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HIV-1 Latency As a Consequence of Chromatin Regulation

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HIV-1 Latency As a Consequence of Chromatin Regulation HIV-1 LATENCY AS A CONSEQUENCE OF CHROMATIN REGULATION by JULIA H. FRIEDMAN Submitted in partial fulfillment of the requirements For the degree of Doctor of Philosophy Dissertation Adviser: Dr. Jonathan Karn Department of Molecular Biology and Microbiology CASE WESTERN RESERVE UNIVERSITY May, 2011 CASE WESTERN RESERVE UNIVERSITY SCHOOL OF GRADUATE STUDIES We hereby approve the thesis/dissertation of ___________Julia Friedman______________________________ candidate for the Doctor of Philosophy degree *. (signed)______________Dr. David McDonald_____ (chair of the committee) ____________Dr. Jonathan Karn________ ____________Dr. Hung-Ying Kao______ ____________Dr. Paul MacDonald_____ ________________________________________________ ________________________________________________ (date) _____January 20, 2010_______ *We also certify that written approval has been obtained for any proprietary material contained therein. 2 Table of Contents Table Legend ...................................................................................................................... 6 Figure Legend ..................................................................................................................... 6 Acknowledgements ............................................................................................................. 9 List of Abbreviations ........................................................................................................ 10 Chapter 1) Introduction ................................................................................................. 17 1A HIV and AIDS ........................................................................................................... 17 1A.1 Towards an HIV Vaccine ..................................................................................... 19 1A.2 The HIV-1 Genome and Life Cycle ..................................................................... 22 1A.2a Entry ................................................................................................................ 26 1A.2b Reverse Transcription ..................................................................................... 28 1A.2c Nuclear Import and Integration ....................................................................... 32 1A.2d HIV Transcription and RNA export ............................................................... 35 1A.2e Cellular Activation Signals Cooperate with Tat/TAR .................................... 35 1A.2f HIV RNA export ............................................................................................ 42 1A.2g Assembly, Release, and Maturation ............................................................... 43 1B HIV Latency ................................................................................................................ 44 1B.1 Pre-integration Latency ........................................................................................ 44 1B.2 Post-integration Latency ....................................................................................... 46 1B.2a In vitro Models ................................................................................................ 46 1B.2b Primary Cells .................................................................................................. 48 1B.2c In vivo Models ................................................................................................. 50 1B.4 Mechanisms of HIV Latency ................................................................................ 51 1B.4a Cellular Factors ............................................................................................... 51 1B.4b Heterochromatic Restriction ........................................................................... 52 1C Hypothesis and Discussion.......................................................................................... 56 Chapter 2) Materials and Methods ............................................................................... 60 2A Cell lines and Tissue Culture Reagents....................................................................... 60 2B Cloning and Lentiviral infections ................................................................................ 60 2C ChIP analysis .............................................................................................................. 61 2D Western Blots .............................................................................................................. 62 3 2E Isolating the C22G Tat mutant clone........................................................................... 63 2F MNase Digest .............................................................................................................. 63 2G Isolation and Analysis of Mononucleosome Fragments ............................................. 64 2H Activations and shutdowns ......................................................................................... 64 2G Viral outgrowth assays ................................................................................................ 65 Chapter 3) The Histone Lysine Methyltransferase EZH2 Plays an Essential Role in Establishing and Maintaining HIV Latency................................................................. 67 3A Abstract ................................................................................................................... 67 3B Introduction ............................................................................................................. 69 3C Results ..................................................................................................................... 71 3C.1 A small scale shRNA screen for factors regulating HIV Latency .................... 71 3C.2 Knockdown of EZH2 leads to activation of HIV transcription ........................ 72 3C.3 EZH2 and M3K27 are present at the LTR of Latent Proviruses ...................... 78 3C.4 EZH2 knockdown sensitizes latent proviruses to cellular activation signals ... 82 3C.5 Reduction of EZH2 delays silencing of HIV transcription ............................... 85 3C.6 Drug candidates to induce reactivation of HIV from latency ........................... 86 3C.7 Treating latent cells with the HKMT inhibitor DZNep activates cells through inhibition of methylation ........................................................................................... 89 3C.8 Other HKMT inhibitors exhibit little activation potential ................................ 91 3C.9 DNA methylation plays an insignificant role in proviral silencing .................. 91 3C.10 Treatment with the HDACi SAHA and DZNep synergistically activate HIV transcription ............................................................................................................... 92 3C.11 Knockdown of histone lysine methyltransferases induces outgrowth of HIV from latently infected resting memory T-cells obtained from patients ..................... 95 3D) Discussion .............................................................................................................. 98 3D.1 Epigenetic silencing of HIV by histone methylation ........................................ 98 3D.2 EZH2 and SUV39H1 play unique roles in the silencing of HIV ..................... 99 3D.3 Therapeutic implications ................................................................................ 100 Acknowledgments ....................................................................................................... 101 Chapter 4) Nuc-1 Remodeling is Required for Activation of HIV-1 Transcription 102 4A Abstract ................................................................................................................. 102 4B Introduction ........................................................................................................... 104 4 4C Results ................................................................................................................... 106 4C.1 The C22G Tat mutant ..................................................................................... 106 4C.2 NXS clones establish latency at a slower rate than their wild-type controls .. 107 4C.3 A novel nucleosome mapping approach ......................................................... 112 4C.4 Brg-1 recruitment to the HIV promoter .......................................................... 113 4D Discussion and Future Directions.......................................................................... 116 4D.1 Nucleosomes as barriers to HIV transcription ................................................ 116 4D.2 The SWI/SNF complex and viral replication ................................................. 119 Chapter 5 Future Experiments .................................................................................... 122 5A Additional compounds inhibiting methylation may also reactivate HIV from latency ......................................................................................................................... 122 5B Evaluating the impact of the Histone Demethylase JMJD3 .................................. 122 5C Assessing the role of protein arginine methyltransferases (PRMTs) .................... 124 5D Investigating the Roles of SUZ12 and EED .......................................................... 125 5E Determine if EZH2 is contributing to latency in primary cells ............................. 125 Chapter 6 Discussion ...................................................................................................
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