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(Hiv-1) Capsid STRUCTURAL BASIS OF STABILITY OF HUMAN IMMUNODEFICIENCY VIRUS TYPE 1 (HIV-1) CAPSID A Dissertation Presented to The Faculty of the Graduate School At the University of Missouri In Partial Fulfillment Of the Requirements for the Degree Doctor of Philosophy By Anna Gres Dr. John J. Tanner, Dissertation Supervisor Dr. Stefan G. Sarafianos, Dissertation Supervisor DECEMBER 2017 The undersigned, appointed by the dean of the Graduate School, have examined the dissertation entitled STRUCTURAL BASIS OF STABILITY OF HUMAN IMMUNODEFICIENCY VIRUS TYPE 1 (HIV-1) CAPSID Presented by Anna Gres A candidate for the degree of Doctor of Philosophy And hereby certify that, in their opinion, it is worthy of acceptance. Professor John J. Tanner Professor Stefan G. Sarafianos Professor Lesa J. Beamer Professor Kent S. Gates To my parents Tadevush and Natallia Hres ACKNOWLEDGEMENTS First, I would like to express my sincere gratitude to my mentor Dr. Sarafianos who was a great advisor and taught me how to think critically, communicate science more efficiently, and collaborate with others. He is a great example for me, and I will be more than happy to continue learning from him if I have the opportunity. I also want to thank my other mentor Dr. John J. Tanner for his honest opinion, critical comments, and professional insights. I am very grateful to committee members, Dr. Lesa J. Beamer and Dr. Kent S. Gates for their time, constructive criticism and valuable input during my committee meetings and Structural Biology Group meetings. Special thanks to our collaborators Dr. Eric Freed, Dr. Emico Urano and Dr. Mariia Novikova from NIH; Dr. Veneet KewalRamani and Dr. Guangai Xue from NIH; Dr. Donald Burke-Agüero and Dr. Margaret Lange from MMI Department of the University of Missouri; Dr. Arthur Olson, Dr. Stefano Forli and Dr. Pierrik Craveur from the Scripps Research Institute; Dr. Christopher Aiken and Jiong Shi from Department of Pathology, Immunology & Microbiology of the Vanderbilt University; Dr. Kalus Schulten, Dr. Juan Perilla and Chaoyi Xu from Department of Physics & Beckman Institute of the University of Illinois at Urbana-Champaign; Dr. Peijun Zhang and Xiaofeng Fu from Department of Structural Biology of the University of Pittsburgh. These collaborations have been vital for the progress of my research. This research was supported in part by the National Institutes of Health (AI112417, AI120860, and GM103368 to SGS). I thank Jay Nix of ALS beamline 4.2.2 for assistance with data collection. The Advanced Light Source is supported by the Director, Office of Science, Office of Basic Energy Sciences, of the U.S. Department of Energy under ii Contract No. DE-AC02-05CH11231. I am also grateful to Ruslan Sanishvili and all the staff of APS Sector 23 (GM/CA-CAT) for helpful discussions regarding data collection, processing, refinement, and validation strategies. This research used resources of the Advanced Photon Source (APS), a U.S. Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under Contract No. DE-AC02-06CH11357. Throughout the years, I had the chance to work with many people in the lab. Of all the people, I want to thank first Dr. Karen Kirby who is an excellent teacher and person. Karen taught me various crystallographic techniques and procedures; her help was immense especially during the beginning of my graduate studies in HIV-1 capsid-related research. Karen’s patience is an incredible example for me. I also thank her for her generous help in organizing the lab functions in the best way possible. I was also fortunate to work with Dr. Elefterios Michailidis who helped me to get started with my project. I was lucky to share the office space with Dr. Zhe Li, who has been a great companion and immense support with crystallography-related projects. I am very grateful to Dr. Dandan Liu, Tom Laughlin and Emily Conrod for their great help with cloning of various HIV-1 capsid mutants. I am extremely thankful to Grace Yang and students Rohit Rao, Emily Conrod, Catie Vornholt, Victoria Grill for their great help with expression and purification of HIV-1 capsid mutants. I also want to thank all the former and current graduate students, Dr. Yee Tsuey Ong, Dr. Tanya Ndongwe, Andrew Huber, Jennifer Wolf, Mary Casey, Maritza Puray Chavez, Obi Ukah, Jackie Flores, Maria Mpoftsi, Seongmi Kim, Vincent Yapo and Mahmoud Farghali, as well as research faculty Dr. Philip Tedbury, Dr. Kamal Singh, Juan iii Ji and Rama Koppisetti for working together, exchanging ideas and reagents, and for the great lab environment. I want to thank my advisor Dr. Natalia Loginova, colleagues and friends from Belarus, Dr. Tatsiana Kavalchuk, Dr. Maryna Savko, Dr. Volha Vaitkevich, and Maryna Lipay, for their full support and kind words of advice. I also thank all the friends I have in the United States, who helped me during all these years to feel like home, and especially my international group of friends Dariya Tsyrenzhapova, Nana Naskidashvili, Iuliia Alieva, Salome Chitorelidze, Zivile Raskauskaite, Katalin Toth, Sera Chiuchiarelli, Fernanda Plucani Amaral, Kateryna Schroeder, Fridah Mubichi, Eleni Galata, Elizavet Levogianni, Yulia Innokentieva, Tatiana Pronina, Marina Materikina, Darima Butitova, Armen Kazarian, Andrick Payen, Veniamin Katykhov, Selim Sukhtaiev, Alex Magnier, David Copeland, and many more. I want to say many thanks to Jerry Brightwell from Chemistry department and to administrative personnel at LSC for their support and help. I dedicated my dissertation thesis to my parents Tadevush and Natallia Hres. My father, Tadevush, passed away shortly before I had to move to the United States. However, he had always been very proud of me and my achievements. My mother, Natallia, has been so far away in Belarus but still, she is so close to every step in my life. Her immense support is beyond words in happy and arduous times. I am also grateful to all other members (aunts, uncles, cousins, nephews, and nieces) of our big family for their continuous support and love. iv TABLE OF CONTENTS Acknowledgements ............................................................................................................. ii Table of contents ................................................................................................................. v List of figures ...................................................................................................................... x List of tables ..................................................................................................................... xiii List of abbreviations ......................................................................................................... xv List of publications .......................................................................................................... xix List of presentations .......................................................................................................... xx Footnotes ......................................................................................................................... xxii Abstract ........................................................................................................................... xxv Chapter 1. General introduction of HIV ............................................................................. 1 1.1. HIV/AIDS ................................................................................................................ 1 1.2. HIV genus and species ............................................................................................. 4 1.3. HIV-1 genome organization .................................................................................... 7 1.4. HIV-1 virion............................................................................................................. 9 1.5. Life cycle and replication....................................................................................... 12 1.6. HIV transmission and pathogenesis ....................................................................... 15 1.6.1. HIV tropism .................................................................................................... 15 1.6.2. HIV transmission ............................................................................................ 15 1.6.3. HIV infection .................................................................................................. 16 1.7. HIV treatment and prevention ............................................................................... 17 1.7.1. Antiretroviral therapy ...................................................................................... 17 1.7.2. Vaccines .......................................................................................................... 20 1.7.3. Latency, reservoirs, and potential cure ........................................................... 23 v 1.8. HIV-1 CA as a drug target ..................................................................................... 27 1.8.1. HIV-1 CA structure ......................................................................................... 27 1.8.2. HIV-1 CA-targeting antivirals ........................................................................ 32 1.9. Cellular factors interacting with HIV-1 CA........................................................... 44 1.9.1. CypA ..............................................................................................................
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