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1.8. Thesis Objectives Discovery and Mechanistic Study of HIV-1 Transcriptional Inhibitors from Natural and Synthetic Products by Cole Schonhofer B.Sc., Simon Fraser University, 2015 Thesis Submitted in Partial Fulfillment of the Requirements for the Degree of Master of Science in the Master of Science Program Faculty of Health Sciences © Cole Schonhofer 2019 SIMON FRASER UNIVERSITY Fall 2019 Copyright in this work rests with the author. Please ensure that any reproduction or re-use is done in accordance with the relevant national copyright legislation. Approval Name: Cole Schonhofer Degree: Master of Science Title: Discovery and Mechanistic Study of HIV-1 Transcriptional Inhibitors from Natural and Synthetic Products Examining Committee: Chair: Tim Takaro Professor, Associate Dean Ian Tietjen Senior Supervisor Assistant Professor Zabrina Brumme Supervisor Associate Professor Jonathan Choy Supervisor Associate Professor Timothy Beischlag Examiner Professor Date Defended/Approved: December 17, 2019 ii Ethics Statement iii Abstract There is currently no safe, scalable cure for HIV-1 infection due to the persistence of a latent viral reservoir. The Block-and-Lock strategy to achieve drug-free HIV remission requires promotion of a durable, deep latent state from which dormant HIV does not reactivate. However, there are currently no licensed HIV inhibitors that target expression from the latent reservoir. Factors that are required for efficient viral transcription, such as the HIV protein Tat and the host factor CDK9, are potential targets for Block-and-Lock approaches. My thesis describes an effort to discover novel antivirals that prevent expression from latently infected cells and inhibit viral replication. I describe the identification of natural and synthetic inhibitors of HIV Tat-mediated transcription, the investigation of their molecular mechanisms, and their potential as Block-and-Lock agents. The work presented here informs the development of future HIV drug-free remission strategies and identifies CDK9 as a potential target for Block-and-Lock strategies. Keywords: HIV; Block-and-Lock; CDK9; flavonoids; Tat iv Dedication To my family, thank you for everything, all the support to help me reach this stage. I couldn’t have done it without the support of my mother, father, wife, sister, grandparents, several cats, and a few dogs. v Acknowledgements While individual contributions are noted in the relevant data chapters, I’d like to use this space to thank my supervisor Dr. Ian Tietjen for all of his support, mentorship, training, and the opportunity to work on these projects. I’d also like to thank every member of the Tietjen, Brumme, and Brockman labs who assisted me throughout my time as a Master’s student. Additionally, thank you to the members of all the labs who collaborated with us on these projects. Finally, I’d also like to acknowledge the financial support provided to me by the Faculty of Health Sciences at SFU and the Canadian Institute for Health Reasearch, in the form of scholarships and travel awards. This work was supported by an SFU Presidential Research Startup Grant, a Canadian Institutes of Health Project Grant (PJT-153057), the Sub-Saharan African Network for TB/HIV Research Excellence (SANTHE), a DELTAS African Initiative (grant # DEL-15- 006), the Canadian Foundation for AIDS Research (CANFAR), and the New Frontiers in Research Fund – Exploration (NFRFE-2018-01386). vi Table of Contents Approval .......................................................................................................................... ii Ethics Statement ............................................................................................................ iii Abstract .......................................................................................................................... iv Dedication ....................................................................................................................... v Acknowledgements ........................................................................................................ vi Table of Contents .......................................................................................................... vii List of Tables ................................................................................................................... x List of Figures................................................................................................................. xi List of Acronyms ............................................................................................................ xii Chapter 1. Introduction .............................................................................................. 1 1.1. The Global HIV-1 Epidemic ................................................................................... 1 1.2. HIV Genome and Life Cycle .................................................................................. 1 1.3. HIV Pathogenesis .................................................................................................. 5 1.4. Antiretroviral Therapies: Drug Classes, Mechanisms, and Limitations ................... 6 1.5. The HIV Latent Reservoir: Barrier to a Cure .......................................................... 9 1.6. HIV Cure or Remission Strategies ....................................................................... 11 1.7. Conclusion........................................................................................................... 16 1.8. Thesis Objectives ................................................................................................ 16 1.9. References .......................................................................................................... 17 Chapter 2. Identification of Flavonoids that Suppress HIV-1 Latency Reversal from African Natural Products .......................................................................... 31 2.1. Abstract ............................................................................................................... 31 2.2. Introduction .......................................................................................................... 31 2.3. Materials and Methods ........................................................................................ 32 2.3.1. Cells and Reagents ..................................................................................... 32 2.3.2. Plasmids ...................................................................................................... 33 2.3.3. Virus Production .......................................................................................... 33 2.3.4. HIV-1 Replication Assays and Compound Screening .................................. 34 2.3.5. Apoptosis Detection Assays ........................................................................ 35 2.3.6. Inhibition of Latency Reversal Assays ......................................................... 35 2.3.7. GFP Quenching Assay ................................................................................ 36 2.3.8. HIV-1 Tat Inhibition Assays.......................................................................... 36 2.3.9. Block and Lock Assays ................................................................................ 36 2.3.10. Data and Statistical Analysis .................................................................... 37 2.4. Results ................................................................................................................ 37 2.4.1. Identification of Flavonoids that Inhibit HIV Replication. ............................... 37 2.4.2. Flavonoids Inhibit HIV Replication in PBMC ................................................ 42 2.4.3. Flavonoids Inhibit Replication of ARV-Resistant Viruses ............................. 44 2.4.4. Flavonoids Inhibit Latency Reversal in Multiple Cell Lines ........................... 47 2.4.5. Aglycone Flavones, but not L7G, Inhibit HIV-1 Tat Function ........................ 51 vii 2.4.6. Apigenin, Chrysin, and Luteolin Reversibly Reinforce Latency .................... 55 2.5. Discussion ........................................................................................................... 57 2.6. Contributions ....................................................................................................... 60 2.7. References .......................................................................................................... 60 Chapter 3. Mechanistic Investigation of Post Integration Activities of Flavonoids 65 3.1. Abstract ............................................................................................................... 65 3.2. Introduction .......................................................................................................... 65 3.3. Methods .............................................................................................................. 69 3.3.1. Reagents ..................................................................................................... 69 3.3.2. Plasmids ...................................................................................................... 69 3.3.3. Kinase Activity Assays ................................................................................. 70 3.3.4. Quantitation of Intracellular HIV mRNA Levels............................................. 70 3.3.5. Screens for Flavonoids that Synergistically Promote Latency Reversal ....... 71 3.3.6. HIV Rev Function
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