Download or read book Identification of HTLV 1 Tax 1 and HBZ Binding Partners and Their Role in HTLV 1 Biology and Pathogenesis written by Jacob Jamal Al-Saleem and published by . This book was released on 2016 with total page 177 pages. Available in PDF, EPUB and Kindle. Book excerpt:

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 The Role of Hbz in Htlv 1 Biology written by Joshua E. Arnold and published by . This book was released on 2008 with total page 165 pages. Available in PDF, EPUB and Kindle. Book excerpt: Abstract: Human T-cell leukemia virus type 1 (HTLV-1) is a pathogenic retrovirus that has the capacity to transform primary human T-lymphocytes in culture and infected individuals. After nearly 30 years of research, the exact mechanism by which HTLV-1 induces cellular transformation and ultimately disease still remains elusive. Tax has been identified as the major viral determinant and is essential to the HTLV-1-mediated T-cell transformation process. The HTLV-1 accessory proteins p12, p13, and p30 are dispensable in culture, but are required for the maintenance of viral loads in vivo. In this dissertation, we sought to broaden our knowledge of HTLV-1 using in vitro culture assays and two animal model approaches focusing our efforts on understanding the contribution of a novel antisense encoded gene, the HTLV-1 basic leucine zipper factor (Hbz), in virus biology. Chapter 1 reviewed important aspects of HTLV-1 pathobiology and highlighted insightful comparative studies between HTLV-1 and HTLV-2. Our work in Chapter 2 determined that the HBZ protein is dispensable for immortalization/transformation of T-lymphocytes in culture, but is required for efficient infectivity and persistence in inoculated rabbits. In Chapter 3, utilizing Hbz-specific short hairpin RNA lentiviral vectors, we showed that Hbz significantly contributed to tumor formation and neoplastic cell spread in the NOG mouse transplant model. Chapter 4 expanded on Chapter 3 to show that Hbz functions in two molecular forms, mRNA and protein, to synergistically increase cell proliferation in vitro. Collectively our results indicate that the Hbz gene negativly regulates Tax-mediated viral gene expression and dysrupts the cellular microenviroment to ultimately support virus survival. The data in this dissertation have allowed us to better understand the contribution of Hbz to HTLV-1 infection, and its involvement in the development of disease.

Download or read book Molecular Pathology of HTLV 1 written by Umberto Bertazzoni and published by Frontiers Media SA. This book was released on 2019-03-25 with total page 225 pages. Available in PDF, EPUB and Kindle. Book excerpt: Human T-cell leukemia virus type 1 (HTLV-1) was the first human retrovirus discovered, in 1980, by Gallo and co-workers. About 5-10% of HTLV-1-infected individuals are at risk of developing either a fatal malignancy, adult T-cell leukemia (ATL), or a chronic neuroinflammatory syndrome, HTLV-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Both diseases are incurable at present. Many issues concerning HTLV-1’s life cycle and pathobiology are still unsolved or controversial, and new approaches for prognostic stratification of patients and eradication of HTLV-1 infection are in high demand. In this Research Topic, the focus has been centered on discussing two main themes: the functional analysis and oncogenic potential of HTLV-1 regulatory proteins and the control of HTLV-1-associated diseases. The 22 articles in this eBook cover many different aspects of HTLV-1 infection and pathogenesis, providing new perspectives and groundwork for future studies.

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 Effects of Chromatin Insulator CTCF and HTLV 1 Hbz MRNA on HTLV 1 Biology and Pathogenesis written by Michael P. Martinez and published by . This book was released on 2020 with total page 156 pages. Available in PDF, EPUB and Kindle. Book excerpt: Human T-cell leukemia virus type 1 (HTLV-1) is deltaretrovirus with an estimated 5-10 million individuals infected worldwide. HTLV-1 is the etiologic agent of a non- Hodgkin’s peripheral T-cell malignancy called adult T-cell leukemia/lymphoma (ATL) and a demyelinating lymphocytic meningomyelitis termed HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Approximately 10% of infected individuals will develop ATL or HAM/TSP and there are limited treatment options. Examining the viral and cellular determinants that modulate early infection is vital to our understanding HTLV-1 pathobiology. Recently a binding site for the multifunctional DNA-binding protein CTCF was identified at a sharp border of epigenetic modification within the HTLV-1 provirus.

Download or read book Human T Cell Lymphotropic Virus Type I written by Per Höllsberg and published by John Wiley & Sons. This book was released on 1996-12-02 with total page 352 pages. Available in PDF, EPUB and Kindle. Book excerpt: HTLV is made up of any of several retroviruses including the retrovirus known as AIDS. Devoted to the rapidly growing field of HTLV, this book explores the many different aspects of the virus.

Download or read book Human T Cell Leukemia Virus Type I Basic Leucine Zipper Factor HBZ Modulates Cellular DNA Damage Repair and Antioxidant Responses to Promote Host Cell Survival and Leukemogenesis written by Amanda W Rushing and published by . This book was released on 2018 with total page 192 pages. Available in PDF, EPUB and Kindle. Book excerpt: Approximately twenty million people worldwide are infected with Human T-cell Leukemia Virus type 1 (HTLV-1). HTLV-1 establishes a life-long, chronic infection which can result in the development of severe HTLV-1 associated diseases: Adult T-cell Leukemia (ATL) or HTLV-1-associated myelopathy/ tropical spastic paraparesis (HAM/TSP). ATL is a fatally-aggressive lymphoproliferative disorder of HTLV-1-infected CD4+ T-cells. HAM/TSP is a debilitating neurodegenerative disorder that greatly reduces quality of life. There exists a distinct lack of effective vaccine and therapeutic options for both ATL and HAM/TSP patients. Though the mechanisms that drive HTLV-1 pathogenesis remain poorly understood, extensive study of the virus has revealed the importance of two viral regulatory proteins in disease progression: Tax and HBZ. Tax is a transcriptional regulator which is important for establishing initial infection; however, Tax is highly immunogenic and stimulates a robust antiviral immune response. To evade immune detection, HTLV-1 host cells often silence Tax expression through the transcriptionally repressive activity of the basic leucine zipper factor HBZ. HBZ is expressed throughout all phases of infection and plays important roles in maintaining host cell survival and clonal expansion. HBZ expression is sufficient to induce ATL-like disease progression in in vivo models, supporting its contribution to leukemogenesis in patients. Here, we report novel functions of HBZ that may promote the long-term survival of infected lymphocytes, including the direct upregulation of antioxidant response gene expression, the detoxification of reactive oxygen species, and the prevention of oxidative stress-induced cell death. We also evaluated the contribution of HBZ to the accumulation of genetic abnormalities which may promote leukemogenesis. Here, we report that HBZ contributes to genetic instability by affecting the double-stranded DNA damage repair system non-homologous end joining (NHEJ), possibly through specific interactions with DNA repair proteins. These findings support the role of HBZ in promoting leukemogenesis through the accumulation of chromosomal abnormalities which arise from double-stranded DNA breaks. Together, the data presented here indicate that HBZ is an important driving force in the prolonged survival and transformation of HTLV-1-infected lymphocytes.

Download or read book Molecular Mimicry Infection Inducing Autoimmune Disease written by Michael B. A. Oldstone and published by Springer Science & Business Media. This book was released on 2006-01-09 with total page 166 pages. Available in PDF, EPUB and Kindle. Book excerpt: (Text will follow)

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.

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.

Download or read book Role of Human T lymphotropic Virus Type 1 P30 II and Surface Envelope as Determinants of in Vivo Pathogenesis written by Lee Silverman 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 (HTVL-1) is the first identified human retrovirus. In addition to gag, pol, and env genes, HTLV-1 contains four open reading frames (ORF) within its pX region. ORF II encodes p30II and p13II. 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 p30II mutant clone (ACH. 30.1). Compared to ACH. 1 rabbits, ACH. 30.1 rabbits had lower antibody titers, a smaller percentage of seropositive animals, a smaller percentage of animals with provirus in peripheral blood mononuclear cells (PBMC), and lower proviral loads. Sequencing revealed that provirus in ACH. 30.1 provirus positive rabbits had reverted to wild-type sequence. We conclude that there is strong selective pressure for expression of p30II in vivo. We next sought to determine if p30II modulates cellular apoptosis. A greater percentage of ACH. 30.1 cells were induced into apoptosis compared to ACH. 1 cells following treatment with camptothecin (specific for S-phase of cell cycle). There was no difference in apoptosis induction between ACH. 30.1 and ACH. 1 cells following treatment with etoposide (intrinsic pathway) or TRAIL (extrinsic pathway). p30II did not modulate susceptibility to apoptosis when expressed in 293T cells or in Jurkat T cells. Expression of p30II in Jurkat T cells reduced cell proliferation by delaying onset of division. Although p30II does not modulate susceptibility to apoptosis, it does reduce cell proliferation. HTLV-1 Env Ser75Ile, Asn95Asp, and Asn195Asp mutants are able to immortalize lymphocytes in vitro. Herein, we examine the effects of these mutations in rabbits via inoculations with ACH. 75, ACH. 95, ACH. 195, and ACH. 1 cell lines. All mutations were maintained in vivo. ACH. 75 and ACH. 95 rabbits had decreased antibody responses to Gag and Env. One ACH. 195 rabbit had an antibody response to HTLV-1 proteins and HTLV-2 Env. Another ACH. 195 rabbit had provirus in PBMC but no serologic response. ACH. 195 rabbits had a diminished antibody response to Env surface (SU) protein. PBMC proviral loads did not correlate with antibody response to SU. These mutations in HTLV-1 Env SU alter proviral loads and antibody responses against Env but do not prevent virus replication in vivo.

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.

Download or read book Kinetic Analysis of Human T cell Leukemia Virus Type 1 Gene Expression written by Min Li and published by . This book was released on 2008 with total page 170 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 human retroviruses that transform T lymphocytes in cell culture and persist in infected individuals. HTLV-1 infection is clearly associated with leukemia/lymphoma and neurological disease, whereas HTLV-2 disease association is less compelling. HTLV replication and survival requires the expression of multiple gene products from an unspliced and a series of highly related alternatively spliced mRNA species. To date, the levels of viral gene expression throughout the process of infection, cellular transformation, and pathogenesis have not been experimentally assessed. We posit that having a concise viral gene expression profile will provide important insight into the function of specific viral genes and their role in the biology and pathogenesis of HTLV-1.

Download or read book Viral Oncology written by George Klein and published by . This book was released on 1980 with total page 874 pages. Available in PDF, EPUB and Kindle. Book excerpt:

Download or read book Flexible Viruses written by Vladimir Uversky and published by John Wiley & Sons. This book was released on 2012-02-07 with total page 532 pages. Available in PDF, EPUB and Kindle. Book excerpt: This book provides up-to-date information on experimental and computational characterization of the structural and functional properties of viral proteins, which are widely involved in regulatory and signaling processes. With chapters by leading research groups, it features current information on the structural and functional roles of intrinsic disorders in viral proteomes. It systematically addresses the measles, HIV, influenza, potato virus, forest virus, bovine virus, hepatitis, and rotavirus as well as viral genomics. After analyzing the unique features of each class of viral proteins, future directions for research and disease management are presented.

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.