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Mechanisms of HIV-1 Restriction by the Host Protein SAMHD1

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Mechanisms of HIV-1 Restriction by the Host Protein SAMHD1 Mechanisms of HIV-1 Restriction by the Host Protein SAMHD1 Dissertation Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Jenna Marie Antonucci Graduate Program in Microbiology The Ohio State University 2018 Dissertation Committee Li Wu, Ph.D., Advisor Irina Artsimovitch, Ph.D. Jesse Kwiek, Ph.D. Karin Musier-Forsyth, Ph.D. Copyrighted by Jenna Marie Antonucci 2018 Abstract Human immunodeficiency virus type 1 (HIV-1) is a human retrovirus that replicates in cells via a well-characterized viral lifecycle. Inhibition at any step in the viral lifecycle results in downstream effects that can impair HIV-1 replication and restrict infection. For decades, researchers have been unable to determine the cause of myeloid-cell specific block in HIV-1 infection. In 2011, the discovery of the first mammalian deoxynucleoside triphosphate (dNTP) triphosphohydrolase (dNTPase) sterile alpha motif and HD domain containing protein 1 (SAMHD1) answered that question and introduced an entirely novel field of study focused on determining the mechanism and control of SAMHD1-mediated restriction of HIV-1 replication. Since then, the research on SAMHD1 has become a timely and imperative topic of virology. The following body of work includes studies furthering the field by confirming the established model and introducing a novel mechanism of SAMHD1-mediated suppression of HIV-1 replication. SAMHD1 was originally identified as a dGTP-dependent dNTPase that restricts HIV-1 infection by hydrolyzing intracellular dNTPs to a level that inhibits efficient reverse transcription of HIV-1 genomic RNA into complementary DNA (cDNA). Although this model was confirmed by several studies, work published in 2014 suggested that SAMHD1 is a nucleic-acid binding protein that restricts HIV-1 i replication through its ribonuclease (RNase) activity against the viral RNA genome in non-dividing immune cells. These findings revealed a new mechanism of SAMHD1-mediated HIV-1 restriction and raised important questions as to the contribution of each enzyme activity, dNTPase and RNase, to HIV-1 restriction. Based on previous studies, we tested our hypothesis that the RNase activity of SAMHD1 might limit HIV-1 protein production in virus producing cells, as transcribed viral RNA would be subject to cleavage by SAMHD1. Our data suggest that newly transcribed mRNAs of HIV-1, Influenza A virus (IAV), and Sendai virus (SeV) are not subjected to nucleolytic cleavage by SAMHD1’s RNase activity. We further confirmed SAMHD1 expression does not affect HIV-1 protein production, viral particle release, and infectivity of newly synthesized HIV-1 when the block in reverse transcription is bypassed. While SAMHD1 had no effect on incoming viral genomic RNA levels, we confirmed that SAMHD1 reduces intracellular dNTPs and inhibits efficient production of HIV-1 late reverse transcription products in non- dividing cells. Taken together, our study confirmed a dNTPase-dependent restriction of HIV-1 infection by SAMHD1. A critical barrier to developing a cure for HIV-1 infection is the long-lived viral reservoir that exists in resting CD4+ T-cells, the main targets of HIV-1. The viral reservoir is maintained through a variety of mechanisms, including regulation of the HIV-1 long terminal repeat (LTR) promoter. Recombinant SAMHD1 binds HIV- 1 DNA or RNA fragments in vitro, but the function of this binding remains unclear. ii SAMHD1 restricts HIV-1 replication in non-dividing cells and is highly expressed in resting CD4+ T-cells, but its role in HIV-1 latency remains unknown. Here we report a new function of SAMHD1 in regulating HIV-1 latency. We found that SAMHD1 suppressed HIV-1 LTR promoter-driven gene expression and reactivation of viral latency in cell lines and primary CD4+ T-cells. Furthermore, SAMHD1 bound to the HIV-1 LTR in vitro and in a latently infected CD4+ T-cell line, suggesting that the binding may negatively modulate reactivation of HIV-1 latency. Our findings indicate a novel role for SAMHD1 in regulating HIV-1 latency, which enhances our understanding of the mechanisms regulating proviral gene expression in CD4+ T-cells. To further understand the mechanism regulating the activity of SAMHD1, we solved novel crystal structures of full-length mouse SAMHD1 (mSAMHD1) to identify residues essential for the intra- and inter-subunit interaction between the SAM and HD domains. Interestingly, while the SAM domain of human SAMHD1 (hSAMHD1) is dispensable for HIV-1 restriction, we found that the SAM domain of mSAMHD1 is required for efficient HIV-1 restriction. Further, we determined that destabilization of the SAM-to-HD domain interaction abrogated the HIV-1 restriction activity of mSAMHD1. Interestingly, stabilization of the SAM-to-HD domain interaction in hSAMHD1 resulted in enhanced HIV-1 restriction. These data increase our understanding of the mechanism regulating SAMHD1-mediated HIV-1 restriction. iii The following studies have been critical for defining the mechanism of SAMHD1- mediated HIV-1 restriction. Taken together, our results can help better understand HIV-1 pathogenesis and how SAMHD1 functions as a retroviral restriction factor. iv Dedication Dedicated to Wendell – for his advice, his patience, and his faith in me. Because he always understood. v Acknowledgments I am overwhelmingly grateful for the patience and guidance of my advisor, Dr. Li Wu. At times he expected more of me than I thought I had to give; however, I now know that if you make every day better than the last, put your heart fully into everything you do, and never give up, anything is possible. I am indebted to my committee members, Dr. Irina Artsimovitch, Dr. Jesse Kwiek, and Dr. Karin Musier- Forsyth, for their advice and encouragement throughout my graduate career. Thank you for emboldening me to feel confident as a student and a scientist, and for always lending an ear when needed. For those who have never visited the basement of the Veterinary Medicine Academic Building, you could not imagine a more supportive, encouraging, laughter-filled, and lovely place to work – in spite of the lack of windows. Dr. Sarah Fritz, Dr. Jacob Al-Saleem, Dr. Amanda Panfil, Dr. Michael Martinez, and my Wu labmates Dr. Feifei Wang, Dr. Suresh de Silva, Dr. Serena Bonifati, Dr. Nagaraja Tirumuru, Dr. Wuxun Lu, Dr. Shuliang Chen, Zhihua Qin, Victoria Maksimova, Taiwei Li, and Sunhee Kim: They say it takes a village, and I couldn’t be more grateful I had you to get me through the ups and downs of the past five years. I don’t think that I could’ve gotten through graduate school without the support of my lab mentor and friend Dr. Corine St Gelais. You make me think better and vi harder everyday, and you helped me realize that the best version of myself is the one that is happiest. I want to especially thank Dr Alice Duchon and Brent Simpson; the best friends anyone could ask for. Brent, your support has never wavered since day one. I am so grateful for all our Sundays watching Game of Thrones, the Pokémon Go hikes, sushi dates, and movie nights. You made me feel calm in times of chaos, and I will be forever thankful for your support. Alice, you made everyday coming to work fun, exciting, and filled with laughter. Thank you for editing virtually everything I wrote in graduate school, for all the advice about science and life, for the mall trips, lunch dates, and yoga classes. Thank you for teaching me to let the bad go and for making the hardest days great again. Lastly, I want to thank my family. The Johnsons: Amy, Kevin, Frances, Andrew, and my nieces and nephew Beatrice, Tabitha, and Alistair: I could not imagine joining a family more supportive and encouraging of my research career. Thank you for welcoming me into your family, and for always being interested in my work. No words can describe how grateful I am for my father, Greg, my mother, Jenine, and my siblings, Cristina, Elizabeth, Joseph, and my new brother-in-law Brian. God knew I would need strong people to raise me - to watch over me while I found my way, to forgive me when I stumbled, and to teach me how to be better - which is why he gave me to you! Thank you for cheering me on as I pursued my dreams. vii Thank you for never letting me give up. Thank you for giving me a home to run away to. Thank you for taking my calls, for checking in, and for reminding me that this is just the beginning. I am so blessed. Lastly, to the love of my life Wendell. I will never forget the gentle presence you’ve been every minute of this journey. You came to Columbus without any reservations and fiercely encouraged me to achieve my dreams. You are my biggest inspiration and my best friend. I am so excited for this beautiful life ahead of us. viii Vita September 25, 1988…………………………..……………….Born—Champagne, IL 2007………..……………………………………….…..Glenbrook South High School 2013……………………………………………….…. B.S. Biology, Suffolk University 2013 to present……………………………………..…Graduate Research Associate Department of Microbiology The Ohio State University Fellowships 2013-2014…………………………………….The Ohio State University Fellowship The Ohio State University 2014-2015……..The Howard Hughes Medical Institute Med-into-Grad Fellowship The Ohio State University College of Medicine 2016-2018………………………………………………….The C. Glenn Barber Fund The Ohio State University College of Veterinary Medicine Awards 2016……………………………..The RNA Center Symposium poster award winner The Ohio State University 2016……The College of Veterinary Medicine Research Day poster award winner The Ohio State University 2017……………………..……The Department of Microbiology travel award winner The Ohio State University 2018…...The American Society of Microbiology Ohio Branch poster award winner ix Publications Antonucci JM, St Gelais C, de Silva S, Yount JS, Tang C, Ji X, Shepard C, Xiong Y, Kim B, Wu L “SAMHD1-mediated HIV-1 restriction in cells does not involve ribonuclease activity.” Nature Medicine 2016.
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