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Impact of Natural HIV-1 Nef Alleles and Polymorphisms on SERINC3/5 Downregulation

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Impact of Natural HIV-1 Nef Alleles and Polymorphisms on SERINC3/5 Downregulation Impact of natural HIV-1 Nef alleles and polymorphisms on SERINC3/5 downregulation by Steven W. Jin B.Sc., Simon Fraser University, 2016 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 © Steven W. Jin 2019 SIMON FRASER UNIVERSITY Spring 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: Steven W. Jin Degree: Master of Science Title: Impact of natural HIV-1 Nef alleles and polymorphisms on SERINC3/5 downregulation Examining Committee: Chair: Kanna Hayashi Assistant Professor Mark Brockman Senior Supervisor Associate Professor Masahiro Niikura Supervisor Associate Professor Ralph Pantophlet Supervisor Associate Professor Lisa Craig Examiner Professor Department of Molecular Biology and Biochemistry Date Defended/Approved: April 25, 2019 ii Ethics Statement iii Abstract HIV-1 Nef is a multifunctional accessory protein required for efficient viral pathogenesis. It was recently identified that the serine incorporators (SERINC) 3 and 5 are host restriction factors that decrease the infectivity of HIV-1 when incorporated into newly formed virions. However, Nef counteracts these effects by downregulating SERINC from the cell surface. Currently, there lacks a comprehensive study investigating the impact of primary Nef alleles on SERINC downregulation, as most studies to date utilize lab- adapted or reference HIV strains. In this thesis, I characterized and compared SERINC downregulation from >400 Nef alleles isolated from patients with distinct clinical outcomes and subtypes. I found that primary Nef alleles displayed a dynamic range of SERINC downregulation abilities, thus allowing naturally-occurring polymorphisms that modulate this activity to be identified. In addition, I found that Nef alleles isolated from patients with better clinical outcomes had a poorer ability to counteract SERINC, suggesting that variation in this activity may contribute to differences in HIV-1 pathogenesis. Keywords: HIV/AIDS; Nef; SERINC3; SERINC5; viral diversity; viral infectivity iv Dedication To my mom, who has given up so much of her life so I can have mine, for that, I am forever in your debt. v Acknowledgements The completion of a Master’s degree program is as much an intellectual journey as it is a personal one; in this regard, there is an army of individuals who have shaped both aspects of my journey. Foremost, I would like to extend my sincerest thanks to my senior supervisor Dr. Mark Brockman, as well as Dr. Zabrina Brumme, who have given me the platform to train and grow as a young scientist; my successes and accomplishments would not have been possible without your continuous support and generosity. Lastly, to every single lab member who I have met since joining the lab, you have all made this journey an unforgettable experience and I’m grateful to be able to call some of you my lifelong friends. vi Table of Contents Approval ............................................................................................................................... ii Ethics Statement ................................................................................................................. iii Abstract ............................................................................................................................... iv Dedication ............................................................................................................................v Acknowledgements ............................................................................................................. vi Table of Contents ............................................................................................................... vii List of Tables ....................................................................................................................... ix List of Figures.......................................................................................................................x List of Acronyms ................................................................................................................. xi Chapter 1. Role of HIV-1 accessory proteins in viral pathogenesis ........................ 1 1.1. Introduction to HIV-1 ................................................................................................ 1 1.2. HIV-1 life cycle and pathogenesis ........................................................................... 1 1.3. HIV-1 accessory proteins......................................................................................... 2 1.3.1. Virulence infectivity factor (Vif) ......................................................................... 3 1.3.2. Virulence protein R (Vpr) .................................................................................. 3 1.3.3. Viral protein U (Vpu) ......................................................................................... 4 1.3.4. Negative factor (Nef) ........................................................................................ 4 1.4. Sequence and function variation in primary Nef alleles .......................................... 7 1.5. Conclusions.............................................................................................................. 9 1.6. Thesis Objectives ................................................................................................... 10 1.7. References ............................................................................................................. 11 Chapter 2. HIV-1 Nef alleles isolated from elite controllers are impaired for SERINC5 downregulation activity ....................................................................... 21 2.1. Abstract .................................................................................................................. 21 2.2. Introduction ............................................................................................................ 22 2.3. Materials and Methods .......................................................................................... 23 2.3.1. Study Participants ........................................................................................... 23 2.3.2. Reagents......................................................................................................... 23 2.3.3. Generation of HIV-1 nef expression and proviral constructs ......................... 23 2.3.4. Generation of SERINC5 knockout Jurkat LTR-GFP reporter cells ............... 24 2.3.5. SERINC5 downregulation assays .................................................................. 24 2.3.6. CD4 and HLA class I downregulation assays ................................................ 25 2.3.7. Infectivity and replication capacity .................................................................. 25 2.3.8. Western blot .................................................................................................... 26 2.3.9. Statistical analysis .......................................................................................... 27 2.4. Results ................................................................................................................... 27 2.4.1. Primary HIV-1 Nef alleles display variable abilities to internalize SERINC5 . 27 2.4.2. Natural Nef polymorphisms are associated with SERINC5 downregulation function………... ............................................................................................................ 30 vii 2.4.3. Nef-mediated SERINC5 downregulation correlates more strongly with CD4 internalization compared to HLA internalization ........................................................... 32 2.4.4. Viral adaptation to host cytotoxic T lymphocytes contributes to variability in Nef-mediated SERINC5 downregulation activity .......................................................... 34 2.4.5. CTL escape mutations K94E and H116N selectively impair Nef-mediated SERINC5 downregulation function ............................................................................... 34 2.5. Discussion .............................................................................................................. 38 2.6. References ............................................................................................................. 40 Chapter 3. Differential ability of HIV-1 Nef alleles across viral subtypes to downregulate SERINC3 and SERINC5 ............................................................... 44 3.1. Abstract .................................................................................................................. 44 3.2. Introduction ............................................................................................................ 45 3.3. Materials and Methods .......................................................................................... 46 3.3.1. Study Participants ........................................................................................... 46 3.3.2. Plasmids ......................................................................................................... 46 3.3.3. Site-directed mutagenesis .............................................................................. 47 3.3.4. SERINC, CD4 and HLA-I downregulation...................................................... 47 3.3.5. Generation
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