demonstrate that Tax can play a role in regulating the amount of HMW complex present in the cell by decreasing the binding of 7SK snRNP/HEXIM1 to P-TEFb. This is seen both in vitro using purified Tax protein and in vivo in cells transduced with Tax expression constructs. Further, we find that a peptide of cyclin T1 spanning the Tax binding domain inhibits the ability of Tax to disrupt HMW P-TEFb complexes. These results suggest that the direct interaction of Tax with cyclin T1 can dissociate P-TEFb from the P-TEFb/7SK snRNP/HEXIM1 complex for activation of the viral long terminal repeat (LTR). We also show that Tax competes with Brd4 for P-TEFb binding. Chromatin immunoprecipitation (ChIP) assays demonstrated that Brd4 and P-TEFb are associated with the basal HTLV-1 LTR, while Tax and P-TEFb are associated with the activated template. Furthermore, the knockdown of Brd4 by small interfering RNA (siRNA) activates the HTLV-1 LTR promoter, which results in an increase in viral expression and production. Our studies have identified Tax as a regulator of P-TEFb that is capable of affecting the balance between its association with the large inactive complex and the small active complex.

scholarly journals Modulation of the Brd4/P-TEFb Interaction by the Human T-Lymphotropic Virus Type 1 Tax Protein

2007 ◽  
Vol 81 (20) ◽  
pp. 11179-11186 ◽  
Author(s):  
Won-Kyung Cho ◽  
Meisheng Zhou ◽  
Moon Kyoo Jang ◽  
Keven Huang ◽  
Soo-Jin Jeong ◽  
...  
Keyword(s):  
Rna Polymerase Ii ◽  
Virus Type ◽  
Active Form ◽  
Viral Gene ◽  
Dependent Manner ◽  
Binding Studies ◽  
T Lymphotropic Virus ◽  
Cyclin T1

ABSTRACT Positive transcription elongation factor (P-TEFb), which is composed of CDK9 and cyclin T1, plays an important role in cellular and viral gene expression. Our lab has recently demonstrated that P-TEFb is required for Tax transactivation of the viral long terminal repeat (LTR). P-TEFb is found in two major complexes: the inactive form, which is associated with inhibitory subunits 7SK snRNA and HEXIM1, and the active form, which is associated with, at least in part, Brd4. In this study, we analyzed the effect of Brd4 on human T-lymphotropic virus type 1 (HTLV-1) transcription. Overexpression of Brd4 repressed Tax transactivation of the HTLV-1 LTR in a dose-dependent manner. In vitro binding studies suggest that Tax and Brd4 compete for binding to P-TEFb through direct interaction with cyclin T1. Tax interacts with cyclin T1 amino acids 426 to 533, which overlaps the region responsible for Brd4 binding. In vivo, overexpression of Tax decreased the amount of 7SK snRNA associated with P-TEFb and stimulates serine 2 phosphorylation of the RNA polymerase II carboxyl-terminal domain, suggesting that Tax regulates the functionality of P-TEFb. Our results suggest the possibility that Tax may compete and functionally substitute for Brd4 in P-TEFb regulation.

scholarly journals Tax Interacts with P-TEFb in a Novel Manner To Stimulate Human T-Lymphotropic Virus Type 1 Transcription

2006 ◽  
Vol 80 (10) ◽  
pp. 4781-4791 ◽  
Author(s):  
Meisheng Zhou ◽  
Hanxin Lu ◽  
Hyeon Park ◽  
Jaime Wilson-Chiru ◽  
Rebecca Linton ◽  
...  
Keyword(s):  
Rna Polymerase Ii ◽  
Virus Type ◽  
Protein Interactions ◽  
Elongation Factor ◽  
Protein Protein Interactions ◽  
T Lymphotropic Virus ◽  
Histone Deacetylase 1

ABSTRACT Human T-lymphotropic virus type 1 (HTLV-1) encodes a transcriptional activator, Tax, whose function is essential for viral transcription and replication. Tax transactivates the viral long-terminal repeat through a series of protein-protein interactions which facilitate CREB and CBP/p300 binding. In addition, Tax dissociates transcription repressor histone deacetylase 1 interaction with the CREB response element. The subsequent events through which Tax interacts and communicates with RNA polymerase II and cyclin-dependent kinases (CDKs) are not clearly understood. Here we present evidence that Tax recruits positive transcription elongation factor b (P-TEFb) (CDK9/cyclin T1) to the viral promoter. This recruitment likely involves protein-protein interactions since Tax associates with P-TEFb in vitro as demonstrated by glutathione S-transferase fusion protein pull-down assays and in vivo as shown by coimmunoprecipitation assays. Functionally, small interfering RNA directed toward CDK9 inhibited Tax transactivation in transient assays. Consistent with these findings, the depletion of CDK9 from nuclear extracts inhibited Tax transactivation in vitro. Reconstitution of the reaction with wild-type P-TEFb, but not a kinase-dead mutant, recovered HTLV-1 transcription. Moreover, the addition of the CDK9 inhibitor flavopiridol blocked Tax transactivation in vitro and in vivo. Interestingly, we found that Tax regulates CDK9 kinase activity through a novel autophosphorylation pathway.

scholarly journals XBP-1, a Novel Human T-Lymphotropic Virus Type 1 (HTLV-1) Tax Binding Protein, Activates HTLV-1 Basal and Tax-Activated Transcription

2008 ◽  
Vol 82 (9) ◽  
pp. 4343-4353 ◽  
Author(s):  
Sebastian C. Y. Ku ◽  
Jialing Lee ◽  
Joanne Lau ◽  
Meera Gurumurthy ◽  
Raymond Ng ◽  
...  
Keyword(s):  
Virus Type ◽  
Binding Protein ◽  
Host Cells ◽  
Mrna Levels ◽  
Transcription Activator ◽  
Basic Leucine Zipper ◽  
T Lymphotropic Virus ◽  
In Cells

ABSTRACT X-box binding protein 1 (XBP-1), a basic leucine zipper transcription factor, plays a key role in the cellular unfolded protein response (UPR). There are two XBP-1 isoforms in cells, spliced XBP-1S and unspliced XBP-1U. XBP-1U has been shown to bind to the 21-bp Tax-responsive element of the human T-lymphotropic virus type 1 (HTLV-1) long terminal repeat (LTR) in vitro and transactivate HTLV-1 transcription. Here we identify XBP-1S as a transcription activator of HTLV-1. Compared to XBP-1U, XBP-1S demonstrates stronger activating effects on both basal and Tax-activated HTLV-1 transcription in cells. Our results show that both XBP-1S and XBP-1U interact with Tax and bind to the HTLV-1 LTR in vivo. In addition, elevated mRNA levels of the gene for XBP-1 and several UPR genes were detected in the HTLV-1-infected C10/MJ and MT2 T-cell lines, suggesting that HTLV-1 infection may trigger the UPR in host cells. We also identify Tax as a positive regulator of the expression of the gene for XBP-1. Activation of the UPR by tunicamycin showed no effect on the HTLV-1 LTR, suggesting that HTLV-1 transcription is specifically regulated by XBP-1. Collectively, our study demonstrates a novel host-virus interaction between a cellular factor XBP-1 and transcriptional regulation of HTLV-1.

scholarly journals Functional Role of pX Open Reading Frame II of Human T-Lymphotropic Virus Type 1 in Maintenance of Viral Loads In Vivo

2000 ◽  
Vol 74 (3) ◽  
pp. 1094-1100 ◽  
Author(s):  
Joshua T. Bartoe ◽  
Björn Albrecht ◽  
Nathaniel D. Collins ◽  
Michael D. Robek ◽  
Lee Ratner ◽  
...  
Keyword(s):  
Virus Type ◽  
Mononuclear Cells ◽  
Ex Vivo ◽  
Peripheral Blood Mononuclear ◽  
T Lymphotropic Virus ◽  
Viral Loads

ABSTRACT Human T-lymphotropic virus type 1 (HTLV-1) causes adult T-cell leukemia/lymphoma and is associated with a variety of immune-mediated disorders. The role of four open reading frames (ORFs), located between env and the 3′ long terminal repeat of HTLV-1, in mediating disease is not entirely clear. By differential splicing, ORF II encodes two proteins, p13II and p30II, both of which have not been functionally defined. p13II localizes to mitochondria and may alter the configuration of the tubular network of this cellular organelle. p30II localizes to the nucleolus and shares homology with the transcription factors Oct-1 and -2, Pit-1, and POU-M1. Both p13II and p30II are dispensable for infection and immortalization of primary human and rabbit lymphocytes in vitro. To test the role of ORF II gene products in vivo, we inoculated rabbits with lethally irradiated cell lines expressing the wild-type molecular clone of HTLV-1 (ACH.1) or a clone containing selected mutations in ORF II (ACH.30/13.1). ACH.1-inoculated animals maintained higher HTLV-1-specific antibody titers than animals inoculated with ACH.30/13.1. Viral p19 antigen was transiently detected in ex vivo cultures of peripheral blood mononuclear cells (PBMC) from only two ACH.30/13.1-inoculated rabbits, while PBMC cultures from all ACH.1-inoculated rabbits routinely produced p19 antigen. In only three of six animals exposed to the ACH.p30II/p13IIclone could provirus be consistently PCR amplified from extracted PBMC DNA and quantitative competitive PCR showed the proviral loads in PBMC from ACH.p30II/p13II-infected rabbits to be dramatically lower than the proviral loads in rabbits exposed to ACH. Our data indicate selected mutations in pX ORF II diminish the ability of HTLV-1 to maintain high viral loads in vivo and suggest an important function for p13II and p30II in viral pathogenesis.

scholarly journals Human T-lymphotropic Virus Type 1-infected Cells Secrete Exosomes That Contain Tax Protein

2014 ◽  
Vol 289 (32) ◽  
pp. 22284-22305 ◽  
Author(s):  
Elizabeth Jaworski ◽  
Aarthi Narayanan ◽  
Rachel Van Duyne ◽  
Shabana Shabbeer-Meyering ◽  
Sergey Iordanskiy ◽  
...  
Keyword(s):  
Virus Type ◽  
T Lymphotropic Virus ◽  
Tax Protein ◽  
Infected Cells

scholarly journals Early Spatial and Temporal Events of Human T-Lymphotropic Virus Type 1 Spread following Blood-Borne Transmission in a Rabbit Model of Infection

2010 ◽  
Vol 84 (10) ◽  
pp. 5124-5130 ◽  
Author(s):  
Rashade A. H. Haynes ◽  
Bevin Zimmerman ◽  
Laurie Millward ◽  
Evan Ware ◽  
Christopher Premanandan ◽  
...  
Keyword(s):  
Virus Type ◽  
Ex Vivo ◽  
Rabbit Model ◽  
Virus Detection ◽  
Mononuclear Leukocytes ◽  
T Lymphotropic Virus ◽  
Viral Spread ◽  
Temporal Events

ABSTRACT Human T-lymphotropic virus type 1 (HTLV-1) infection causes adult T-cell leukemia/lymphoma (ATL) and is associated with a variety of lymphocyte-mediated disorders. HTLV-1 transmission occurs by transmission of infected cells via breast-feeding by infected mothers, sexual intercourse, and contaminated blood products. The route of exposure and early virus replication events are believed to be key determinants of virus-associated spread, antiviral immune responses, and ultimately disease outcomes. The lack of knowledge of early events of HTLV-1 spread following blood-borne transmission of the virus in vivo hinders a more complete understanding of the immunopathogenesis of HTLV-1 infections. Herein, we have used an established animal model of HTLV-1 infection to study early spatial and temporal events of the viral infection. Twelve-week-old rabbits were injected intravenously with cell-associated HTLV-1 (ACH-transformed R49). Blood and tissues were collected at defined intervals throughout the study to test the early spread of the infection. Antibody and hematologic responses were monitored throughout the infection. HTLV-1 intracellular Tax and soluble p19 matrix were tested from ex vivo cultured lymphocytes. Proviral copy numbers were measured by real-time PCR from blood and tissue mononuclear leukocytes. Our data indicate that intravenous infection with cell-associated HTLV-1 targets lymphocytes located in both primary lymphoid and gut-associated lymphoid compartments. A transient lymphocytosis that correlated with peak virus detection parameters was observed by 1 week postinfection before returning to baseline levels. Our data support emerging evidence that HTLV-1 promotes lymphocyte proliferation preceding early viral spread in lymphoid compartments to establish and maintain persistent infection.

scholarly journals HTLV-1 AND TUBERCULOSIS ASSOCIATION: A REVIEW OF THE LITERATURE

2014 ◽  
Vol 2 (2) ◽  
Author(s):  
Normeide Pedreira dos Santos ◽  
Monique Lírio ◽  
Rita Elizabeth Moreira Mascarenhas ◽  
Leonardo Pereira Santana ◽  
Bernardo Galvão Castro ◽  
...  
Keyword(s):  
Cochrane Library ◽  
T Lymphotropic Virus ◽  
Negative Results ◽  
Size Number ◽  
Group Response ◽  
Increased Risk ◽  
The Relationship

Objective: To review and evaluate the scientific evidences on the relationship between tuberculosis (TB) and HTLV-1 infection. Methods: Searches on MEDLINE, LILACS/SciELO and Cochrane Library databases were performed using the following keywords: HTLV-1 Infection, Human T-lymphotropic virus type 1; Paraparesis Tropical Spastic; Tuberculosis. The following data were evaluated: Study design, sample size, number of controls, frequency of HTLV-1 infection in patients with TB and uninfected controls, mortality in HTLV-1/TB coinfected individuals compared with controls group, response in vivo and in vitro to PPD, frequency of individuals with tuberculin skin test (TST) positive or negative. Results: Nineteen articles were selected: twelve investigated prevalence, four mortality, three evaluated both prevalence and mortality and six described immunological findings. The majority of the studies was conducted in South America (Brazil and Peru), and Japan. Seven out of 12 studies found an increased risk of HTLV-1 in patients with TB diagnosis. The prevalence of HTLV-1/TB co-infection ranged from1.49 % in Brazil to 11.4 % in patients in Peru. Two out of five studies found a higher mortality of patients with HTLV-1/TB co-infection compared to patients with TB alone. Three studies conducted in Africa (Guinea Bissau and Senegal) found no increase in the mortality of patients co-infected with TB and HTLV-1. A decreased response to PPD in vitro or in vivo was observed in co-infected individuals compared with patients with TB alone. Conclusion: Patients with TB diagnosis have a higher prevalence of HTLV-1, compared with uninfected controls. Co-infection HTLV-1/TB increases the mortality of TB.

scholarly journals In vivo and in vitro reactivation impairment of a herpes simplex virus type 1 latency-associated transcript variant in a rabbit eye model.

1991 ◽  
Vol 65 (12) ◽  
pp. 6989-6993 ◽  
Author(s):  
M D Trousdale ◽  
I Steiner ◽  
J G Spivack ◽  
S L Deshmane ◽  
S M Brown ◽  
...  
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Virus Type ◽  
Herpes Simplex Virus Type ◽  
Eye Model ◽  
Rabbit Eye ◽  
Simplex Virus
Sign in / Sign up

Export Citation Format

Share Document