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Prediction of Host-Virus Interaction Networks

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Prediction of Host-Virus Interaction Networks Prediction of host-virus interaction networks Janet M. Doolittle A dissertation submitted to the faculty of the University of North Carolina at Chapel Hill in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Curriculum of Bioinformatics and Computational Biology. Chapel Hill 2012 Approved by: Tim Elston, PhD Shawn Gomez, Eng.Sc.D. Klaus Hahn, PhD Keith Burridge, PhD Anne Taylor, PhD Jennifer Webster-Cyriaque, PhD ©2012 Janet M. Doolittle ALL RIGHTS RESERVED ii ABSTRACT JANET DOOLITTLE: Prediction of host-virus interaction networks (Under the direction of Shawn Gomez) As with other viral pathogens, HIV-1 and dengue virus (DENV) are dependent on their hosts for the bulk of the functions necessary for viral survival and replication. Thus, successful infection depends on the pathogen's ability to manipulate the biological pathways and processes of the organism it infects, while avoiding elimination by the immune system. Protein-protein interactions are one avenue through which viruses can connect with and exploit these host cellular pathways and processes. We developed a computational approach to predict interactions between HIV and human proteins based on structural similarity of 9 HIV-1 proteins to human proteins having known interactions. Using functional data from RNAi studies as a filter, we generated over 2,000 interaction predictions between HIV proteins and 406 unique human proteins. Additional filtering based on Gene Ontology cellular component annotation reduced the number of predictions to 502 interactions involving 137 human proteins. We find numerous known interactions as well as novel interactions showing significant functional relevance based on supporting Gene Ontology and literature evidence. We then applied this approach to predict interactions between (DENV) and both of its hosts, Homo sapiens and the insect vector Aedes aegypti. We predict over 4,000 interactions between DENV and humans, as well as 176 interactions between DENV and iii A. aegypti. Additional filtering based on shared Gene Ontology cellular component annotation reduced the number of predictions to approximately 2,000 for humans and 18 for A. aegypti. Of 19 experimentally validated interactions between DENV and humans extracted from the literature, this method was able to predict nearly half. Our results suggest specific interactions between virus and host proteins relevant to interferon signaling, transcriptional regulation, stress, and the unfolded protein response. Viruses manipulate cellular processes to their advantage through specific interactions with the host's protein interaction network. The interaction networks presented here provide a set of hypothesis for further experimental investigation into viral life cycles and potential therapeutic targets. iv ACKNOWLEDGMENTS I am very grateful to the many people who have made this dissertation possible. First, I would like to sincerely thank my co-advisors Shawn Gomez and Klaus Hahn, who have supported me in countless ways over the years. They have given me advice, encouragement, scientific opportunities, financial support, and taught me how to think about science. I am also indebted to Keith Burridge, Erica Wittchen, and Tim Elston for their support and advice on various projects. Thank you to the members of my committee for your guidance and suggestions. I would also like to thank all the members of the Gomez and Hahn labs. From the Hahn lab, I would especially like to recognize Evan Trudeau, Marie Rougie, Jason Yi, and Ellen O’Shaughnessy for training me in “wet bench” biology and helping me with collaborative projects. From the Gomez lab, special thanks to Jen Staab, Matt Berginski, and Kyla Lutz for their friendship and suggestions on my work. I am grateful to the administrative staff of the Pharmacology, Biomedical Engineering, and Genetics departments, who have helped me in many different ways, especially Sausyty Hermreck. I acknowledge the Bioinformatics and Computational Biology training program at UNC for financial support during 2009-2010. I am grateful to all my friends that have not been mentioned yet, especially Alicia Midland, for their moral support. Thanks to Richard Hall for his constant support and love and many good times together. I would also like to thank Vinny and Celia for giving me companionship and entertainment during the past couple years and for “helping” me v write. Last but not least, I would like to thank my parents, Frank and Deb, and brother, John. My family has always given me unconditional love and support, and they made me who I am today. I dedicate this dissertation to them. vi PREFACE Parts of this dissertation have been previously published in Open Access journals: Doolittle, J. M., & Gomez, S. M. (2010). Structural similarity-based predictions of protein interactions between HIV-1 and Homo sapiens. Virology Journal, 7, 82. Doi:10.1186/1743-422X-7-82 Doolittle, J. M., & Gomez, S. M. (2011). Mapping protein interactions between Dengue virus and its human and insect hosts. PloS Neglected Tropical Diseases, 5(2), e954. Doi:10.1371/journal.pntd.0000954 vii TABLE OF CONTENTS LIST OF TABLES ............................................................................................................. xi LIST OF FIGURES .......................................................................................................... xii LIST OF ABBREVIATIONS .......................................................................................... xiii CHAPTER I: INTRODUCTION .........................................................................................1 Importance of Host-Virus Interactions ....................................................................1 Experimental Host-Virus Interactomes ....................................................................2 Previous Methods to Predict Host-Pathogen Interactions .......................................4 CHAPTER II: STRUCTURAL SIMILARITY-BASED PREDICTIONS OF PROTEIN INTERACTIONS BETWEEN HIV-1 AND HOMO SAPIENS ....................................................................................................7 Introduction ..............................................................................................................7 Results and Discussion ............................................................................................9 Conclusions ............................................................................................................20 Methods..................................................................................................................22 Figures and Legends ..............................................................................................29 CHAPTER III: MAPPING PROTEIN INTERACTIONS BETWEEN DENGUE VIRUS AND ITS HUMAN AND INSECT HOSTS ...........................39 Introduction ............................................................................................................39 Results and Discussion ..........................................................................................42 viii Conclusions ............................................................................................................63 Methods..................................................................................................................64 Figures and Legends ..............................................................................................69 CHAPTER IV: CONCLUSION ........................................................................................82 Summary of Findings .............................................................................................82 Challenges ..............................................................................................................82 Continuing Progress in the Field............................................................................85 Future Directions ...................................................................................................88 Concluding Remarks ..............................................................................................89 APPENDICES ...................................................................................................................91 APPENDIX 1: Twenty-five selected structural similarities between HIV-1 and human proteins from the Dali Database .........................91 APPENDIX 2: Twenty-five selected interaction predictions between HIV-1 and human .............................................................................92 APPENDIX 3: Full prediction network .................................................................93 APPENDIX 4: Twenty-five selected interactions after the CC filter ....................94 APPENDIX 5: HIV-1 protein identifiers ...............................................................95 APPENDIX 6: Twenty-five selected interaction predictions between DENV2 and human ..........................................................................97 APPENDIX 7: Twenty-five selected interaction predictions between DENV2 and A. aegypti .....................................................................98 APPENDIX 8: Twenty-five selected interaction predictions between DENV2 and human after the CC Filter ............................................99 APPENDIX 9: Twenty-five selected interaction predictions between DENV2 and A. aegypti after the CC Filter .....................................100 APPENDIX 10: Twenty-five selected interaction
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