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The Expression of Human Endogenous Retroviruses Is Modulated by the Tat Protein of HIV‐1

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The Expression of Human Endogenous Retroviruses Is Modulated by the Tat Protein of HIV‐1 The Expression of Human Endogenous Retroviruses is modulated by the Tat protein of HIV‐1 by Marta Jeannette Gonzalez‐Hernandez A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy (Immunology) in The University of Michigan 2012 Doctoral Committee Professor David M. Markovitz, Chair Professor Gary Huffnagle Professor Michael J. Imperiale Associate Professor David J. Miller Assistant Professor Akira Ono Assistant Professor Christiane E. Wobus © Marta Jeannette Gonzalez‐Hernandez 2012 For my family and friends, the most fantastic teachers I have ever had. ii Acknowledgements First, and foremost, I would like to thank David Markovitz for his patience and his scientific and mentoring endeavor. My time in the laboratory has been an honor and a pleasure. Special thanks are also due to all the members of the Markovitz laboratory, past and present. It has been a privilege, and a lot of fun, to work near such excellent scientists and friends. You all have a special place in my heart. I would like to thank all the members of my thesis committee for all the valuable advice, help and jokes whenever needed. Our collaborators from the Bioinformatics Core, particularly James Cavalcoli, Fan Meng, Manhong Dai, Maureen Sartor and Gil Omenn gave generous support, technical expertise and scientific insight to a very important part of this project. Thank you. Thanks also go to Mariana Kaplan’s and Akira Ono’s laboratory for help with experimental designs and for being especially generous with time and reagents. iii Table of Contents Dedication ............................................................................................................................ ii Acknowledgements ............................................................................................................. iii List of Figures .................................................................................................................... viii List of Tables ........................................................................................................................ x Chapter I. Introduction Human Endogenous Retrovirus Type K (HML‐2) and HIV‐1 infection ............................................................................................ 1 Part I. Retroviruses and their General Properties ...................................... 1 A. Structure of Retroviruses a) General Properties ...................................................................... 4 b) Genomic Composition ................................................................ 6 Genome Organization ......................................................... 7 Long Terminal Repeats ....................................................... 8 c) Core Proteins Gag Protein ....................................................................... 10 Pol Protein‐Polymerase .................................................... 11 Pro Protein‐Protease......................................................... 12 Env Protein‐Envelope ........................................................ 12 Retroviral accesory proteins ............................................. 12 B. Replication of Retroviruses ................................................................... 13 iv C. Retroviral Classification ........................................................................ 14 Part II. Human Endogenous Retroviruses (HERVs) ................................... 17 A. General properties of HERVs ................................................................ 17 B. Classification of HERVs .......................................................................... 20 Class I HERVs ................................................................................. 21 Class II HERVs ................................................................................ 22 Class III HERVs ............................................................................... 23 C. HERV expression within Humans .......................................................... 23 D. Pathological Role of HERVs ................................................................... 28 E. Human Endogenous Retrovirus Type K (HML‐2) ............................................. 31 Part III. Human Endogenous Retrovirus Type K and HIV‐1 infection ....... 36 A. Expression of HERV‐K (HML‐2) during HIV‐1 infection ......................... 36 B. Mechanism of activation of HERV‐K (HML‐2) during HIV‐1 infection ............. 37 Thesis Focus and Hypothesis .................................................................... 40 II. Expression of Human Endogenous Retrovirus Type K (HML‐2) is activated by the Tat protein of HIV‐1 ....................................................... 42 Abstract ..................................................................................................... 42 Introduction .............................................................................................. 43 HERV‐K (HML‐2) RNA expression is increased in HIV‐1‐infected cell lines .......... 47 HIV‐1 Tat and Vif independently cause an increase in HERV‐K (HML‐2) gag RNA expression ............................................................................................. 50 Recombinant HIV‐1 Tat increases HERV‐K (HML‐2) expression ............... 54 Activation of the HERV‐K (HML‐2) promoter by HIV‐1 Tat ....................... 61 Activation of the HERV‐K (HML‐2) promoter by Tat is mediated by NF‐κB and NF‐AT ....................................................................................... 65 Discussion.................................................................................................. 76 v Materials and Methods ............................................................................. 80 III. HIV‐1 Tat causes the activation of a novel centromeric Human Endogenous Retrovirus Type K (HML‐2) discovered through HIV infection ............................ 93 Abstract ..................................................................................................... 93 Introduction .............................................................................................. 94 A new HERV‐K (HML‐2) virus, K111, is discovered in the plasma of HIV‐1‐infected individuals and is only activated during HIV‐1 infection ........ 96 In vitro infection of cell lines with HIV‐1 causes expression of K111 ....... 99 HIV‐1 Tat induces the expression of K111 from centromeric regions through chromatin remodeling .............................................................. 101 Discussion................................................................................................ 105 Materials and Methods ........................................................................... 107 IV. The HERV‐K (HML‐2) transcriptome induced by the HIV‐1 Tat protein .............................................................................................. 114 Abstract ................................................................................................... 114 Introduction ............................................................................................ 115 HIV‐1 Tat both activates and silences specific HERV‐K (HML‐2) proviruses in normal PBLs ....................................................................... 120 HIV‐1 Tat both activates and silences specific HERV‐K (HML‐2) proviruses in normal PBLs ....................................................................... 120 qPCR validation of specific HERV‐K (HML‐2) provirus activation and silencing by HIV‐1 Tat corroborates RNA‐Seq data analysis ................... 128 Nature of the HERV‐K (HML‐2) Tat‐activated transcripts ....................... 132 vi Most of the Tat‐induced HERV‐K (HML‐2) proviruses are Type 2, yet do not contain ORFs ................................................................................ 133 Correlation of HERV‐K (HML‐2) proviruses activated by Tat to those detected in the plasma of HIV‐1‐infected patients ................................ 136 Discussion................................................................................................ 138 Materials and Methods ........................................................................... 140 V. Conclusions ………………………………………………………………………………………..146 HERV‐K (HML‐2) and HIV‐1 Tat ............................................................... 150 Future explorations: testing the consequences of increased HERV‐K (HML‐2) expression ................................................................................. 152 Appendix ......................................................................................................................... 158 Bibliography .................................................................................................................... 165 vii List of Figures Figure Page 1.1 Basic structure of the retroviral virion. 4 1.2 Organization of the retroviral genome. 6 1.3 Proviral Genome and LTR. 10 1.4 Basic retroviral lifecycle. 14 2.1 HIV‐1 infection and Tat stimulate HERV‐K (HML‐2) gene expression. 49 2.2 HIV‐1 Tat and Vif proteins activate HERV‐K (HML‐2) RNA expression. 52 2.3 Recombinant HIV‐1 Tat activates HERV‐K (HML‐2) gene expression. 58 2.4 HIV‐1 Tat activates the HERV‐K (HML‐2) promoter by a different mechanism than it uses to activate HIV‐1. 63 2.5 Inhibition of the NF‐κB or NF‐AT transcription factors suppresses Tat‐mediated activation from the HERV‐K (HML‐2) LTR. 69 2.6 Tat responsive elements
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