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.
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.
Download or read book Role of the Tax Gene of the Human T cell Leukemia Virus Type 2 in Transformation of Human T lymphocytes written by Ted Milburn Ross and published by . This book was released on 1996 with total page 252 pages. Available in PDF, EPUB and Kindle. Book excerpt:
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.
Download or read book Studies with the Human T cell Leukemia Virus Tax and Rex Positive Trans regulatory Proteins written by Matthew David Anderson and published by . This book was released on 2004 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: Abstract: Retroviruses have highly organized genomes that encode a large number of proteins from a relatively short nucleic acid sequence. They utilize a variety of methods to achieve this, including the use of overlapping reading frames and the production of multiple RNAs through alternative splicing. In order to efficiently express RNAs encoding structural and enzymatic proteins, complex retroviruses like human T-cell leukemia virus (HTLV) must first express a doubly spliced RNA encoding both the Tax and Rex positive transregulatory proteins in separate but partially overlapping reading frames. As a result, functional studies of each of these proteins in the context of replicating virus, particularly mutational studies, present unique challenges. This dissertation both describes and utilizes experimental systems for the study of Tax and Rex that model in vivo in the context of replicating virus in human T cells, the natural target of HTLV infection. As a whole, the work described in this dissertation uses methods for the study of the HTLV regulatory proteins Tax-1 and Rex-2 that closely approximate conditions that occur in in vivo HTLV infections. Ideally this is an infection of primary human T-lymphocytes. This approach provides highly relevant insight into the molecular mechanisms utilized by these proteins, validates previous results obtained from in vitro studies as well as extends and refines our understanding of the way these proteins function in natural infection.
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:
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.
Download or read book Human T Cell Leukemia Virus written by P.K. Vogt and published by Springer Science & Business Media. This book was released on 2012-12-06 with total page 266 pages. Available in PDF, EPUB and Kindle. Book excerpt: characteristic features in common with the genome of other retroviruses: long terminal repeats (L TR), and coding regions for internal proteins (gag), for re verse transcriptase (pol), and for glycosylated virion surface proteins (env) , ar ranged in the sequence gag, pol, env from the 5' to the 3' end of the genome. However, the HTL V genome also contains some specific features not shared with all other retroviruses: the LTR regions are unusually long (745 base pairs, with 298 base pairs constituting the R region), but unlike the long L TRs of mouse mammary tumor viruses, they do not contain open reading frames. A stretch of noncoding sequences separates the gag and the pol genes. Most interestingly, the HTLV genome contains a region between the 3' end of the env gene and the L TR, called the pX region, that encompasses four open reading frames. Leukemic T cells freshly obtained from patients contain the HTL V provirus but usually do not express it. However, once established in culture, these cells produce viral proteins and release type C particles. Likewise, T cells infected and transformed by HTL V in vitro synthesize virus. Such producing cell lines have been widely used in seroepidemiological surveys and continue to be of importance for detailed studies of viral proteins and nucleic acids.
Download or read book Transformation Properties of the Human T cell Leukemia Virus Type I Tax Oncoprotein in a Transgenic Mouse Model written by William Jon Grossman and published by . This book was released on 1999 with total page 344 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Download or read book The Regulation of RNA Processing by the Rex Protein of Human T cell Leukemia Virus Type II written by Andreas Bakker and published by . This book was released on 1995 with total page 312 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Download or read book Subcellular Localization of Human T cell Leukemia Virus Type 1 Tax Oncoprotein written by Kimberly Anne Fryrear and published by . This book was released on 2008 with total page 218 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Download or read book Comparative Studies on Molecular Mechanisms Utilized by HTLV 1 and HTLV 2 in Viral Replication and Induction of T cell Transformation written by Li Xie 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 (HTLV)-1 and HTLV-2 are closely related human retroviruses that have similar genetic organization and biological properties. However, they display distinct pathogenicity. HTLV-1 has been identified as a causal agent for two human diseases, adult T-cell leukemia (ATL) and HTLV-associated myelopathy/tropical spastic paraparesis (HAM/TSP), whereas HTLV-2 appears much less pathogenic without conclusive disease association. In order to understand the distinct pathogenicity between HTLV-1 and HTLV-2, studies in this dissertation manipulate viral elements in the context of full-length proviral clones, analyze their function and mechanism of action in a system closely mimicking in vivo HTLV infection, and focus on the unique strategies employed by HTLV-1 and/or HTLV-2 to replicate and induce cellular transformation, the initial stage of HTLV oncogenesis. First, our results indicate that the PDZ domain binding motif (PBM) uniquely present in HTLV-1 viral oncoprotein Tax, but absent in HTLV-2 Tax, plays a key role in HTLV-1-induced cell proliferation and genetic instability in vitro and facilitate viral spread and persistence in vivo. Next, we identified a major viral determinant of HTLV T-cell transformation tropism, the envelope, using recombinant proviral clones between HTLV-1 and HTLV-2. Lastly, viral trans-regulatory protein Rex facilitates efficient viral replication and its functional activity is regulated by phosphorylation events. A c-terminal phosphorylation domain (CTPD) has been previously described in HTLV-2 Rex. Here mutational analyses indicate that either introducing phosphomimetic amino acids into the CTPD or deletion of the CTPD can lock Rex in active state. However, HTLV-2 with Rex phosphomimetic mutants, but not HTLV-2 with Rex CTPD deletion mutants, can efficiently infect and stimulate cellular proliferation and immortalization of human primary T-cell, implying the critical role of the Rex CTPD in HTLV-2 life cycle. Overall, our studies provide important insight into the distinct molecular pathogenesis of HTLV-1 and HTLV-2.
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:
Download or read book Isolation and Functional Mapping of Human T cell Leukemia Virus Type 1 Tax Oncoprotein DNA damage Complexes written by Sarah Saionz Durkin and published by . This book was released on 2006 with total page 135 pages. Available in PDF, EPUB and Kindle. Book excerpt: Physical mapping of purified Tax protein revealed novel phosphorylation sites at T48, T184, T215 and S336. Mutational analysis demonstrated phosphorylation at T215 is associated with loss of Tax trans-activation of CREB and NF-kappaB-responsive promoters, while T48 preferentially affects NF-kappaB-responsive promoters, and T184 and 5336 have no effect on these Tax functions.
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.
Download or read book Human T cell Leukemia lymphoma Virus written by Robert C. Gallo and published by Cold Spring Harbor Laboratory Press. This book was released on 1984 with total page 432 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Download or read book Viral and Immunological Malignancies written by Paul Volberding and published by PMPH-USA. This book was released on 2006 with total page 440 pages. Available in PDF, EPUB and Kindle. Book excerpt: The precise relationship between viral infection and malignancy remains an epidemiologic association and the subject of active investigation. Nonmalignant hematologic disorders have a similarly complex relationship with cancer-associated viruses and may offer insight into the pathogenesis of oncogenesis. This book explores the relationships between viral infections, immune impairments and the hematologic and malignant diseases, particularly against the backdrop of the HIV epidemic. By extending the scope to all of viral oncology the editors provide an invaluable resource on tumors related to other viruses other than HIV, particularly carcinomas of the cervix and anus with HPV and tumors of the liver with the various hepatitis viruses.
