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Studies on the Assembly and Morphology of Human T STUDIES ON THE ASSEMBLY AND MORPHOLOGY OF HUMAN T-CELL LEUKEMIA VIRUS TYPE 1 A DISSERTATION SUBMITTED TO THE FACULTY OF THE GRADUATE SCHOOL OF THE UNIVERSITY OF MINNESOTA José Orlando Maldonado-Ortiz IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY Advisor: Louis M. Mansky, PhD August 2018 © José Maldonado, 2018 ACKNOWLEDGEMENTS I would like to thank: My wife, Lorie, whom since high school has been on my side, supporting every decision I have made, motivating me to continue regardless on the lengthiness of my studies, and for helping me stay sane during my graduate studies. My family, whom have supported and motivated me during my 25+ years as a student; they are always there to assist me whenever I need them. My friends, which in one-way or the other have provided support and friendship. My advisor, Dr. Louis Mansky, for always being supportive and providing me with knowledge, freedom, and the necessary equipment to complete my projects. I am also thankful to Lou for encouraging me to extend my graduate studies for another year, which was essential for me to better train as an independent investigator. My PhD dissertation committee members Drs. Paul Jardine, Peter Southern, and Wei Zhang, for their continued support, insightful discussions, and scientific and career advice. All members of the Mansky laboratory for their continued support and scientific discussions. My partial funding from the Institute for Molecular Virology Training Program (T32 AI083196) and my ongoing individual fellowship from the National Institute of Dental and Craniofacial Research (F30 DE22286). i DEDICATION I dedicate this thesis to my family and my wife, Lorie, for their constant support and unconditional love ii ABSTRACT The group-specific antigen (Gag) polyprotein is an essential retrovirus structural protein required for the assembly and release of virus particles. Present knowledge of Gag biology has been limited to a few retroviruses. Furthermore, current understanding of the diversity in the nature of Gag structure and function in virus particle assembly is limited. Human T-cell leukemia virus type 1 (HTLV-1) is a deltaretrovirus that causes an adult T-cell leukemia/lymphoma (ATLL), HTLV-1-associated-myelopathy/tropical spastic paraparesis (HAM/TSP), and other neurotropic conditions. HTLV-1 has infected approximately 15 million individuals worldwide. A general knowledge gap exists regarding the details of HTLV-1 replication, including particle assembly. To address this, and to test the overarching hypothesis that HTLV-1 particle assembly is distinct from that of other retroviruses, this dissertation focused on investigating three key aspects of HTLV-1 immature and mature particle morphology. First, an analysis of the morphology and Gag stoichiometry of HTLV-1-like particles and authentic, mature HTLV-1 particles by using cryogenic transmission electron microscopy (cryo-TEM) and scanning transmission electron microscopy (STEM) was conducted. HTLV-1-like particles mimicked the morphology of immature authentic HTLV-1 virions. Importantly, it was observed for the first time that the morphology of these virus-like particles (VLPs) has the unique local feature of a flat Gag lattice that does not follow the curvature of the viral membrane, resulting in an enlarged distance between the Gag lattice and the viral membrane. Measurement of the average size and mass of VLPs and authentic HTLV-1 particles suggested a consistent range of size and Gag copy numbers in these two groups of particles. The unique local flat Gag iii lattice morphological feature observed suggests that HTLV-1 Gag could be arranged in a lattice structure that is distinct from that of other retroviruses characterized to date. Second, the effects of Gag proteins labeled at the carboxy terminus with a fluorophore protein were analyzed for their influence on particle morphology. In particular, a HTLV-1 Gag expression construct with the yellow fluorescence protein (YFP) fused to the carboxy-terminus was used as a surrogate for the HTLV-1 Gag-Pro to assess the effects of co-packaging of Gag and a Gag-YFP on virus-like particle morphology and particles were analyzed by cryo-TEM. STEM and fluorescence fluctuation spectroscopy (FFS) were also used to determine the Gag stoichiometry. Ratios of 3:1 (Gag:Gag-YFP) or greater were found to result in a particle morphology indistinguishable from that of VLPs produced with the untagged HTLV-1 Gag, i.e., a mean diameter of ~113 nm and a mass of 220 MDa as determined by cryo-TEM and STEM, respectively. This information is useful for the quantitative analysis of Gag-Gag interactions that occur during virus particle assembly and in released immature particles. Third, cryo-electron tomography (cryo-ET) was used to analyze mature HTLV-1 particle morphology. Particles produced from MT-2 cells were polymorphic, roughly spherical, and varied in size. Capsid cores, when present, were typically poorly defined polyhedral structures with at least one curved region contacting the inner face of the viral membrane. Most of the particles observed lacked a defined capsid core, which likely impacts HTLV-1 particle infectivity. Taken together, the findings of this dissertation provide new insights into the nature of immature and mature HTLV-1 assembly and morphology and provide foundational knowledge towards an advanced understanding of the HTLV particle assembly pathway. iv TABLE OF CONTENTS PAGE List of tables ix List of figures x List of publications xii CHAPTER I: GENERAL INTRODUCTION 1 History and identification of human T-cell leukemia virus type 1 2 HTLV-1 clinical association 2 HTLV-1 head and neck clinical association 4 HTLV-1 genome organization 5 HTLV-1 infectious replication cycle 6 Attachment and fusion 6 Reverse transcription, nuclear transport and integration 7 Viral gene transcription 8 Post-transcriptional regulation 8 Viral protein translation 9 Gag trafficking 9 Gag and viral RNA trafficking 10 Budding and maturation 10 Gag-membrane interactions 11 Identification of Gag assembly sites along the inner leaflet of the plasma membrane 12 v Determinants of Gag-Gag interactions 13 Gag oligomerization 14 HTLV-1 transmission 15 Inter-host transmission 15 Cell-to-cell transmission 16 Virological synapses 17 Viral biofilms 18 Monoclonal expansion of HTLV-1 infected cells & leukemogenesis 18 Dissertation objectives 19 Figures 22 CHAPTER II: DISTINCT MORPHOLOGY OF HUMAN T-CELL LEUKEMIA VIRUS TYPE 1-LIKE PARTICLES 27 Introduction 28 Material and methods 30 Transfection and HTLV-1-like particle production 30 Gradient purification of authentic virus particles and VLPs 31 Cryo-TEM of HTLV-1-like particles and authentic virus particles 32 Determination of particle size 32 Determination of particle mass by STEM 33 Results 34 Analysis of the morphology of HTLV-1-like particles 34 Morphology of authentic HTLV-1 mature particles produced from MT-2 cells 35 STEM analyses of HTLV-1-like particles and authentic mature HTLV-1 vi Particles 36 Calculation of Gag stoichiometry in HTLV-1-like particles 37 Estimating Gag stoichiometry in authentic immature HTLV-1 particles by calculating Gag copy number in authentic mature HTLV-1 particles 38 Discussion 39 Figures 42 CHAPTER III: PERTURBATION OF HUMAN T-CELL LEUKEMIA VIRUS TYPE 1 PARTICLE MORPHOLOGY BY DIFFERENTIAL GAG CO-PACKAGING 48 Introduction 49 Materials and methods 52 Production and purification of HTLV-1-like particles 52 Cryo-TEM analysis of HTLV-1-like particles 53 Measurement of virus-like particle size 53 Fluorescence fluctuation spectroscopy, experimental setup and data analysis 54 Scanning transmission electron microscopy mass measurements of virus-like particles 56 Protein and RNA content of HTLV-1 virus-like particles 57 Results 58 Morphology of HTLV-1-like particles 58 Gag stoichiometry of HTLV-1-like particles determined by FFS 59 VLP diameter as determined by FFS 60 STEM analysis of HTLV-1-like particle mass 61 STEM determination of Gag stoichiometry in HTLV-1-like particles 62 Discussion 63 vii Conclusions 65 Figures 67 CHAPTER IV: ANALYSIS OF HUMAN T-CELL LEUKEMIA VIRUS TYPE 1 PARTICLES USING CRYO-ELECTRON TOMOGRAPHY 78 Text 79 Figures 88 CHAPTER V: DISSERTATION SUMMARY AND FINAL DISCUSSION 92 BIBLIOGRAPHY 101 APPENDIX I: DECLARATION OF CONTRIBUTIONS TO CO- AUTHORED PUBLICATIONS: DISTINCT PARTICLE MORPHOLOGIES REVEALED THROUGH COMPARATIVE PARALLEL ANALYSES OF RETROVIRUS-LIKE PARTICLES 129 APPENDIX II: DECLARATION OF CONTRIBUTIONS TO CO-AUTHORED PUBLICATIONS: DUAL ANTI-HIV MECHANISM OF CLOFARABINE 149 APPENDIX III: DECLARATION OF CONTRIBUTIONS TO CO- AUTHORED PUBLICATIONS: THE HIV-1 REVERSE TRANSCRIPTASE A62V MUTATION INFLUENCES REPLICATION FIDELITY AND VIRAL FITNESS IN THE CONTEXT OF MULTI-DRUG RESISTANCE MUTATIONS 168 APPENDIX IV: COPYRIGHT PERMISSIONS 183 viii LIST OF TABLES CHAPTER II PAGE Table 2-1 Summary of the mass determinations and the calculated Gag copy number per particle in human T-cell leukemia virus type 1(HTLV-1)- like particles and authentic HTLV-1 particles 47 CHAPTER III Table 3-1 Summary of HTLV-1-like particle mass determination and calculation of Gag copy number per particle 76 CHAPTER V Table 5-1 Summary of authentic HTLV-1 particle, HTLV-1-like particle, and HTLV-1-like particle expressing Gag/Gag-YFP at a 3 to 1 ratio particle size, mass determination and calculation of Gag copy number per particle 100 ix LIST OF FIGURES CHAPTER I PAGE Figure 1-1 HTLV-1 genome organization 22 Figure 1-2 HTLV-1 life cycle 23 Figure 1-3 Gag and retrovirus particle
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