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Research.Pdf (4.530Mb) RESTRICTION OF HIV BY TIM-FAMILY PROTEINS AND ANTAGONISM BY NEF _______________________________________ A Dissertation presented to the Faculty of the Graduate School at the University of Missouri-Columbia _______________________________________________________ In Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy _____________________________________________________ by Minghua Li Dr. Shan-Lu Liu, Dissertation Supervisor JULY 2016 The undersigned, appointed by the dean of the Graduate School, have examined the dissertation entitled RESTRICTION OF HIV BY TIM-FAMILY PROTEINS AND ANTAGONISM BY NEF presented by Minghua Li, a candidate for the degree of Doctor of Philosophy, and hereby certify that, in their opinion, it is worthy of acceptance. Dr. Shan-Lu Liu Dr. Donald Burke Dr. Marc Johnson Dr. David Pintel Dr. Guoquan Zhang ACKNOWLEDGEMENTS First and foremost, I would like to express my sincere gratitude to my mentor Dr. Shan-Lu Liu, who accepted me to join his team as the first Ph.D. student at Mizzou. I am very grateful for his continuous support and guidance throughout my five years of Ph.D. study. As a mentor, he has taught me not only how to design the experiments and analyze the data but also how to become a successful scientist and enjoy science. I appreciate all his contributions of time, ideas, and funding that have led to my Ph.D. experience enjoyable and productive. I will never forget the weekends he spent with me in the lab to discuss my research projects or revise manuscripts. I am also thankful for the excellent example he has set as a successful professor, with motivation, enthusiasm, patience, and broad knowledge. I believe that the Ph.D. experience in his laboratory will become a lifetime memory. I would like to thank my thesis committee members, Drs. Donald Burke, Marc Johnson, David Pintel, and Guoquan Zhang, for their time and valuable input during my committee meetings and Virology Works in Progress (VWIP) meetings. Their comments and suggestions have promoted me to think my research projects thoroughly and sometimes from different angels. Also, their insightful comments in my comprehensive examination have been extremely helpful for my proposal writing. I would like to thank all the past and present members of Dr. Liu lab. My sincere thanks firstly goes to Yi-Min Zheng for teaching me cell culture and making a wonderful lab environment for research. I would also like to thank Kun Li, who taught me cell-cell fusion assay and flow cytometry. I thank Chunhui Miao, Jingyou Yu and Fushun Zhang ii for their assistance for my projects in the lab and their friendship. I thank Daniel Steitz, John Bryan, Justin Ehehardt, Lane Adams, Michael Wolski, Kristina Freund, Jacob Bly, and Mikko Viudez for their help in plasmids preparation and lab jobs. I would like to thank Dr. Wendy Maury at University of Iowa for providing the TIM-1 construct and soluble proteins to initiate this project; Dr. Eric Freed and Sherimay Ablan at National Cancer Institute for sharing reagents as well as assistance in TEM analysis. Last but not the least, I would like to thank my family for their love. I thank my wife Huili Jia for her continuous support to the family and my career development. I thank my two cute children, Michael and Katherine for the wonderful time and happiness they bring to us. I also thank my parents and my mother-in-law for their time to take care of my kids as well as housework. The love and encouragement from the family will be my spiritual support forever. iii TABLE OF CONTENTS ACKNOWLEDGEMENTS ............................................................................................. ii LIST OF FIGURES AND TABLES ............................................................................... vi LIST OF ABBREVIATIONS ....................................................................................... viii ABSTRACT .................................................................................................................... xiv CHAPTER 1–INTRODUCTION .....................................................................................1 1.1 Discovery, Origins and Evolution of HIV .................................................................1 1.1.1 Discovery of HIV .................................................................................................1 1.1.2 HIV Infections Worldwide ..................................................................................2 1.1.3 Origins and Evolution ..........................................................................................5 1.2 HIV Replication .........................................................................................................7 1.2.1 Taxonomic Classification ....................................................................................7 1.2.2 Genomic Structure ...............................................................................................9 1.2.3 Overview of HIV Replication ............................................................................14 1.2.4 Receptor Binding and Viral Entry .....................................................................15 1.2.5 Reverse Transcription ........................................................................................18 1.2.6 Integration ..........................................................................................................22 1.2.7 Viral DNA Transcription and Regulation ..........................................................25 1.2.8 Assembly, Release and Maturation....................................................................29 1.3 HIV Transmission and Pathogenesis .......................................................................35 1.3.1 Transmission Routes ..........................................................................................35 1.3.2 Acute Infection...................................................................................................35 1.3.3 Latency ...............................................................................................................39 1.4 HIV Treatment and Prevention ................................................................................40 1.4.1 Antiviral Drugs ..................................................................................................40 1.4.2 Broadly Neutralizing Antibodies .......................................................................44 1.4.3 Vaccine Trials ....................................................................................................45 1.5 Innate Immunity to HIV-1 Infection and Viral Countermeasures ...........................47 1.5.1 Immune Sensing to HIV-1 Infection..................................................................47 1.5.2 Restriction Factors .............................................................................................52 1.5.3 Accessory Proteins and Their Antagonistic Strategies ......................................59 1.6 T-cell Immunoglobulin and Mucin Domain (TIM) Family Proteins .......................62 iv 1.6.1 Structures and Expression Patterns ....................................................................62 1.6.2 Functions in Innate Immune Regulation ............................................................66 1.6.3 Role of TIMs in Viral Infection .........................................................................68 1.6.4 Functions in HIV/AIDS .....................................................................................70 CHAPTER 2–TIM-FAMILY PROTEINS INHIBIT HIV-1 RELEASE ...................73 2.1 Abstract ....................................................................................................................74 2.2 Introduction ..............................................................................................................74 2.3 Materials and Methods .............................................................................................76 2.4 Results ......................................................................................................................80 2.5 Discussion ................................................................................................................88 CHAPTER 3–LENTIVIRAL NEF PROTEINS ANTAGONIZE TIM-MEDIATED INHIBITION OF VIRAL RELEASE ..........................................................................108 3.1 Abstract ..................................................................................................................109 3.2 Introduction ............................................................................................................109 3.3 Materials and Methods ...........................................................................................111 3.4 Results ....................................................................................................................116 3.5 Discussion ..............................................................................................................124 CHAPTER 4–OVERALL SUMMARY, DISCUSSION, AND FUTURE DIRECTIONS ................................................................................................................137 LIST OF PUBLICATIONS ..........................................................................................142 REFERENCES ...............................................................................................................143 VITA................................................................................................................................169
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