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Book Two Decades of Adult T cell Leukemia and HTLV I Research

Download or read book Two Decades of Adult T cell Leukemia and HTLV I Research written by Kazuo Sugamura and published by S. Karger AG (Switzerland). This book was released on 2003 with total page 394 pages. Available in PDF, EPUB and Kindle. Book excerpt: In April 2001, the Japanese Cancer Association was privileged to host a symposium in Kyoto to commemorate the twentieth anniversary of the discovery of the viral pathogenesis of adult T-cell leukemia (ATL). In this monograph, the editors have selected not only papers presented at the symposium but also eminent papers of several individuals from around the world who have extensively researched human T-cell-leukemia virus type I (HTLV-I), the etiological virus of ATL, over the years. During the last two decades, HTLV-I was molecularly characterized as harboring a variety of oncogenic properties in its Tax protein. Epidemiological studies not only revealed the existence of HTLV-I-endemic areas in the world, but also disclosed the routes of transmission. Despite these great strides, the mechanisms of ATL development have not yet been fully clarified, and viable therapeutic measures are still to be established. This monograph contains recent exciting achievements in molecular virology, epidemiology, immunology and therapeutic trials as well as historical profiles of HTLV-I and HTLV-I-associated diseases.

Book Human T cell leukemia virus 1 HTLV 1 infection associated pathology and response of the host

Download or read book Human T cell leukemia virus 1 HTLV 1 infection associated pathology and response of the host written by Roberto S. Accolla and published by Frontiers Media SA. This book was released on 2023-06-30 with total page 248 pages. Available in PDF, EPUB and Kindle. Book excerpt:

Book Analysis of Amino Acid Signals Within the Human T Cell Leukemia Virus Type I Transactivator Protein Tax that Control Nuclear Export Cytoplasmic Intracellular Localization and Secretion

Download or read book Analysis of Amino Acid Signals Within the Human T Cell Leukemia Virus Type I Transactivator Protein Tax that Control Nuclear Export Cytoplasmic Intracellular Localization and Secretion written by Timothy Gerard Alefantis and published by . This book was released on 2003 with total page 227 pages. Available in PDF, EPUB and Kindle. Book excerpt:

Book Study of the DNA Damage Complexes Within the HTLV 1 Tax Oncoprotein Interactome

Download or read book Study of the DNA Damage Complexes Within the HTLV 1 Tax Oncoprotein Interactome written by Sidi Mehdi Belgnaoui and published by . This book was released on 2009 with total page 228 pages. Available in PDF, EPUB and Kindle. Book excerpt:

Book Regulation of Human T cell Leukemia Virus Type 1 Infection and Replication

Download or read book Regulation of Human T cell Leukemia Virus Type 1 Infection and Replication written by Gunjan Choudhary and published by . This book was released on 2010 with total page 156 pages. Available in PDF, EPUB and Kindle. Book excerpt: Retroviruses have evolved complex mechanisms to regulate their cellular tropism and gene expression. It is generally accepted that productive infections proceed via interactions between viral envelope molecules and specific receptors on the host cell surface. Currently, there is no known receptor for HTLV-1, though a number of factors that enhance entry have been identified. In an effort to identify a cellular receptor or attachment factor for HTLV-1, we carried out a retroviral cDNA library screen, in which cDNA from permissive HeLa S3 cells was introduced into poorly susceptible NIH 3T3 cells. These cells were selected after infection with HTLV-1 envelope pseudotyped viral particles expressing a drug resistance gene. We isolated approximately 460 cDNAs, of which 20 were prioritized as potential candidates. These candidates are being tested to determine if they participate in viral entry. In addition to encoding the structural and enzymatic genes common to all retroviruses, HTLV-1 also encodes several accessory genes which contribute to viral replication and the maintenance of gene expression. A newly identified viral gene, HTLV-1 bZIP factor or hbz, has been shown to have pleiotropic effects as it functions differently in its protein and mRNA forms. In an effort to elucidate its role in HTLV-1 replication, we identified a novel function. Mutations that abrogated the hbz mRNA or disrupted a stem-loop in hbz mRNA, or mutations that eliminated or truncated the HBZ protein were introduced in a functional molecular clone of HTLV-1. The protein and stem-loop mutants had no effect on viral gene expression. However, the mutant that disrupted hbz mRNA expressed lower levels of tax mRNA, suggesting that hbz promotes tax expression. We found that this effect of hbz was indirect, as hbz represses another accessory gene, p30II, which is known to sequester tax mRNA in the nucleus. These results provide new insights into the regulation of HTLV-1 infection, specifically viral entry and gene expression.

Book Studies on the Tax Proteins of Human T cell Leukemia Virus Type I

Download or read book Studies on the Tax Proteins of Human T cell Leukemia Virus Type I written by Laura Virgilio and published by . This book was released on 1989 with total page 334 pages. Available in PDF, EPUB and Kindle. Book excerpt:

Book Comparative studies between HTLV 1 and HTLV 2 function and pathobiology

Download or read book Comparative studies between HTLV 1 and HTLV 2 function and pathobiology written by Umberto Bertazzoni and published by Frontiers Media SA. This book was released on 2015-06-11 with total page 95 pages. Available in PDF, EPUB and Kindle. Book excerpt: Human T-cell leukemia viruses type 1 and 2 (HTLV-1 and HTLV-2) share a common genetic organization, expression strategy and ability to infect and immortalize T-cells in vitro; however, HTLV-1 and HTLV-2 are strikingly different in terms of clinical impact. HTLV-1 is recognized as the aetiological agent of adult T-cell leukemia/lymphoma (ATLL), and HTLV-associated myeolopathy/tropical spastic paraparesis (HAM/TSP), in contrast, HTLV-2 does not cause hematologic disorders and is only sporadically associated with cases of subacute myelopathy. HTLV-1 and HTLV-2 also exhibit distinct cellular tropisms in vivo: HTLV-1 is mainly found in CD4+T lymphocytes, whereas CD8+T-cells are the preferred target for HTLV-2. The articles contributed in this Research Topic are covering all the different aspects that characterize HTLV-1 and HTLV-2, by highlighting differences in their biology that might provide clues to their distinct pathogenic properties.

Book Human T Lymphotropic Virus Type 1 HTLV 1 Accessory Protein P30 II Modulates Cellular and Viral Gene Expression

Download or read book Human T Lymphotropic Virus Type 1 HTLV 1 Accessory Protein P30 II Modulates Cellular and Viral Gene Expression written by Bindhu Michael and published by . This book was released on 2004 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: Abstract: Human T-lymphotropic virus type-1 (HTLV-1), a deltaretrovirus cause adult T-cell leukemia/lymphoma and other lymphocyte-mediated disorders. HTLV-1 provirus encodes various regulatory and accessory genes, including p30(II). Our laboratory has identified the functional properties of pX ORF-II encoded p30(II), but the role of this viral protein in virus replication or pathogenesis remains unclear. We have reported that HTLV-1 p30(II), a nuclear-localizing protein, interacts with CBP/p300, disrupts CREB-Tax-CBP/p300 complex formation at HTLV-1 Tax-Responsive Elements repeats (TRE) and differentially modulates CREB and TRE-mediated transcription. We have also recently demonstrated that p30(II) is critical in maintaining viral loads in vivo. Herein, we further characterized the role of p30(II) in regulation of cellular gene expression, using microarrays and identified alterations of interrelated pathways of cell-proliferation, T-cell signaling, apoptosis and cell-cycle in p30(II)-expressing T-lymphocytes. We are the first to test the overall effect of an HTLV-1 accessory protein, on cellular gene expression and demonstrate that p30(II) activates transcription factors involved in T-cell signaling/activation, such as NFAT, NF-KB and AP-1. We further characterized the role of p30(II) in regulation of viral gene expression, by identifying motifs critical in binding p300 and regulating TRE-mediated transcription. By analysing the amino acid domain of p30(II) critical for repressing LTR-mediated transcription, we identified a lysine residue at amino acid 106 of p30(II), that is critical for repressing TRE-mediated transcription. Additionally, we found that p300 reverses p30(II)-dependent repression of TRE-mediated transcription, in a dose-responsive manner. Our data confirms the role of p30(II) as a regulator of viral gene transcription, in association with p300. However, unlike wildtype p300, p300 HAT mutants only partially rescue p30(II)-mediated LTR repression. Additionally, p30(II) is acetylated and deacetylation enhances p30(II)-mediated LTR repression. Besides, inhibition of deacetylation decreases p30(II)-mediated LTR repression. We are the first to demonstrate that HAT activity of p300 is crucial in modulating viral gene expression from HTLV-1 LTR by p30(II). Collectively, our data indicates that HTLV-1, a complex retrovirus associated with lymphoproliferative disorders, uses accessory genes to enhance clonal expansion of the virus, avoid immune elimination and maintain proviral loads in vivo through coordinated modulation of cellular environment and tightly regulated control of viral gene expression.

Book Molecular Analysis of Human T cell Leukemia Virus Regulatory and Accessory Proteins

Download or read book Molecular Analysis of Human T cell Leukemia Virus Regulatory and Accessory Proteins written by Ihab H. Younis and published by . This book was released on 2005 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: Abstract: Human T-cell leukemia virus type 1 (HTLV-1) and type 2 (HTLV-2) are closely related pathogenic human retroviruses. Although, they both transform human primary T cells in vitro, in humans, HTLV-1 is the causative agent for ATLL and HAM/TSP, whereas HTLV-2 disease association is less clear. In this dissertation, we report molecular studies regarding the regulation of HTLV replication and its impact on viral persistence in vivo. In Chapter 2, we generate a novel HTLV-1 clone (H1IT) in which the two regulatory proteins, Tax and Rex, have been separated in an attempt to provide a better reagent to study mutants of these proteins in the context of the provirus and analyze their contribution to HTLV-mediated transformation. In vitro data indicates that H1IT is replication competent and is capable of cellular transformation of primary human T-cells. However, H1IT was unable to persist in vivo, emphasizing the importance of temporal and quantitative regulation of Tax RNA to viral replication. In Chapter 3, we report that both HTLV-1 and HTLV-2 have evolved accessory genes whose products are able to restrict viral replication at a post-transcriptional level. The HTLV-1 p30 and the related HTLV-2 p28 proteins inhibit both Tax and Rex by binding to and retaining tax/rex mRNA in the nucleus, thereby inhibiting virion production. In Chapter 4, we show that p28 is recruited to the viral promoter in a Tax-dependent manner. After recruitment to the promoter, p28 or p30 travels with the transcription elongation machinery until its target mRNA is synthesized. Since the above data is consistent with a critical role of these accessory proteins in viral persistence in vivo, in Chapter 5, we used an animal model of HTLV infection to study the specific contribution of p28 on HTLV-2 survival. In this study, all wtHTLV-2 infected rabbits showed persistent infection, whereas those infected with HTLV-2[delta]p28 were able to eliminate the virus as early as 2 weeks, indicating that p28 is critical for early viral infectivity, spread and/or persistence in rabbits. Collectively, data presented within this dissertation support the conclusion that the regulation of HTLV gene expression a complicated but a tightly controlled process.

Book Novel Role of Human T cell Leukemia Virus Type 1 Encoded Protein HBZ in Viral Transmission Through Cell to cell Contact

Download or read book Novel Role of Human T cell Leukemia Virus Type 1 Encoded Protein HBZ in Viral Transmission Through Cell to cell Contact written by Ana Laura Fazio-Kroll and published by . This book was released on 2017 with total page 170 pages. Available in PDF, EPUB and Kindle. Book excerpt: The complex retrovirus Human T cell leukemia virus type I (HTLV-1) is the etiologic agent of several diseases, including Adult T cell leukemia (ATL), a fatal hematological malignancy that affects mainly CD4+ T-cells. Freshly isolated ATL and HTLV-1 infected cells aggregate spontaneously in vitro. We have observed this same phenotype in T-cells exclusively expressing one of the viral proteins called HTLV-1 basic leucine zipper factor (HBZ). The hbz gene is uniquely encoded by the complementary strand of the HTLV-1 provirus and, in contrast to other HTLV-1 proteins, is constitutively expressed in ATL and HTLV-1-infected cells. High levels of aggregation in ATL cells have been correlated to an upregulation of the intercellular adhesion molecule-1 (ICAM-1). This protein is usually activated after T-cell stimulation and plays an important role in forming and stabilizing the immunological synapse. Interestingly, we found that cells expressing HBZ have an increase in ICAM-1 mRNA, which correlates with an increase in ICAM-1 at the cell surface. We confirmed by luciferase assay that HBZ expression stimulates ICAM-1 transcription. We found that blocking antibodies or peptides against ICAM-1 and its ligand, lymphocyte function-associated antigen 1 (LFA-1), dissociate the aggregates formed by HBZ-expressing cells, suggesting that ICAM-1 overexpression by HBZ mediates T-cell aggregation through interaction with LFA-1. Increased ICAM-1 expression at the cell surface is crucial for the formation of cell-to-cell contacts and efficient HTLV-1 transmission. To determine whether overexpression of ICAM-1 by HBZ plays a role in viral spread, we performed infection assays using a single-cycle, replication dependent reporter system. Interestingly, we found that HBZ expression significantly enhances HTLV-1 transmission. We confirmed that this effect involves the presence of LFA-1 on target cells. In addition, blocking the ICAM-1/LFA-1 interaction with an ICAM-1 antibody significantly reduced viral transmission. Therefore, ICAM-1 overexpression by HBZ plays a role in mediating viral transmission in our assays. A better understanding of the mechanisms used by HBZ to upregulate ICAM-1, induce cell-to-cell contact, and enhance virus transmission is important for future efforts to limit viral spread and prevent diseases in HTLV-1-infected individuals.

Book Molecular Analysis of Human T cell Leukemia Virus Type 2 Accessory Protein

Download or read book Molecular Analysis of Human T cell Leukemia Virus Type 2 Accessory Protein written by Brenda Michiyo Yamamoto and published by . This book was released on 2009 with total page 162 pages. Available in PDF, EPUB and Kindle. Book excerpt: Abstract: The human T-cell leukemia virus type 1 (HTLV-1) and type 2 (HTLV-2) are two pathogenic retroviruses. Although both viruses share a common genome organization and amino acid homology in common viral proteins, the incidence of disease with infection is distinct. Infection with HTLV-1 may result in the development of adult T-cell leukemia/lymphoma (ATL), an aggressive neoplastic disease, or a variety of immune-mediated/inflammatory disorders such as HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP), whereas HTLV-2 is less pathogenic. Our studies focused on the open reading frame II encoded p28 protein of HTLV-2, which has been shown to negatively regulate viral expression by the nuclear retention of the tax/rex mRNA. A similar post-transcriptional regulatory function has been observed with HTLV-1 ORF-II p30. However, p28 contrasts p30 in that there appears to be no significant transcriptional effects. In Chapter 2, we examined the functional significance of p28 in HTLV-2 infection, proliferation, and immortalization of primary T-cells in culture, and viral infection and survival in a rabbit model of HTLV infection. We generated a novel HTLV-2 p28 termination clone (HTLV2Deltap28) in which a stop codon had been introduced into the p28 sequence without altering the amino acid sequence of the overlapping regulatory proteins, Tax and Rex. In short-term proliferation and long-term immortalization coculture assays, HTLV2Deltap28 infected and immortalized primary human T-cells, similar to wtHTLV-2. However, HTLV2Deltap28 had a lower capacity to establish persistent infection in rabbits, indicating the in vivo importance of HTLV-2 p28. These results are consistent with the hypothesis that p28 repression of Tax and Rex-mediated viral gene expression allows infected cells to avoid immune recognition and elimination, or acts to enhance early viral spread by enhancing the survival of HTLV-2 infected cells. In Chapter 3, we generated and characterized various dual-promoter and single-promoter lentiviral expression vectors. Post-transduction, p28 protein was readily detected with the dual-promoter vectors in 293T cells but not in Jurkat T-cells. The differential p28 protein expression was found to be due to cell-type specific translation mechanisms. To circumvent this problem we utilized a single-promoter lentiviral vector that expresses p28 via the murine stem cell virus (MSCV)-promoter, which resulted in efficient p28 protein expression in both T-cell lines and primary human CD8+ T-lymphocytes. In Chapter 4, the capacity of p28 to modify cellular gene expression was examined. In transient transfection studies, low doses of p28 modulated CRE- and NF[kappa]B-driven reporter constructs in 293T cells, suggesting the ability of p28 in modulating cellular gene expression. Interestingly, transduction of Jurkat T-cells with the lentiviral p28 expression vector had no significant effect on cellular proliferation. Additionally, initial analysis of global cellular gene expression by microarray analysis suggests that p28 results in nominal alterations in cellular gene expression. Collectively, data presented in this thesis indicates that p28 is critical for the establishment and survival of HTLV-2, compatible with the conclusion that the regulation of HTLV gene expression is a tightly controlled and complex process. Ultimately, while minimal, the impact of p28 upon cellular genes likely contributes to HTLV-2 establishment of infection in vivo.

Book Transformation Studies of Human T cell Leukemia Virus with Emphasis on the Role of Tax and Rex

Download or read book Transformation Studies of Human T cell Leukemia Virus with Emphasis on the Role of Tax and Rex written by Jianxin Je and published by . This book was released on 2003 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: Abstract: HTLV-1 and HTLV-2 both transform human primary T cells but the precise transformation mechanism remains to be elucidated. We studied two HTLV regulatory proteins, Tax and Rex, and their role in HTLV-mediated cellular transformation. HTLV-1 has a preferential transformation tropism of CD4+ T cells, whereas HTLV-2 transforms primarily CD8+ T cells. Since Tax is critical for cellular transformation and differences have been identified between Tax-1 and Tax-2, we hypothesize 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 as compared to the wild-type clones. Stable transfectants expressing recombinant viruses were established, irradiated, and cocultured with peripheral blood mononuclear cells (PBMC). Both recombinants were competent to transform T-lymphocytes with efficiency similar to the parental viruses. Flow cytometry analysis indicated that HTLV-1 and HTLV-1/TR2 had a preferential tropism for CD4+ T cells and 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 tropism. We also studied the contribution of Rex in HTLV-1-mediated immortalization of primary T-cells in vitro and viral survival in a rabbit animal model. Our results provide the first direct evidence that Rex and its function to modulate viral gene expression and virion production is not required for in vitro immortalization by HTLV-1. However, Rex is critical for efficient infection of cells and persistence in vivo. Efficient HTLV replication requires Rex/RxRE regulation of incompletely spliced viral mRNAs that encode the viral enzymatic and structural proteins. Overall, our results indicate that post-transcriptional control elements identified in other viruses have a partial capacity to substitute for HTLV Rex/RxRE function, although the low activities of these elements are insufficient to maintain viral replication and virus spread in culture. Together this work provides important information on the role of Tax and Rex on HTLV replication and cellular transformation and further insight into the biological differences between HTLV-1 and HTLV-2.