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 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 Molecular Analysis of Htlv 2 Aph 2 in Viral Transformation Persistence and Host Immune Response written by Han Yin and published by . This book was released on 2011 with total page 149 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 two closely related human retroviruses but they display distinct differences in pathogenicity. HTLV-1 causes 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. Chapter 1 reviews important aspects of HTLV-1 pathobiology and highlights insightful comparative studies between HTLV-1 and HTLV-2. Chapter 2 and chapter 3 focus on APH-2, the antisense protein of HTLV-2, which shares functional homology to HTLV-1 HBZ as a negative viral regulator. In chapter 2, we investigated the contribution of APH-2 to HTLV-2-mediated immortalization of primary T-lymphocytes in vitro and HTLV-1 infection in a rabbit animal model. HTLV-2 APH-2 mutant viruses were generated and evaluated for viral gene expression, protein production, and immortalization capacity. In short-term proliferation and long-term immortalization assays, APH-2 mutant viruses were indistinguishable from wild-type HTLV-1 suggesting that APH-2 is dispensable for viral replication and cellular immortalization in culture. Rabbits inoculated with irradiated cells expressing HTLV-2 APH-2 mutant viruses became persistently infected. In addition, these rabbits displayed an increased antibody response to viral gene products and a higher proviral load in PBMCs as compared to wild type HTLV-2 infected animals. These observations indicate that APH-2 is not required for viral survival and persistence in vivo during the early stage of infection, which is contrary to what has been observed for HTLV-1 HBZ. To broaden our knowledge of the contribution of antisense proteins to HTLV biology, in chapter 3 we further examined the role of APH-2 and HBZ in regulating the host immune response. We found that both APH-2 and HBZ can potentially reduce type I interferon (IFN) production by inhibiting IFN regulatory factor 7 (IRF-7)-mediated gene transcription. This result indicates that HTLV-1 and HTLV-2 have evolved a common way to antagonize host immune attack upon viral infection. Chapter 4 focuses on the cellular tropism of HTLV-1 and HTLV-2 during the early stage after infection. In vivo, CD4+ T cells are the primary target cells for HTLV-1 in ATL patients even though CD8+ T cells serve as a natural reservoir in HAM/TSP patients and asymptomatic carriers. The HTLV-2 proviral burden has been shown to be higher in CD8+ T cells than in CD4+ T cells in infected individuals. Since most individuals are chronically infected at the time of detection, the early T cell preference of HTLV-1 and HTLV-2 in an immunocompetent host is not known. In chapter 4, we utilized the rabbit animal model to measure the early HTLV-1 and HTLV-2 proviral loads and gene expression patterns in purified CD4+ and CD8+ T cells over time. Our data indicate that the viruses do not exhibit cellular preference during the initial infection stage and the preferential transformation tropism is probably due to a selective clonal expansion during the clinical latency period. Collectively, the data presented in this thesis provides insights into the regulation of HTLV gene expression and the mechanism of cellular transformation and host-virus interplay.
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 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 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 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 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 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 The Human Retroviruses written by Robert C. Gallo and published by Academic Press. This book was released on 1991-06-28 with total page 450 pages. Available in PDF, EPUB and Kindle. Book excerpt: This book presents twenty-four tightly focused reviews on the biology, molecular biology, pathology, and epidemiology of the human retroviruses, particularly HIV and HTLV (Types I and II), as well as animal model systems (simian retroviruses, STLV and SIV, and mouse models). Editor Robert C. Gallo is recognized as a co-discoverer of the AIDS virus.
Download or read book Dissertation Abstracts International written by and published by . This book was released on 2005 with total page 918 pages. Available in PDF, EPUB and Kindle. Book excerpt:
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 Persistent Viral Infections written by R. Ahmed and published by Wiley-Blackwell. This book was released on 1999 with total page 754 pages. Available in PDF, EPUB and Kindle. Book excerpt: Persistent Viral Infections Edited by Rafi Ahmed Emory Vaccine Center, Atlanta, USA and Irvin S. Y. Chen UCLA School of Medicine, Los Angeles, USA During the past decade much of our attention has focused on diseases associated with viral persistence. Major breakthroughs in immunology, and the advent of molecular approaches to study pathogenesis have increased our understanding of the complex virus-host interactions that occur during viral persistence. Persistent Viral Infections focuses on: * The pathogenesis and immunology of chronic infections * Animal models that provide, or have the potential to provide, major insights This volume will be essential reading for virologists, immunologists, oncologists and neurologists.
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 Retroviruses written by Bryan Cullen and published by Oxford University Press. This book was released on 1993 with total page 220 pages. Available in PDF, EPUB and Kindle. Book excerpt: The first book to specifically cover the molecular biology of retroviruses - of immense importance since the high profile of HIV. International contributors provide detailed reviews of the latest knowledge. An excellent text for both medical and non-medical researchers, it also serves as an illuminating introduction for scientists active in other areas.
Download or read book Leong s Manual of Diagnostic Antibodies for Immunohistology written by Runjan Chetty and published by Cambridge University Press. This book was released on 2016-11-28 with total page 525 pages. Available in PDF, EPUB and Kindle. Book excerpt: Providing a unique A-Z guide to antibodies for immunohistology, this is an indispensable source for pathologists to ensure the correct application of immunohistochemistry in daily practice. Each entry includes commercial sources, clones, descriptions of stained proteins/epitopes, the full staining spectrum of normal and tumor tissues, staining pattern and cellular localization, the range of conditions of immunoreactivity, and pitfalls of the antibody's immunoprofile, giving pathologists a truly thorough quick-reference guide to sources, preparation and applications of specific antibodies. Appendices provide useful quick-reference tables of antibody panels for differential diagnoses, as well as summaries of diagnostic applications. Expanded from previous editions with over forty new entries, this handbook for diagnostic, therapeutic, prognostic and research applications of antibodies is an essential desktop book for practicing pathologists as well as researchers, residents and trainees.
Download or read book Regulatory Aspects of Gene Therapy and Cell Therapy Products written by Maria Cristina Galli and published by Springer. This book was released on 2015-09-15 with total page 235 pages. Available in PDF, EPUB and Kindle. Book excerpt: This book discusses the different regulatory pathways for gene therapy (GT) and cell therapy (CT) medicinal products implemented by national and international bodies throughout the world (e.g. North and South America, Europe, and Asia). Each chapter, authored by experts from various regulatory bodies throughout the international community, walks the reader through the applications of nonclinical research to translational clinical research to licensure for these innovative products. More specifically, each chapter offers insights into fundamental considerations that are essential for developers of CT and GT products, in the areas of product manufacturing, pharmacology and toxicology, and clinical trial design, as well as pertinent "must-know" guidelines and regulations. Regulatory Aspects of Gene Therapy and Cell Therapy Products: A Global Perspective is part of the American Society of Gene and Cell Therapy sub-series of the highly successful Advances in Experimental Medicine and Biology series. It is essential reading for graduate students, clinicians, and researchers interested in gene and cell therapy and the regulation of pharmaceuticals.
