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Distribution Agreement in Presenting This Thesis Or Dissertation As A Distribution Agreement In presenting this thesis or dissertation as a partial fulfillment of the requirements for an advanced degree from Emory University, I hereby grant to Emory University and its agents the non-exclusive license to archive, make accessible, and display my thesis or dissertation in whole or in part in all forms of media, now or hereafter known, including display on the world wide web. I understand that I may select some access restrictions as part of the online submission of this thesis or dissertation. I retain all ownership rights to the copyright of the thesis or dissertation. I also retain the right to use in future works (such as articles or books) all or part of this thesis or dissertation. Signature: _____________________________ ______________ Lynette Siv Chea Date Novel Vaccines and Therapeutic Approaches Against HIV-1 By Lynette Siv Chea Doctor of Philosophy Graduate Division of Biological and Biomedical Science Immunology and Molecular Pathogenesis _________________________________________ Rama Rao Amara, Ph.D. Advisor _________________________________________ Lawrence Boise, Ph.D. Committee Member _________________________________________ Eric Hunter, Ph.D. Committee Member _________________________________________ Bernard Moss, M.D., Ph.D. Committee Member _________________________________________ Paul Spearman, M.D. Committee Member Accepted: _________________________________________ Lisa A. Tedesco, Ph.D. Dean of the James T. Laney School of Graduate Studies ___________________ Date Novel Vaccines and Therapeutic Approaches Against HIV-1 By Lynette Siv Chea B.S., University of California, Los Angeles, 2010 Advisor: Rama Rao Amara, Ph.D. An abstract of A dissertation submitted to the Faculty of the James T. Laney School of Graduate Studies of Emory University in partial fulfillment of the requirements for the degree of Doctor of Philosophy Graduate Division of Biological and Biomedical Science Immunology and Molecular Pathogenesis 2019 Abstract Novel Vaccines and Therapeutic Approaches Against HIV-1 By Lynette S. Chea Currently, approximately 37 million people are infected with Human Immunodeficiency Virus-1 (HIV) world-wide and there is a great need for developing both preventative and functional cure approaches to control the epidemic. Advancements toward a preventive vaccine and functional cure for HIV have made significant progress in the past decade. A successful vaccine aims to achieve antibody and T cell responses of high magnitude and durability to prevent infection. Thus, the development of vaccine delivery vectors to generate potent immune responses is critical. Modified vaccinia Ankara (MVA) has been used as a promising viral vaccine vector for inducing vaccine-specific humoral and cellular responses against multiple infectious diseases including HIV. A primary goal of this dissertation was to further enhance the immunogenicity of MVA by targeting the apoptotic pathway induced after MVA infection of cells. We provide evidence that delaying apoptosis during MVA vaccination improves antigen-specific humoral responses. We generated an MVA expressing an anti-apoptotic gene B13R, MVA-B13R, and showed that MVA-B13R infection markedly delays apoptosis of infected cells. We further demonstrate that MVA-B13R expressing Simian Immunodeficiency Virus (SIV) and HIV antigens develop greater vaccine-induced humoral responses with enhanced durability. Interestingly, MVA-B13R immunization resulted in a delayed interferon response. These findings report a novel MVA that can be used as a vaccine vector for enhancing humoral immunity against multiple infectious diseases. HIV cure research aims to allow individuals to control viremia in the absence of anti-retroviral therapy (ART). Dysfunctional anti-viral immunity and persistence of the latent HIV reservoir are the main barriers to HIV cure. This dissertation additionally aimed to investigate the ability of PD-1 checkpoint blockade therapy combined with ART to restore and improve anti-viral immunity and reduce the HIV viral reservoir. Our findings demonstrate that this regimen enhanced anti-viral CD8+ T cell functionality and destabilized the viral reservoir leading to improved control of viral rebound after ART interruption. This study provides evidence that PD-1 blockade co-administered with ART can effectively enhance immune functionality during chronic SIV infection and establishes the foundation for identifying optimal HIV cure therapies. Novel Vaccines and Therapeutic Approaches Against HIV-1 By Lynette Siv Chea B.S., University of California, Los Angeles, 2010 Advisor: Rama Rao Amara, Ph.D. A dissertation submitted to the Faculty of the James T. Laney School of Graduate Studies of Emory University in partial fulfillment of the requirements for the degree of Doctor of Philosophy Graduate Division of Biological and Biomedical Science Immunology and Molecular Pathogenesis 2019 ACKNOWLEDGEMENTS I would first like to thank my mentor, Rama Amara, for all the support and guidance he has imparted on me over the years as a graduate student in his lab. I am grateful for all the opportunities to learn not only skills in the lab but the skills that has made me a better scientist. You provided me a supportive environment to make mistakes, learn, and grow in the process. I leave your lab better prepared to think critically about scientific questions which I will take with me any where I go. I also would like to thank all current and past lab members of the Amara lab and the community of Yerkes as a whole for creating an atmosphere that has made me want to come to work every day. Everyone has made the last six and a half years an enjoyable experience filled with laughs, food, and random coffee breaks which I will always cherish. A special thanks to Dr. Sailaja Gangadhara for teaching me all she knows about virology and being a constant source of advice and help whenever I needed it. Additionally, a special thank you to Dr. Geetha Mylvaganam for allowing me to work with her and being an amazing friend and collaborator in the process. I would next like to acknowledge and thank all of the friends I have made throughout my years in Atlanta. These relationships I developed mainly through Emory are among the closest I have had in my life and they are too numerous to list here. Their support and love throughout this journey of graduate school cannot be understated. In each of their own ways, everyone has helped me to retain calm and focus when I needed it, work through frustrations, and supported me when I needed it the most. Through all the dinners, the road trips, and the festivals, it was all of my friends that has made the adventure of being at Emory and in Atlanta worthwhile. Finally, I would like to thank my family for their unwavering support of me throughout the years and in particularly during graduate school when I was away from home the longest. My parents Vinson and Aimee worked hard for me to be able to pursue my scholarly aspirations without burdens and I hope to have made them proud with my accomplishments over the years and in the future. My dad helped to develop my scientific curiosity by always wanting to better understand how things worked and how things can be fixed. I believe this helped mold me into the scientist and person I am today and for that I will always be grateful. I also want to thank my baby brother, sister-in-law, grandparents, baby cousins, aunts, and uncles who also may not have always understood what I was trying to do with a Ph.D. but were always there for me with encouraging words and love which I will never forget. Thank you all. TABLE OF CONTENTS CHAPTER I Introduction ……………………………………………………………………... 1 CHAPTER II Novel MVA Vector Expressing Anti-apoptotic Gene B13R Delays Apoptosis and Enhances Humoral Responses …………………………...……. 49 CHAPTER III Combination Anti-PD-1 and Anti-retroviral Therapy Provides Therapeutic Benefit Against SIV …………………………….………………………….…. 85 CHAPTER IV Discussion & Future Directions ………………………….……………………160 CHAPTER V Bibliography …………………………….………….…………………………177 FIGURE INDEX CHAPTER I Figure 1 Potential Target Genes of the MVA Genome to Improve Immunogenicity ……….…….……….…….……….………………… 46 Figure 2 Overview of Dissertation Aims ……….…….……….……………….. 47 Table 1 Clinical Trials Using MVA-based Vector as a Vaccine Candidate …... 48 CHAPTER II Figure 1 B13R expression by MVA during infection delays apoptosis of infected cells ………............................................................................................ 76 Figure 2 MVA-B13R delays cell death of infected cells compared to MVA ….. 78 Figure 3 Generation of recombinant MVAs expressing HIV Env 1086C and SIV Gag ……………………………………………………………………. 80 Figure 4 MVA-B13R/SHIV immunization enhances Env-specific humoral responses ……………………………………………………………… 82 Figure 5 MVA-B13R/SHIV induces less robust type I and II interferon responses than MVA/SHIV ……………………………………………………… 83 CHAPTER III Figure 1 PD-1 blockade administered prior to ART (phase I) results in improved T cell functionality in SIV-infected RMs ………………… 112 Figure 2 PD-1 blockade administered prior to ART results in improved viral suppression following ART initiation ………………………………. 114 Figure 3 PD-1 blockade during suppressive ART (phase II) results in T cell proliferation and potential destabilization of the viral reservoir ……. 116 Figure 4 PD-1 blockade during suppressive ART (phase II) stimulates anti- viral cellular response pathways …………………………………….. 117 Figure 5 Enhanced viral control in PD-1 Ab treated
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