DOCSLIB.ORG

Both Wild-Type and Strongly Attenuated Bovine Leukemia

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Both Wild-Type and Strongly Attenuated Bovine Leukemia JOURNAL OF VIROLOGY, Jan. 1997, p. 630–639 Vol. 71, No. 1 0022-538X/97/$04.0010 Copyright q 1997, American Society for Microbiology Both Wild-Type and Strongly Attenuated Bovine Leukemia Viruses Protect Peripheral Blood Mononuclear Cells from Apoptosis FRANCK DEQUIEDT,1 EMMANUEL HANON,2 PIERRE KERKHOFS,3 PAUL-PIERRE PASTORET,2 4 1,5 1 1 DANIEL PORTETELLE, ARSE`NE BURNY, RICHARD KETTMANN, AND LUCAS WILLEMS * Department of Molecular Biology and Animal Physiology1 Faculty of Agronomy, B5030 Gembloux, and Department of Microbiology,4 Department of Immunology/Vaccinology, University of Lie´ge, B43 bis, B4000 Lie`ge,2 National Institute of Veterinary Research, B1120 Uccle,3 and Department of Molecular Biology, University of Brussels, B1640 Rhode-St-Gene`se,5 Belgium Received 17 June 1996/Accepted 7 October 1996 Bovine leukemia virus (BLV) and the human T-cell leukemia viruses belong to the same subfamily of oncoviruses. Although much attention has focused on the mechanisms of cell proliferation and transformation by these viruses, experiments on the apoptotic process have yielded conflicting data in in vitro cell culture. Experimental infection of sheep with BLV proviruses offers the opportunity to analyze apoptosis in vivo. Here, we show that BLV-infected peripheral mononuclear cells, cultivated ex vivo, are protected from spontaneous programmed cell death. Moreover, the virus is able to specifically interfere with the apoptotic program of infected B lymphocytes. Strongly attenuated mutant proviruses that harbor deletions in the G4 and/or R3 genes also decrease the global susceptibility to apoptosis at levels similar to those obtained with the wild-type virus. In addition, cell culture supernatants from wild-type and mutant viruses can prevent uninfected cells from undergoing programmed cell death. These observations demonstrate that the R3 and G4 genes are not required to maintain both direct and indirect protection against apoptosis. They also imply that the level of programmed cell death observed ex vivo is independent of the amounts of proviruses in the animals. The failure of these cells to undergo apoptosis might be related to the pathogenesis induced by BLV. The survival of multicellular organisms is regulated by a tight cellular genes involved in the control of cell proliferation (14, control of the critical balance between cell proliferation and 23, 36, 42). The Tax proteins have an immortalization potential death (reviewed in reference 44). Apoptosis is an encoded in cell culture and collaborate with the Ha-ras oncogene to suicide program allowing for the elimination of cells that have transform primary cells (16, 30, 43, 50, 51, 55). At least two been produced in excess, developed improperly, or sustained other mRNAs encoding putative proteins are transcribed from genetic damage. Apoptotic cell death involves a characteristic alternative open reading frames located in the region between panel of morphological and biochemical changes including cy- the env and the tax/rex genes (R3 and G4 for BLV; p30, p13, toskeletal disruption, cell shrinkage, and membrane blebbing. and p12 for HTLV) (1, 2, 5, 20). HTLV-1 p12 has been shown Furthermore, the biochemical hallmark of apoptosis is the to cooperate with bovine papillomavirus E5 in cell transforma- endonuclease-mediated degradation of the genomic DNA into tion and to bind to the b and g chains of the interleukin-2 internucleosomal fragments. receptor (13, 26). In the HTLV-2 system, deletion of the se- A number of studies reported that deregulation of apoptosis quences located between the env and tax genes does not affect is an important feature of virus-induced pathogenesis (for re- the expression of viral proteins and the immortalization of views, see references 33 and 44). The viruses have developed a blood lymphocytes in culture (17). However, the precise role of series of strategies to either enhance or inhibit apoptosis. Vi- these proteins in the pathogenesis of the viruses remains to be ruses that cause persistent infections may prevent or delay identified. The use of recombinant BLVs has allowed the iden- normal cellular suicide programs. Among these viruses, mem- tification of genes required for the viral infectivity. The dele- bers of the family Oncovirinae are nonacutely lymphotropic tion of the R3 and G4 genes does not alter the infectious retroviruses that induce leukemia/lymphoma after long latency potential of the virus but drastically decreases the proviral periods. These viruses include bovine leukemia virus (BLV) loads in vivo (52, 53). This observation suggests a biological and human T-lymphotropic virus types 1 and 2 (HTLV-1 and relevance of these genes in vivo. Similar conclusions were -2), which are similar in genetic organization (34, 37). In ad- obtained after infection of recombinant HTLV-2 proviruses in dition to the classical gag, pol, and env retroviral genes, they rabbits (6). The pathologic effects induced by these recombi- contain an X region coding for a number of regulatory genes nants remain unknown. (37, 39). This region contains two genes, tax and rex, that are Because of the lack of an appropriate animal system, it has involved in transcriptional and posttranscriptional regulation been difficult to understand the role of HTLV-1 in the apo- of viral expression (4, 9, 10, 41, 48). BLV Tax and HTLV-1 Tax ptotic process. Depending on the experimental conditions, are nuclear proteins that transactivate long terminal repeat- contradictory conclusions have been obtained in in vitro cell directed gene expression (9, 12, 40, 48). In addition, the Tax culture. The HTLV-1 Tax protein was initially described as an protein from HTLV-1 activates transcription of a number of inducer of apoptosis in murine fibroblasts (54). Indeed, Tax- transformed Rat-1 cells undergo apoptotic cell death after serum deprivation. This Tax-mediated apoptosis is blocked by * Corresponding author. Mailing address: Avenue Mare´chal Juin, the coexpression of the bcl-2 proto-oncogene. In contrast, no. 13, B5030, Gembloux, Belgium. Phone: 32-81-62-21-57. Fax: 32- transfection of the tax gene into Jurkat T cells reduced their 81-61-38-88. susceptibility to anti-APO-1-induced apoptosis (7). Further- 630 VOL. 71, 1997 PROTECTION BY BLV FROM APOPTOSIS 631 more, when Jurkat cells were treated with soluble Tax protein, amplified by 22 cycles (30 s at 948C,30sat608C, and 1 min at 728C). Ten the proportion of cells undergoing apoptosis decreased more microliters of the amplification products were migrated on a 1% agarose gel. After denaturation, the DNA was transferred to a Hybond N1 membrane than twofold. This reduction in the apoptotic levels was less (Amersham) and hybridized with a BLV probe (EcoRI insert from plasmid pronounced when primary human lymphocytes were used. The pSGX3A). This plasmid contains the viral sequences (positions 6755 to 7202 specificity of these assays was supported by the seroneutraliza- according to reference 36) derived from a cDNA isolated from the BLV-infected tion of Tax. Both experimental protocols lack an animal model FLK cell line. BLV p24 titration. After 40 h of culture, 2 3 106 PBMCs were harvested by for HTLV to support the biological relevance of their conclu- centrifugation (800 3 g, 10 min) and resuspended in 100 ml of PBS. The p24 sions. To date, the closest model system where a leukemia major Gag antigen was then titrated from the cells by using an ELISA procedure occurs in vivo is provided by the experimental infection of as previously described (28, 29). Briefly, 96-well microtiter plates were precoated sheep by BLV. We therefore propose to analyze the apoptotic with the anti-p24 monoclonal antibody (MAb) 49G9. The antigen mixtures to be tested were then added to the wells. After washing of the plates, the p24 antigen process in this animal model. was revealed by colorimetric assay using two antibodies (29C1 and 49F5) conju- gated with peroxidase. MAbs and immunophenotyping. As a B-cell marker, we used the anti-bovine MATERIALS AND METHODS immunoglobulin M (IgM) MAb 1H4 (kindly provided by J. J. Letesson, Univer- Peripheral blood mononuclear cell (PBMC) isolations and cultures. Sheep site´ Notre Dame de la Paix, Namur, Belgium), which cross-reacts with ovine infected with the recombinant and wild-type (WT) viruses were previously de- surface (sIgM). The IgM ST8 and IgG1 ST4 MAbs (provided by I. Schwartz, scribed (52, 53). Sheep 234 and 235, sheep 247 and 261, and sheep 265 were URA-INRA, Maisons-Alfort, France) define the sheep CD8 and CD4 homologs, infected with proviruses pBLV344, pBLVIX, and pBLVX3C, respectively. These respectively. Fluorescein isothiocyanate (FITC)-conjugated F(ab9)2 goat anti- three BLVs are similar in terms of infectivity, replication, and pathogenesis in mouse Ig and phycoerythrin (PE)-conjugated F(ab9)2 goat anti-mouse Ig were vivo. Sheep 237, 240, and 272 were initially transfected with the pBLVIG4 purchased from DAKO (Gentbrugge, Belgium). For immunophenotyping, MAbs 1H4, ST4, and ST8 were diluted in PBS with provirus, which contains a translational stop codon in the G4 gene (genotype 6 R31 G42 Tax1 Rex1). The pBLVDX provirus, which harbors deletions of both 10% FCS (PBS-FCS). After their isolation, 2 3 10 PBMCs were incubated for the R3 and G4 genes, was used to infect sheep 245, 246, and 263 (genotype R32 30 min at 48Cin100ml of each primary MAb, washed twice in PBS-FCS, and G42 Tax1 Rex1). In addition, uninfected sheep (sheep 291, 294, 295, 296, 430, incubated in 100 ml of FITC-conjugated antiserum (dilution 1:100 in PBS-FCS). and 441) were used as controls. All infected sheep were 4 or 5 years old. The After two washes in PBS-FCS, the cells were resuspended in PBS and analyzed uninfected sheep 294, 295, and 296 were 1 year old, while sheep 430 and 441 were by flow cytometry (fluorescence-activated cell sorting [FACS]) for green fluo- 3 years old.
Load more

Recommended publications
  • Human T-Cell Leukemia Virus Type I Tax Transactivates Human Interleukin 8 Gene Through Acting Concurrently on AP-1 and Nuclear Factor-KB-Like Sites
    [CANCER RESEARCH 58. 3993-4000. September 1. 1998] Human T-Cell Leukemia Virus Type I Tax Transactivates Human Interleukin 8 Gene through Acting Concurrently on AP-1 and Nuclear Factor-KB-like Sites Naoki Mori,1 Naofumi Mukaida, Dean W. Ballard, Kouji Matsushima, and Naoki Vaniamolo Department of Preventive Medicine and AIDS Research. Research Field of Palhogenesis and Clinical Sciences, Institute of Tropical Medicine, Nagasaki University, Nagasaki 852, Japan ¡N.M.. N. YJ; Department of Pharmacology. Cancer Research Institute, Kanazawa University, Kanayiwa 920, Japan ¡N.M.¡:Department of Molecular Preventive Medicine, School of Medicine. University of Tok\o. Tokyo 113, Japan ¡K.M.I: and Howard Hughes Medical Institute. Vanderhilt University School of Medicine. Nashville, Tennessee 37232-0295 [D. W. BJ ABSTRACT unclear but could be one of the common pathological findings among diseases associated with HTLV-I infection. The transactivator protein, Tax, from the human T-cell leukemia virus IL-8 has potent chemotactic activity for T lymphocytes, as well as type I (HTLV-I) transactivates both viral and cellular genes. Previously, neutrophils (1, 2). Interestingly, T lymphocytes are 10-fold more we had shown that interleukin 8 (II.-8) is constitutively expressed in sensitive to IL-8 than neutrophils in chemotaxis (3). Thus, IL-8 is an HTLV-I-infected cells and in cells transiently expressing Tax. We show here that the II -X promoter is Tax responsive in Jurkat T cells. Further important mediator for tissue infiltration of various subsets of leuko more, using several deletion and mutated plasmids of the 5'-flanking cytes (7).
    [Show full text]
  • Interaction of Bovine Leukemia Virus Transactivator Tax with Bzip Proteins
    VIROLOGY 214, 207–214 (1995) Interaction of Bovine Leukemia Virus Transactivator Tax with bZip Proteins IMRE M. BOROS,1 FENG TIE, and CHOU-ZEN GIAM2 Division of Infectious Diseases, Department of Medicine, Case Western Reserve University, Cleveland, Ohio 44106 Received June 7, 1995; accepted October 2, 1995 The bovine leukemia virus transactivator, BLV Tax, augments transcription from three imperfect 21-bp repeats in the viral transcriptional regulatory region. Each BLV 21-bp repeat contains a cAMP response element (CRE) in the center and unique 5* and 3* neighboring sequences which are crucial for the transcriptional activation by BLV Tax. Here we describe the interactions of recombinant BLV Tax with cellular bZip proteins. The recombinant BLV Tax, tagged at the carboxy terminus with a hexahistidine extension, was prepared by solubilization in 6 M guanidine hydrochloride and renaturation on the Ni2/- chelating Sepharose gel matrix. The renatured BLV TaxH6 activates the BLV LTR when introduced into HeLa cells by scrape loading. Furthermore, the purified BLV TaxH6 enhances binding of members of the CREB/ATF family of bZip proteins to CRE motifs by interacting with their bZip domains in vitro. Chemical cross-linking indicates that dimerization of bZip proteins such as CREB becomes greatly facilitated in the presence of BLV Tax. These results suggest that BLV Tax interacts directly with CREB/ATF-like factors to activate viral mRNA transcription. q 1995 Academic Press, Inc. INTRODUCTION flanking the CRE dictate the exclusive inducibility of the 3 BLV or HTLV-I 21-bp repeats by the respective Tax pro- Bovine leukemia virus (BLV) and human T-lympho- teins (Fujisawa et al., 1989; Montagne et al., 1990; Paca tropic virus type I (HTLV-I) belong to a group of oncore- Uccaralertkun et al., 1994).
    [Show full text]
  • S12977-020-00538-W.Pdf
    Millen et al. Retrovirology (2020) 17:30 https://doi.org/10.1186/s12977-020-00538-w Retrovirology RESEARCH Open Access A novel positive feedback-loop between the HTLV-1 oncoprotein Tax and NF-κB activity in T-cells Sebastian Millen, Lina Meretuk, Tim Göttlicher, Sarah Schmitt, Bernhard Fleckenstein and Andrea K. Thoma‑Kress* Abstract Background: Human T‑cell leukemia virus type 1 (HTLV‑1) infects primarily CD4+ T‑lymphocytes and evoques severe diseases, predominantly Adult T‑Cell Leukemia/ Lymphoma (ATL/L) and HTLV‑1‑associated Myelopathy/ Tropical Spastic Paraparesis (HAM/TSP). The viral transactivator of the pX region (Tax) is important for initiating malignant transformation, and deregulation of the major signaling pathway nuclear factor of kappa B (NF‑κB) by Tax represents a hallmark of HTLV‑1 driven cancer. Results: Here we found that Tax mutants which are defective in NF‑κB signaling showed diminished protein expres‑ sion levels compared to Tax wildtype in T‑cells, whereas Tax transcript levels were comparable. Strikingly, constant activation of NF‑κB signaling by the constitutive active mutant of inhibitor of kappa B kinase (IKK2, IKK‑β), IKK2‑EE, rescued protein expression of the NF‑κB defective Tax mutants M22 and K1‑10R and even increased protein levels of Tax wildtype in various T‑cell lines while Tax transcript levels were only slightly afected. Using several Tax expres‑ sion constructs, an increase of Tax protein occurred independent of Tax transcripts and independent of the promoter used. Further, Tax and M22 protein expression were strongly enhanced by 12‑O‑Tetradecanoylphorbol‑13‑Acetate [TPA; Phorbol 12‑myristate 13‑acetate (PMA)]/ ionomycin, inducers of NF‑κB and cytokine signaling, but not by tumor necrosis factor alpha (TNF‑α).
    [Show full text]
  • Chimeric Proteins Composed of Jun and CREB Define Domains
    JOURNAL OF VIROLOGY, Oct. 1995, p. 6209–6218 Vol. 69, No. 10 0022-538X/95/$04.0010 Copyright q 1995, American Society for Microbiology Chimeric Proteins Composed of Jun and CREB Define Domains Required for Interaction with the Human T-Cell Leukemia Virus Type 1 Tax Protein MIN JEAN YIN, EVYIND PAULSSEN, JACOB SEELER,† AND RICHARD B. GAYNOR* Departments of Internal Medicine and Microbiology, Divisions of Molecular Virology and Hematology-Oncology, University of Texas Southwestern Medical Center, Dallas, Texas 75235-8594 Received 5 April 1995/Accepted 26 June 1995 The regulation of human T-cell leukemia virus type 1 (HTLV-1) long terminal repeat gene expression is dependent on three cis-acting elements known as 21-bp repeats and the transactivator protein Tax. Mutagen- esis has demonstrated that sequences in each of the 21-bp repeats can be divided into three domains designated A, B, and C. Tax stimulates the binding of CREB to the B domain, which is essential for Tax activation of HTLV-1 gene expression. In this study, we demonstrate that Tax will stimulate the binding of CREB to the HTLV-1 21-bp repeats but does not stimulate CREB binding to the consensus cyclic AMP response element (CRE) element found in the somatostatin promoter. However, Tax stimulates CREB binding to a consensus CRE in the context of the 21-bp repeats, indicating the importance of these sequences in stimulating CREB binding. To determine the mechanism by which Tax stimulates CREB binding and determine potential interactions between Tax and CREB, we used the mammalian two-hybrid system in conjunction with in vitro binding and gel retardation assays.
    [Show full text]
  • The Internal Methionine Codons of Human T-Cellleukemia Virus Type
    JOURNAL OF VIROLOGY, Oct. 1990, p. 4914-4921 Vol. 64, No. 10 0022-538X/90/104914-08$02.00/0 Copyright C) 1990, American Society for Microbiology The Internal Methionine Codons of Human T-Cell Leukemia Virus Type II rex Gene Are Not Required for p24rex Production or Virus Replication and Transformation PATRICK L. GREEN,' YIMING XIE,' AND IRVIN S. Y. CHEN' 2* Division of Hematology-Oncology, Department of Medicine,' and Department of Microbiology and Immunology,2 UCLA School of Medicine and Jonsson Comprehensive Cancer Center, Los Angeles, California 90024-1736 Received 21 May 1990/Accepted 12 July 1990 Human T-cell leukemia virus types I (HTLV-I) and II (HTLV-II) have two nonstructural trans-acting regulatory genes, tax and rex, located in the 3' region of the viral genome. The tax gene product (HTLV-I p4O't and HTLV-II p37) is the transcriptional activator of the viral long terminal repeat. The rex gene encodes two protein products, p27rex/p2lrex and p26`ex/p24rex in HTLV-I and HTLV-II, respectively. Rex acts posttran- scriptionally to facilitate accumulation of full-length gaglpol and singly spliced env mRNA in the cytoplasm of HTLV-infected cells. Previous studies showed that the first ATG of the rex gene is critical for Rex production and function. The importance of the internal ATGs to Rex function is not known. However, in vitro mutagenesis of the HTLV-I rex gene has provided indirect evidence which suggests that p2lrex, and by analogy HTLV-II p24rex, results from initiation at an internal AUG of the taxlrex mRNA.
    [Show full text]
  • Transcription Profile of Cells Infected with Human T-Cell Leukemia Virus Type I Compared with Activated Lymphocytes1
    [CANCER RESEARCH 62, 3562–3571, June 15, 2002] Transcription Profile of Cells Infected with Human T-cell Leukemia Virus Type I Compared with Activated Lymphocytes1 Cynthia A. Pise-Masison, Michael Radonovich, Renaud Mahieux, Pramita Chatterjee, Craig Whiteford, Janet Duvall, Claire Guillerm, Antoine Gessain, and John N. Brady2 Basic Research Laboratory, Virus Tumor Biology Section, National Cancer Institute, Bethesda, Maryland 20892 [C. A. P-M., M. R., P. C., J. D., C. G., J. N. B.]; Unite d’Epidemiologie et Physiopathologie des Virus Oncogenes, Batiment SIDA-Retrovirus, Institut Pasteur, 75724, Cedex 15, Paris, France [R. M., A. G.]; and Advanced Technology Center, National Institutes of Health, Gaithersburg, Maryland [C. W.] ABSTRACT vivo for viral infectivity and replication (12–16). In addition, the p12 protein has been implicated in the MHC class I-mediated immune Human T-cell leukemia virus type I (HTLV-I) is the etiologic agent for response and T-cell signaling (16–18). The viral protein p13 has also adult T-cell leukemia and the neurological disorder tropical spastic para- recently been reported to regulate cellular signaling pathways (19). -paresis/HTLV-I-associated myelopathy. CD4؉ T lymphocytes, the pri mary hosts for HTLV-I, undergo a series of changes that lead to T-cell Finally, the p30 protein is reported to play a role in transcriptional activation, immortalization, and transformation. To gain insight into the regulation with the use of Gal4-p30 fusion constructs (20). genetic differences between activated and HTLV-I-infected lymphocytes, DNA microarray technology has facilitated the development of a we performed Affymetrix GeneChip analysis of activated and HTLV-I- more complete and inclusive analysis of gene expression profiles in infected cells.
    [Show full text]
  • Development of Ultra-Super Sensitive Immunohistochemistry and Its Application to the Etiological Study of Adult T-Cell Leukemia/Lymphoma
    Advance Publication Acta Histochem. Cytochem. 45 (2): 83–106, 2012 doi:10.1267/ahc.11034 AHCActa0044-59911347-5800JapanTokyo,AHC1103410.1267/ahc.11034Review Histochemica Society Japan of Histochemistry et Cytochemica and Cytochemistry Review Development of Ultra-Super Sensitive Immunohistochemistry and Its Application to the Etiological Study of Adult T-Cell Leukemia/Lymphoma Kazuhisa Hasui1, Jia Wang1,5, Yuetsu Tanaka2, Shuji Izumo3, Yoshito Eizuru4 and Takami Matsuyama1 1Division of Immunology, Department of Infection and Immunity, Institute Research Center (Health Research Course), Kagoshima University Graduate School of Medical and Dental Sciences, 2Department of Immunology, Graduate School of Medicine, University of the Ryukyus, 3Chronic Viral Diseases Div. of Molecular Pathology, Center for Chronic Viral Diseases (Infection and Immunity), Institute Research Center (Health Research Course), Kagoshima University Graduate School of Medical and Dental Sciences, 4Chronic Viral Diseases Div. of Persistent & Oncogenic Viruses, Center for Chronic Viral Diseases (Infection and Immunity), Institute Research Center (Health Research Course), Kagoshima University Graduate School of Medical and Dental Sciences and 5Present address: INAMORI Frontier Research Center, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka 819–0395, Japan 00 Received July 15, 2011; accepted February 14, 2012; published online April 21, 2012 © 2012Antigen The Japanretrieval Society (AR) andof Histochemistry ultra-super sensitive and immunohistochemistry (ultra-IHC) have been established for application to archival human pathology specimens. The original ultra-IHC was the ImmunoMax method or the catalyzed signal amplification system (ImmunoMax/CSA method), comprising the streptavidin-biotin complex (sABC) method and catalyzed reporter deposition (CARD) reaction with visualization of its deposition. By introducing procedures to diminish non-specific staining in the original ultra-IHC method, we developed the modified ImmunoMax/CSA method with AR heating sections in an AR solution (heating-AR).
    [Show full text]
  • Gene Regulation Mediated by Interaction Between HTLV-1 Promoter Elements and Transcription Factors Tax and CREB
    Virology 256, 303–312 (1999) Article ID viro.1999.9600, available online at http://www.idealibrary.com on Gene Regulation Mediated by Interaction between HTLV-1 Promoter Elements and Transcription Factors Tax and CREB Itamar Goren, Eynat Tavor, and Alik Honigman1 Department of Virology, The Hebrew University–Hadassah Medical School, Jerusalem, Israel Received October 13, 1998; returned to author for revision November 23, 1998; accepted January 13, 1999 In this work we examine the role of three genetic control components in the regulation of HTLV-1 transcription: cyclic AMP-responsive element (CRE)-binding protein (CREB), the HTLV-1 trans-activator Tax, and the three Tax-responsive elements (TREs). We demonstrate that the in vivo efficiency of the HTLV-1 promoter basal expression in cell culture depends on the spacing between the three TRE elements, located at the HTLV-1 LTR (long terminal repeat), whereas the level of transcription activation mediated by Tax is affected by the number of TREs. In the presence of only one TRE, the enhancement of expression by Tax is affected by the distance between the single TRE and the transcription start site. Following CREB binding to the LTR, additional DNase I hypersensitive sites are generated in the region between the two distal TREs (I and II), while in the presence of Tax, such sites are generated also in the region between TREs II and III. Neither cooperative binding of CREB to the TREs nor preferential binding of CREB to a particular TRE was observed. Tax binding to the CREB/TRE complex does not change the DNase I protection pattern.
    [Show full text]
  • Human T Lymphotropic Virus Type 1 (HTLV-1): Molecular Biology and Oncogenesis
    Viruses 2010, 2, 2037-2077; doi:10.3390/v2092037 OPEN ACCESS viruses ISSN 1999-4915 www.mdpi.com/journal/viruses Review Human T Lymphotropic Virus Type 1 (HTLV-1): Molecular Biology and Oncogenesis Priya Kannian 1,2 and Patrick L. Green 1,2,3,4,* 1 Center for Retrovirus Research, The Ohio State University, Columbus, OH 43210, USA; E-Mail: [email protected] 2 Department of Veterinary Biosciences, The Ohio State University, Columbus, OH 43210, USA 3 Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, OH 43210, USA 4 Comprehensive Cancer Center and Solove Research Institute, The Ohio State University, Columbus, OH 43210, USA * Author to whom correspondence should be addressed; E-Mail: [email protected]; Tel.: +1 614-688-4899; Fax: +1 614-292-6473. Received: 7 July 2010; in revised form: 25 August 2010 / Accepted: 15 September 2010 / Published: 24 September 2010 Abstract: Human T lymphotropic viruses (HTLVs) are complex deltaretroviruses that do not contain a proto-oncogene in their genome, yet are capable of transforming primary T lymphocytes both in vitro and in vivo. There are four known strains of HTLV including HTLV type 1 (HTLV-1), HTLV-2, HTLV-3 and HTLV-4. HTLV-1 is primarily associated with adult T cell leukemia (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). HTLV-2 is rarely pathogenic and is sporadically associated with neurological disorders. There have been no diseases associated with HTLV-3 or HTLV-4 to date. Due to the difference in the disease manifestation between HTLV-1 and HTLV-2, a clear understanding of their individual pathobiologies and the role of various viral proteins in transformation should provide insights into better prognosis and prevention strategies.
    [Show full text]
  • Role of Human T-Lymphotropic Virus Type 1 P30(Ii) And
    ROLE OF HUMAN T-LYMPHOTROPIC VIRUS TYPE 1 P30(II) AND SURFACE ENVELOPE AS DETERMINANTS OF IN VIVO PATHOGENESIS DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Lee Silverman, DVM, DACVP * * * * * The Ohio State University 2005 Dissertation Committee: Approved by Dr. Michael Lairmore, Advisor Dr. Kathleen Boris-Lawrie Advisor Dr. Natarajan Muthusamy Veterinary Biosciences Graduate Dr. Thomas Rosol Program ABSTRACT Human T-cell leukemia virus type 1 (HTLV-1) is the first identified human retrovirus. It is the causative agent of adult T-cell leukemia/lymphoma and HTLV-1-associated myelopathy/tropical spastic paresis, and it has been implicated in a variety of other immune-mediated disorders such as dermatitis, polymyositis, and uveitis. HTLV-1 exhibits high genetic stability in vivo. In addition to the canonical retroviral gag, pol, and env genes, HTLV-1 contains four open reading frames (ORF) in its pX region. ORF II encodes two proteins, p30II and p13II, both of which are incompletely characterized. p30II localizes to the nucleus/nucleolus and has distant homology to the transcription factors, Oct-1, Pit-1, and POU-M1. p30II modulates cellular and viral gene expression at the transcriptional and post-transcriptional level. Herein, we determine the in vivo significance of p30II by inoculating rabbits with cell lines expressing either a wild-type clone of HTLV-1 (ACH.1) or a clone containing a mutation in ORF II, which eliminated wild-type p30II expression (ACH.30.1). ACH.1-inoculated rabbits maintained higher HTLV-1- specific antibody titers than ACH.30.1-inoculated rabbits, and all ACH.1- inoculated rabbits were seropositive for HTLV-1, whereas only two of six ACH.30.1-inoculated rabbits were seropositive.
    [Show full text]
  • 263.Full.Pdf
    The HTLV-I Tax Protein Transcriptionally Modulates OX40 Antigen Expression Rüdiger Pankow, Horst Dürkop, Ute Latza, Hans Krause, Ulrich Kunzendorf, Thomas Pohl and Silvia Bulfone-Paus This information is current as of October 2, 2021. J Immunol 2000; 165:263-270; ; doi: 10.4049/jimmunol.165.1.263 http://www.jimmunol.org/content/165/1/263 Downloaded from References This article cites 48 articles, 23 of which you can access for free at: http://www.jimmunol.org/content/165/1/263.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on October 2, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2000 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The HTLV-I Tax Protein Transcriptionally Modulates OX40 Antigen Expression1 Ru¨diger Pankow,* Horst Du¨rkop,† Ute Latza,†‡ Hans Krause,§ Ulrich Kunzendorf,¶ Thomas Pohl,* and Silvia Bulfone-Paus2* OX40 is a member of the TNF receptor family, expressed on activated T cells.
    [Show full text]
  • Identification of HTLV-1 Tax-1 and HBZ Binding Partners, and Their Role in HTLV-1 Biology and Pathogenesis
    Identification of HTLV-1 Tax-1 and HBZ Binding Partners, and Their Role in HTLV-1 Biology and Pathogenesis DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Jacob Jamal Al-Saleem Graduate Program in Molecular, Cellular and Developmental Biology The Ohio State University 2016 Dissertation Committee: Dr. Patrick L. Green, Ph.D, Advisor Dr. Jesse Kwiek, Ph.D Dr. Li Wu, Ph.D Dr. Stefan Niewiesk, DVM, Ph.D Copyrighted by Jacob Jamal Al-Saleem 2016 Abstract Human T cell Leukemia Virus type 1 (HTLV-1) is estimated to have infected 15-20 million individuals world-wide. A subgroup of infected individuals develop diseases associated with viral infection, which include adult T cell leukemia and HTLV-1 associated myelopathy/tropic spastic paraparesis. A closely related virus, HTLV-2, shares 70% nucleotide similarity with HTLV-1, but is not associated with any disease. Previous research has demonstrated that Tax-1 serves as the primary oncoprotein of HTLV-1, and its deletion or functional disruption completely ablates the transforming capacity of HTLV-1. Tax-2 (HTLV-2) has been demonstrated to have lower transforming capabilities than Tax-1. These differences are attributed to two domains present in Tax-1 yet absent in Tax-2; the four-amino acid PDZ binding motif (PBM) and an eight-amino acid leucine zipper-like region (LZ). These domains have been demonstrated to be required for the ability of Tax-1 to activate the alternative NF-κB pathway. Chapter Two of this dissertation analyzes the role that the alternative NF-κB pathway plays in HTLV-1 mediated T cell transformation.
    [Show full text]