DOCSLIB.ORG

Insights Into the Cytotoxic Potential of Human CD8+ T Cells: Implications for Virologic Control of HIV

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Insights Into the Cytotoxic Potential of Human CD8+ T Cells: Implications for Virologic Control of HIV University of Pennsylvania ScholarlyCommons Publicly Accessible Penn Dissertations Fall 2010 Insights into the Cytotoxic Potential of Human CD8+ T Cells: Implications for Virologic Control of HIV Adam R. Hersperger University of Pennsylvania, [email protected] Follow this and additional works at: https://repository.upenn.edu/edissertations Part of the Immunology of Infectious Disease Commons, and the Microbiology Commons Recommended Citation Hersperger, Adam R., "Insights into the Cytotoxic Potential of Human CD8+ T Cells: Implications for Virologic Control of HIV" (2010). Publicly Accessible Penn Dissertations. 270. https://repository.upenn.edu/edissertations/270 This paper is posted at ScholarlyCommons. https://repository.upenn.edu/edissertations/270 For more information, please contact [email protected]. Insights into the Cytotoxic Potential of Human CD8+ T Cells: Implications for Virologic Control of HIV Abstract CD8+ T cells are often referred to as cytotoxic T lymphocytes because of their ability to induce the apoptosis of cells infected with an intracellular pathogen, thereby limiting the spread of an infection to previously uninfected cells. CD8+ T cells produce many proteins - including perforin, various granzymes, and granulysin - that are responsible for inducing target cell cytolysis. These cytolytic proteins are found pre-packaged into secretory granules within many resting CD8+ T cells, but their de novo synthesis can also occur after activation. In the setting of HIV infection, a rare group of HIV-positive patients, termed elite controllers (EC), naturally control HIV viremia to virtually undetectable levels without the intervention of drug therapy. Some evidence has implicated HIV-specific CD8+ T cells in achieving or maintaining this virologic control; however, the mechanism(s) to explain these findings emainsr largely undefined. In this work, we report that HIV-specific CD8+ T cells from EC demonstrated a superior ability to express perforin and granzyme B after activation compared to patients with progressive disease. Therefore, HIV-specific CD8+ T cells from EC possessed a greater cytotoxic potential by expressing higher levels of two principal cytolytic mediators, which may at least partially explain the ability of EC to suppress the replication of HIV in vivo. One critical upstream regulator of effector functionality and differentiation is the T-box transcription factor T-bet. We demonstrated a clear link between levels of T-bet and the presence of perforin and granzyme B within human CD8+ T cells. Notably, HIV-specific CD8+ T cells from EC expressed higher amounts of T-bet than progressors, suggesting that therapeutic modulation of T-bet may restore the cytolytic potential that is deficient among patients with uncontrolled viremia. Collectively, our results imply that the underlying defect(s) in effector function by HIV-specific CD8+ T cells from progressors lie not in the cytolytic proteins themselves, but rather in the elements controlling their expression, including T-bet. Degree Type Dissertation Degree Name Doctor of Philosophy (PhD) Graduate Group Cell & Molecular Biology First Advisor Michael R. Betts Keywords HIV, Immunology, perforin, cytotoxicity, T-bet, granzyme B Subject Categories Immunology of Infectious Disease | Microbiology This dissertation is available at ScholarlyCommons: https://repository.upenn.edu/edissertations/270 INSIGHTS INTO THE CYTOTOXIC POTENTIAL OF HUMAN CD8+ T CELLS: IMPLICATIONS FOR VIROLOGIC CONTROL OF HIV Adam R. Hersperger A DISSERTATION in Cell and Molecular Biology Presented to the Faculties of the University of Pennsylvania in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy 2010 Supervisor of Dissertation: ___________________________ Michael R. Betts, Ph.D., Assistant Professor of Microbiology Graduate Group Chairperson: ___________________________ Daniel S. Kessler, Ph.D., Associate Professor of Cell and Developmental Biology Dissertation Committee: E. John Wherry, Ph.D., Associate Professor of Microbiology David B. Weiner, Ph.D., Professor of Pathology and Laboratory Medicine David Artis, Ph.D., Associate Professor of Pathobiology and Microbiology Guido Silvestri, M.D., Professor of Pathology and Laboratory Medicine, Emory University School of Medicine DEDICATION I dedicate this work to my parents, Stephen and Edna, and my wife, Chelsea, for their continuous love and support during the course of my graduate studies. I am eternally grateful for their presence in my life. ii ACKNOWLEDGEMENTS First and foremost, I would like to thank my thesis mentor, Mike Betts, for his guidance and support during my time in his laboratory. He has helped me to mature and grow as a young scientist and provided many opportunities to travel and present our work at international meetings. I would also like to thank my thesis committee for the helpful discussion and suggestions they provided over the last several years. Finally, I am grateful to the various members of the Betts Lab who have provided useful advice and assistance during my graduate school career. iii ABSTRACT INSIGHTS INTO THE CYTOTOXIC POTENTIAL OF HUMAN CD8+ T CELLS: IMPLICATIONS FOR VIROLOGIC CONTROL OF HIV Adam R. Hersperger Supervisor: Michael R. Betts CD8+ T cells are often referred to as cytotoxic T lymphocytes because of their ability to induce the apoptosis of cells infected with an intracellular pathogen, thereby limiting the spread of an infection to previously uninfected cells. CD8+ T cells produce many proteins - including perforin, various granzymes, and granulysin - that are responsible for inducing target cell cytolysis. These cytolytic proteins are found pre- packaged into secretory granules within many resting CD8+ T cells, but their de novo synthesis can also occur after activation. In the setting of HIV infection, a rare group of HIV-positive patients, termed elite controllers (EC), naturally control HIV viremia to virtually undetectable levels without the intervention of drug therapy. Some evidence has implicated HIV-specific CD8+ T cells in achieving or maintaining this virologic control; however, the mechanism(s) to explain these findings remains largely undefined. In this work, we report that HIV-specific CD8+ T cells from EC demonstrated a superior ability to express perforin and granzyme B after activation compared to patients with progressive disease. Therefore, HIV-specific CD8+ T cells from EC possessed a greater cytotoxic potential by expressing higher levels of two principal cytolytic mediators, which may at least partially explain the ability of EC to suppress the replication of HIV in iv vivo. One critical upstream regulator of effector functionality and differentiation is the T- box transcription factor T-bet. We demonstrated a clear link between levels of T-bet and the presence of perforin and granzyme B within human CD8+ T cells. Notably, HIV- specific CD8+ T cells from EC expressed higher amounts of T-bet than progressors, suggesting that therapeutic modulation of T-bet may restore the cytolytic potential that is deficient among patients with uncontrolled viremia. Collectively, our results imply that the underlying defect(s) in effector function by HIV-specific CD8+ T cells from progressors lie not in the cytolytic proteins themselves, but rather in the elements controlling their expression, including T-bet. v TABLE OF CONTENTS CHAPTER 1: INTRODUCTION.....................................................................................1 Overview..................................................................................................................1 Biology and functionality of CD8+ T cells..............................................................2 Cytotoxic granule-resident proteins and their regulation.........................................5 Biology and pathogenesis of Human Immunodeficiency Virus............................13 Current insights into HIV elite controllers.............................................................16 Measuring immune responses using multiparametric flow cytometry..................28 Conclusion and Project Aims.................................................................................32 CHAPTER 2: IDENTIFICATION AND ASSESSMENT OF DE NOVO PERFORIN PRODUCTION BY HUMAN CD8+ T CELLS USING POLYCHROMATIC FLOW CYTOMETRY..............................................................34 Summary................................................................................................................34 Introduction............................................................................................................35 Materials and Methods...........................................................................................36 Results....................................................................................................................38 Discussion..............................................................................................................48 vi CHAPTER 3: PERFORIN EXPRESSION DIRECTLY EX VIVO BY HIV-SPECIFIC CD8+ T CELLS IS A CORRELATE OF LONG-TERM VIROLOGIC CONTROL OF HIV...............................................................................51 Summary................................................................................................................51 Introduction............................................................................................................52 Materials and Methods...........................................................................................54
Load more

Recommended publications
  • Transmission Within Discordant Couples in Relation To
    Human Leukocyte Antigen Class I Genotypes in Relation to Heterosexual HIV Type 1 Transmission within Discordant Couples This information is current as Jianming Tang, Wenshuo Shao, Yun Joo Yoo, Ilene Brill, of September 25, 2021. Joseph Mulenga, Susan Allen, Eric Hunter and Richard A. Kaslow J Immunol 2008; 181:2626-2635; ; doi: 10.4049/jimmunol.181.4.2626 http://www.jimmunol.org/content/181/4/2626 Downloaded from References This article cites 67 articles, 19 of which you can access for free at: http://www.jimmunol.org/content/181/4/2626.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 25, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2008 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Human Leukocyte Antigen Class I Genotypes in Relation to Heterosexual HIV Type 1 Transmission within Discordant Couples1 Jianming Tang,2* Wenshuo Shao,† Yun Joo Yoo,3‡ Ilene Brill,† Joseph Mulenga,§ Susan Allen,§¶ Eric Hunter,§ʈ and Richard A.
    [Show full text]
  • Divergence in Cd8 T Cell Epitopes of Hiv-1 As An
    DIVERGENCE IN CD8+ T CELL EPITOPES OF HIV-1 AS AN IMMUNE ESCAPE MECHANISM by Bonnie Colleton B.A., Wheaton College, 1993 Submitted to the Graduate Faculty of Graduate School of Public Health in partial fulfillment of the requirements for the degree of Doctor of Philosophy University of Pittsburgh 2007 UNIVERSITY OF PITTSBURGH GRADUATE SCHOOL OF PUBLIC HEALTH This dissertation was presented by Bonnie Colleton It was defended on August 17, 2007 and approved by Simon Barratt-Boyes, BVSc, PhD Associate Professor Department of Infectious Diseases and Microbiology Graduate School of Public Health, University of Pittsburgh Phalguni Gupta, PhD Professor Department of Infectious Diseases and Microbiology Graduate School of Public Health, University of Pittsburgh Russell Salter, PhD Professor Department of Immunology School of Medicine, University of Pittsburgh Walter Storkus, PhD Professor Department of Dermatology School of Medicine, University of Pittsburgh Dissertation Advisor: Charles Rinaldo Jr., PhD Chairman and ProfessorDepartment of Infectious Diseases and Microbiology Graduate School of Public Health, University of Pittsburgh ii Copyright Bonnie Colleton 2007 iii Charles R. Rinaldo, Jr. PhD DIVERGENCE IN CD8+ T CELL EPITOPES OF HIV-1 AS AN IMMUNE ESCAPE MECHANISM Bonnie Colleton, PhD University of Pittsburgh, 2007 More than 40 million people are living with human immunodeficiency virus-1 (HIV-1). A prophylactic vaccine inducing a ‘sterilizing immunity’ is desired to prevent further infections, but will require many years to develop. Moreover, prophylactic vaccines will not help the millions of people who are already infected with the virus, and who face life-long treatment with expensive and toxic antiretroviral therapy (ART). This dissertation is based on the proposal that the best strategy for these individuals is a therapeutic vaccine that will attack residual viral reservoirs by expanding HIV-1 specific, primary T cell responses to the persons’s own, autologous virus.
    [Show full text]
  • Genome-Wide Association for HIV on the Trail of Transcription Factors
    R ESEARCH HIGHLIGHTS TechnologY On the trail of transcription factors Recently developed techniques such transcription factors. For each tran- as chromatin immunoprecipitation scription factor fused to Sir4, they Using this coupled to DNA microarray analysis used a Ty5 element that was engi- method, they (ChIP–chip) or ChIPseq, in which neered to contain a short sequence were able immunoprecipitated DNA fragments that could function as a ‘barcode’ (or are sequenced using a ‘next-generation ‘calling card’, as the authors propose) to mark — sequencing’ technology, allow the specific for that factor. through Ty5 identification of any DNA sequence Following cell transformation integration that is bound by a specific protein. (with a plasmid carrying the fusion — the DNA But is it possible to do the opposite gene and another carrying the sequences and identify which proteins bind a corresponding Ty transposon) and that were certain sequence? A recent study in induction of transposition, the DNA yeast offers a promising approach to of the cells selected for the transposi- ‘visited’ by tackle this question. tion events was harvested, amplified transcription The retrotransposon Ty5 encodes and analysed by DNA sequencing factors. an integrase that interacts with the or DNA microarray hybridization. robust; moreover, it identified both silent information regulator 4 (Sir4) The authors tested the method first known and unknown genomic targets. chromatin component and catalyses by using two transcription factors, Implementing this technology for its insertion into the yeast genome, Gal4 and Gcn4, independently, then all of the ~200 yeast DNA-binding near Sir4-binding sites. The authors together with five other transcrip- proteins could allow the whole yeast took advantage of the fact that fusing tion factors, each fused to Sir4 along transcription factor network to be DNA-binding proteins to Sir4 directs with its corresponding Ty5 element.
    [Show full text]
  • C Haplotype Block Contains Major Determinants for Host Control of HIV
    Genes and Immunity (2009), 1–5 & 2009 Macmillan Publishers Limited All rights reserved 1466-4879/09 $32.00 www.nature.com/gene ORIGINAL ARTICLE The HLA-B/-C haplotype block contains major determinants for host control of HIV E Trachtenberg1,6, T Bhattacharya2,3,6, M Ladner1,6, J Phair4, H Erlich1,5 and S Wolinsky4 1Center for Genetics, Children’s Hospital Oakland Research Institute, Oakland, CA, USA; 2The Santa Fe Institute, Santa Fe, NM, USA; 3Theoretical Division, Los Alamos National Laboratory, Los Alamos, NM, USA; 4Division of Infectious Diseases, The Feinberg School of Medicine, Northwestern University, Chicago, IL, USA and 5Department of Human Genetics, Roche Molecular Systems, Pleasanton, CA, USA A genome-wide association study of people with incident human immunodeficiency virus (HIV) infection selected from nine different cohorts identified allelic polymorphisms, which associated with either viral set point (HCP5 and 50 HLA-C) or with HIV disease progression (RNF39 and ZNRD1). To determine the influence of these polymorphisms on host control of HIV, we carried out a population-based association study. The analysis revealed complete linkage disequilibrium between HCP5 and HLA-B*5701/HLA-Cw*06, a modest effect of 50 HLA-C on viral set point in the absence of HLA-B*5701, and no influence of the RNF39 /ZNRD1 extended haplotype on HIV disease progression. No correlation was found between the infection status and any of these genetic variants (P40.1, Fisher’s exact test). These findings suggest a pattern of strong linkage disequilibrium consistent with an HLA-B/-C haplotype block, making identification of a causal variant difficult, and underscore the importance of validating polymorphisms in putative determinants for host control by association analysis of independent populations.
    [Show full text]
  • Host Genes Important to HIV Replication and Evolution
    Downloaded from http://perspectivesinmedicine.cshlp.org/ on September 26, 2021 - Published by Cold Spring Harbor Laboratory Press Host Genes Important to HIV Replication and Evolution Amalio Telenti1 and Welkin E. Johnson2 1Institute of Microbiology, University Hospital and University of Lausanne, 1011 Lausanne, Switzerland 2New England Primate Research Center, Department of Microbiology and Molecular Genetics, Harvard Medical School, Southborough, Massachusetts 01772 Correspondence: [email protected] Recent years have seen a significant increase in understanding of the host genetic and genomic determinants of susceptibility to HIV-1 infection and disease progression, driven in large part by candidate gene studies, genome-wide association studies, genome-wide transcriptome analyses, and large-scale in vitro genome screens. These studies have iden- tified common variants in some host loci that clearly influence disease progression, charac- terized the scale and dynamics of gene and protein expression changes in response to infection, and provided the first comprehensive catalogs of genes and pathways involved in viral replication. Experimental models of AIDS and studies in natural hosts of primate lentiviruses have complemented and in some cases extended these findings. As the relevant technology continues to progress, the expectation is that such studies will increase in depth (e.g., to include host whole exome and whole genome sequencing) and in breadth (in par- ticular, by integrating multiple data types). ost genetics has been of considerable allowed the identification of a host genetic con- Hinterest to the field of HIV/AIDS since tribution to .50% of the observed differences the identification of the role of CCR5D32 in cell susceptibility to transduction with a (Dean et al.
    [Show full text]
  • HIV-1-Negative Female Sex Workers Sustain High Cervical IFN&Epsiv
    nature publishing group ARTICLES HIV-1-negative female sex workers sustain high cervical IFNe, low immune activation, and low expression of HIV-1-required host genes SA Abdulhaqq1, C Zorrilla2, G Kang3, X Yin1, V Tamayo2, KE Seaton4, J Joseph1, S Garced2, GD Tomaras4, KA Linn5, AS Foulkes6, L Azzoni1, M VerMilyea7, C Coutifaris7, AV Kossenkov1, L Showe1,EN Kraiselburd8,QLi3 and LJ Montaner1 Sex workers practicing in high HIV endemic areas have been extensively targeted to test anti-HIV prophylactic strategies. We hypothesize that in women with high levels of genital exposure to semen changes in cervico-vaginal mucosal and/or systemic immune activation will contribute to a decreased susceptibility to HIV-1 infection. To address this question, we assessed sexual activity and immune activation status (in peripheral blood), as well as cellular infiltrates and gene expression in ectocervical mucosa biopsies in female sex workers (FSWs; n ¼ 50), as compared with control women (CG; n ¼ 32). FSWs had low-to-absent HIV-1-specific immune responses with significantly lower CD38 expression on circulating CD4 þ or CD8 þ T-cells (both: Po0.001) together with lower cervical gene expression of genes associated with leukocyte homing and chemotaxis. FSWs also had increased levels of interferon-e (IFNe) gene and protein expression in the cervical epithelium together with reduced expression of genes associated with HIV-1 integration and replication. A correlative relationship between semen exposure and elevated type-1 IFN expression in FSWs was also established. Overall, our data suggest that long-term condomless sex work can result in multiple changes within the cervico-vaginal compartment that would contribute to sustaining a lower susceptibility for HIV-1 infection in the absence of HIV-specific responses.
    [Show full text]
  • Impact of Immune-Driven Sequence Variation in HIV-1 Subtype C Gag-Protease on Viral Fitness and Disease Progression
    i IMPACT OF IMMUNE-DRIVEN SEQUENCE VARIATION IN HIV-1 SUBTYPE C GAG- PROTEASE ON VIRAL FITNESS AND DISEASE PROGRESSION SUBMITTED BY: JACLYN WRIGHT SUPERVISED BY: PROFESSOR THUMBI NDUNG’U Submitted in fulfilment of the requirements for the degree of Doctor of Philosophy in Virology in the Nelson R. Mandela School of Medicine, College of Health Sciences, University of KwaZulu-Natal, Durban. 2011 i This project represents original work done by the author and where others have made contributions it has been acknowledged in the text. The experimental work described in this thesis was performed in the HIV Pathogenesis Programme Laboratory, Hasso Plattner Research Laboratory, and Africa Centre Laboratory, in the Doris Duke Medical Research Institute, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa, under the supervision of Professor T. Ndung’u. J. Wright: Date: Professor T. Ndung’u: Date: As the candidate’s supervisor I agree to the submission of this thesis. Professor T. Ndung’u: Date: ii DECLARATION I, Jaclyn Wright, declare that (i) The research reported in this thesis, except where otherwise indicated, is my original work. (ii) This thesis has not been submitted for any degree or examination at any other university. (iii) This thesis does not contain other person’s data, pictures, graphs or other information, unless specifically acknowledged as being sourced from other persons. (iv) This thesis does not contain other persons’ writing, unless specifically acknowledged as being sourced from other researchers. Where other written sources have been quoted, then: (a) Their words have been re-written but the general information attributed to them has been referenced; (b) where their exact words have been used, their writing has been placed inside quotation marks, and referenced.
    [Show full text]
  • Modeling and Analysis of Acute Leukemia Using Human Hematopoietic Stem and Progenitor Cells
    Modeling and analysis of acute leukemia using human hematopoietic stem and progenitor cells A dissertation submitted to the Graduate School of the University of Cincinnati in partial fulfillment of the requirement for the degree of Doctor of Philosophy in the Molecular &Developmental Biology Graduate Program of the College of Medicine by Shan Lin BS, Tsinghua University, 2009 Dissertation Committee: James C. Mulloy, PhD (Chair) Geraldine Guasch, PhD Ashish R. Kumar, MD, PhD Daniel T. Starczynowski, PhD Yi Zheng, PhD Abstract For decades, elegant mouse models have yielded important insights into the complex biology of acute leukemia development. However, species differences between human and mouse could have significant influences on biological and translational applications. Therefore, human primary hematopoietic cells and xenograft mouse models have become important research tools in the field. In this report, we briefly review the methodologies that use human primary hematopoietic cells to model acute leukemia and examine the effects of leukemic oncogenes. The advantages and limitations of the human model system compared to syngeneic mouse models are discussed. The species-related complexity in human disease modeling is highlighted in the study establishing a faithful model of proB-ALL caused by MLL-AF4, the fusion product of the t(4;11). MLL-AF4 proB-ALL has poor prognosis, the lack of an accurate model hampers the study of disease pathobiology and therapeutic testing. We find human AF4 cDNA inhibits retroviral production and efficient transduction, this limitation can be overcome by fusing MLL with murine Af4, highly conserved with human AF4. Whereas MLL-Af4-transduced murine cells induce only AML, transduced human CD34+ cells produce proB-ALL faithful to t(4;11) disease, fully recapitulating the immunophenotypic and molecular aspects of the disease.
    [Show full text]
  • Alimentaria Y De Biosistemas
    UNIVERSIDAD POLITÉCNICA DE MADRID ESCUELA TÉCNICA SUPERIOR DE INGENIERÍA AGRONÓMICA, ALIMENTARIA Y DE BIOSISTEMAS GRADO EN BIOTECNOLOGÍA Validación del polimorfismo rs2395029 del gen HCP5 para la predicción de hipersensibilidad a abacavir. Validation of HCP5 rs2395029 gene polymorphism as a biomarker for abacavir hypersensitivity prediction. TRABAJO FIN DE GRADO Autor: Gonzalo Villapalos García Tutoras: Miriam Saiz Rodríguez y Eva Miedes Vicente Junio de 2019 UNIVERSIDAD POLITÉCNICA DE MADRID ESCUELA TÉCNICA SUPERIOR DE INGENIERÍA AGRONÓMICA, ALIMENTARIA Y DE BIOSISTEMAS GRADO EN BIOTECNOLOGÍA VALIDACIÓN DEL POLIMORFISMO RS2395029 DEL GEN HCP5 PARA LA PREDICCIÓN DE HIPERSENSIBILIDAD A ABACAVIR VALIDATION OF HCP5 RS2395029 GENE POLYMORPHISM AS A BIOMARKER FOR ABACAVIR HYPERSENSITIVITY PREDICTION TRABAJO FIN DE GRADO Gonzalo Villapalos García MADRID, 2019 Directora: Dra. Miriam Saiz Rodríguez Servicio de Farmacología Clínica. Hospital Universitario de La Princesa Profesora: Dra. Eva Miedes Vicente Dpto. de Biotecnología-Biología Vegetal i VALIDACIÓN DEL POLIMORFISMO RS2395029 DEL GEN HCP5 PARA LA PREDICCIÓN DE HIPERSENSIBILIDAD A ABACAVIR VALIDATION OF HCP5 RS2395029 GENE POLYMORPHISM AS A BIOMARKER FOR ABACAVIR HYPERSENSITIVITY PREDICTION Memoria presentada por Gonzalo Villapalos García para la obtención del título de Graduado en Biotecnología por la Universidad Politécnica de Madrid Fdo: Gonzalo Villapalos García VºBº Tutor y directores del TFG Directora: Miriam Saiz Rodríguez Profesora: Eva Miedes Vicente Dpto de Biotecnología-Biología Vegetal ETSIAAB – Universidad Politécnica de Madrid Madrid, 25, julio, 2019 ii INDEX I. INTRODUCTION. 1 1. HUMAN IMMUNODEFICIENCY VIRUS TREATMENT. 1 2. ABACAVIR HYPERSENSITIVITY REACTION. 2 3. PHARMACOGENETICS. 3 4. HLA-B*57:01 BIOMARKER: TRADITIONAL GENOTYPING AND ALTERNATIVE METHODS. 4 5. HOSPITAL DE LA PRINCESA HLA-B*57:01 DETERMINATION PROCESS.
    [Show full text]
  • ZNRD1, HCP5 and HLA-C Alleles Are Attributable Mainly to Either HLA-A10 Or HLA-B*57 Alleles
    HIV-1 Disease-Influencing Effects Associated with ZNRD1, HCP5 and HLA-C Alleles Are Attributable Mainly to Either HLA-A10 or HLA-B*57 Alleles Gabriel Catano1,2., Hemant Kulkarni1,2., Weijing He1,2., Vincent C. Marconi3,4, Brian K. Agan3,4,5, Michael Landrum3,4,5, Stephanie Anderson3,5, Judith Delmar3,4, Vanessa Telles1,2, Li Song1,2, John Castiblanco1,2, Robert A. Clark1,2, Matthew J. Dolan3,4,5*, Sunil K. Ahuja1,2,6,7* 1 Veterans Administration Research Center for AIDS and HIV-1 Infection, South Texas Veterans Health Care System, San Antonio, Texas, United States of America, 2 Department of Medicine, University of Texas Health Science Center, San Antonio, Texas, United States of America, 3 Infectious Disease Clinical Research Program (IDCRP), Uniformed Services University of the Health Sciences, Bethesda, Maryland, United States of America, 4 Infectious Disease Service, San Antonio Military Medical Center (SAMMC), Ft. Sam Houston, Texas, United States of America, 5 Henry M. Jackson Foundation, Wilford Hall United States Air Force Medical Center, Lackland AFB, Texas, United States of America, 6 Department of Microbiology and Immunology, University of Texas Health Science Center, San Antonio, Texas, United States of America, 7 Department of Biochemistry, University of Texas Health Science Center, San Antonio, Texas, United States of America Abstract A recent genome-wide association study (GWAS) suggested that polymorphisms in or around the genes HCP5, HLA-C and ZNRD1 confer restriction against HIV-1 viral replication or disease progression. Here, we also find that these alleles are associated with different aspects of HIV disease, albeit mainly in European Americans.
    [Show full text]
  • 1 Novel Expression Signatures Identified by Transcriptional Analysis
    ARD Online First, published on October 8, 2009 as 10.1136/ard.2009.108043 Ann Rheum Dis: first published as 10.1136/ard.2009.108043 on 7 October 2009. Downloaded from Novel expression signatures identified by transcriptional analysis of separated leukocyte subsets in SLE and vasculitis 1Paul A Lyons, 1Eoin F McKinney, 1Tim F Rayner, 1Alexander Hatton, 1Hayley B Woffendin, 1Maria Koukoulaki, 2Thomas C Freeman, 1David RW Jayne, 1Afzal N Chaudhry, and 1Kenneth GC Smith. 1Cambridge Institute for Medical Research and Department of Medicine, Addenbrooke’s Hospital, Hills Road, Cambridge, CB2 0XY, UK 2Roslin Institute, University of Edinburgh, Roslin, Midlothian, EH25 9PS, UK Correspondence should be addressed to Dr Paul Lyons or Prof Kenneth Smith, Department of Medicine, Cambridge Institute for Medical Research, Addenbrooke’s Hospital, Hills Road, Cambridge, CB2 0XY, UK. Telephone: +44 1223 762642, Fax: +44 1223 762640, E-mail: [email protected] or [email protected] Key words: Gene expression, autoimmune disease, SLE, vasculitis Word count: 2,906 The Corresponding Author has the right to grant on behalf of all authors and does grant on behalf of all authors, an exclusive licence (or non-exclusive for government employees) on a worldwide basis to the BMJ Publishing Group Ltd and its Licensees to permit this article (if accepted) to be published in Annals of the Rheumatic Diseases and any other BMJPGL products to exploit all subsidiary rights, as set out in their licence (http://ard.bmj.com/ifora/licence.pdf). http://ard.bmj.com/ on October 2, 2021 by guest. Protected copyright. 1 Copyright Article author (or their employer) 2009.
    [Show full text]
  • Long Noncoding RNA HCP5, a Hybrid HLA Class I Endogenous Retroviral Gene: Structure, Expression, and Disease Associations
    cells Review Long Noncoding RNA HCP5, a Hybrid HLA Class I Endogenous Retroviral Gene: Structure, Expression, and Disease Associations Jerzy K. Kulski 1,2 1 Faculty of Health and Medical Sciences, UWA Medical School, The University of Western Australia, Crawley, WA 6009, Australia; [email protected] or [email protected]; Tel.: +61-047-799-9943 2 Department of Molecular Life Science, Division of Basic Medical Science and Molecular Medicine, Tokai University School of Medicine, Isehara 259-1193, Japan Received: 5 May 2019; Accepted: 17 May 2019; Published: 20 May 2019 Abstract: The HCP5 RNA gene (NCBI ID: 10866) is located centromeric of the HLA-B gene and between the MICA and MICB genes within the major histocompatibility complex (MHC) class I region. It is a human species-specific gene that codes for a long noncoding RNA (lncRNA), composed mostly of an ancient ancestral endogenous antisense 30 long terminal repeat (LTR, and part of the internal pol antisense sequence of endogenous retrovirus (ERV) type 16 linked to a human leukocyte antigen (HLA) class I promoter and leader sequence at the 50-end. Since its discovery in 1993, many disease association and gene expression studies have shown that HCP5 is a regulatory lncRNA involved in adaptive and innate immune responses and associated with the promotion of some autoimmune diseases and cancers. The gene sequence acts as a genomic anchor point for binding transcription factors, enhancers, and chromatin remodeling enzymes in the regulation of transcription and chromatin folding. The HCP5 antisense retroviral transcript also interacts with regulatory microRNA and immune and cellular checkpoints in cancers suggesting its potential as a drug target for novel antitumor therapeutics.
    [Show full text]