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Maize Seeds As a Production and Delivery Platform for HIV Microbicides Maite Sabalza Gallues

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Maize Seeds As a Production and Delivery Platform for HIV Microbicides Maite Sabalza Gallues Nom/Logotip de la Universitat on s’ha llegit la tesi Maize seeds as a production and delivery platform for HIV microbicides Maite Sabalza Gallues Dipòsit Legal: L.1327-2013 http://hdl.handle.net/10803/127189 ADVERTIMENT. L'accés als continguts d'aquesta tesi doctoral i la seva utilització ha de respectar els drets de la persona autora. Pot ser utilitzada per a consulta o estudi personal, així com en activitats o materials d'investigació i docència en els termes establerts a l'art. 32 del Text Refós de la Llei de Propietat Intel·lectual (RDL 1/1996). Per altres utilitzacions es requereix l'autorització prèvia i expressa de la persona autora. En qualsevol cas, en la utilització dels seus continguts caldrà indicar de forma clara el nom i cognoms de la persona autora i el títol de la tesi doctoral. 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MAIZE SEEDS AS A PRODUCTION AND DELIVERY PLATFORM FOR HIV MICROBICIDES Maite Sabalza Gallues Doctoral dissertation January 2013 School of Agricultural and Forestry Engineering Department of Plant Production and Forest Science University of Lleida MAIZE SEEDS AS A PRODUCTION AND DELIVERY PLATFORM FOR HIV MICROBICIDES by Maite Sabalza Gallues School of Agricultural and Forestry Engineering Department of Plant Production and Forest Science University of Lleida Spain Applied Plant Biotechnology Doctoral dissertation January 2013 Supervisor: Prof. Paul Christou Departement de Producció Vegetal i Ciència Forestal Escola Técnica i Superior d‘Enginyeria Agrària University of Lleida Signature Date Co-supervisor: Prof. Teresa Capell Departement de Producció Vegetal i Ciència Forestal Escola Técnica i Superior d‘Enginyeria Agrària University of Lleida Signature Date DEDICATION To my parents, without their support and efforts this work would not have been possible TABLE OF CONTENTS Page # SUMMARY (ENGLISH) ....................................................................................... I RESUM (CATALÁN) ............................................................................................. III RESUMEN (CASTELLANO) ................................................................................ V ACKNOWELDGEMENTS ................................................................................... VII INDEX OF FIGURES ............................................................................................ IX INDEX OF TABLES ............................................................................................... XIII ABBREVATIONS ................................................................................................... XIV CHAPTER 1: GENERAL INTRODUCTION 1.1 HIV infection statistics ..................................................................................... 3 1.2 Current HIV therapies ...................................................................................... 4 1.3 New preventive strategies: microbicides .......................................................... 6 1.3.1 Types of microbicides and their mechanisms of action ........................ 9 1.3.2 Current microbicide candidates ............................................................. 10 1.4 Molecular pharming ......................................................................................... 16 1.5 Plant expression systems for the production of pharmaceutical proteins ......... 18 1.6 Molecular pharming in maize seeds ................................................................. 19 1.7 References ......................................................................................................... 22 CHAPTER 2: AIMS AND OBJECTIVES .................................................................. 35 CHAPTER 3: FUNCTIONAL CHARACTERIZATION OF THE RECOMBINANT HIV- NEUTRALIZING MONOCLONAL ANTIBODY 2F5 PRODUCED IN MAIZE SEEDS 3.1 Abstract ............................................................................................................. 39 3.2 Introduction ...................................................................................................... 40 3.3 Aim ................................................................................................................... 44 3.4 Materials and methods ...................................................................................... 44 3.4.1 Transformation vectors ........................................................................... 44 3.4.2 Transient expression of mAb 2F5 in N. benthamiana leaves ................. 48 3.4.3 Stable expression of mAb 2F5 in transgenic maize seeds ...................... 48 3.4.4 DNA blot analysis .................................................................................. 48 3.4.5 Enzyme-linked immunosorbent assay (ELISA) ..................................... 49 3.4.6 Western blot analysis .............................................................................. 50 3.5 Results .............................................................................................................. 50 TABLE OF CONTENTS Page # 3.5.1 Functional 2F5 antibody transiently expressed in N. benthamiana leaves ................................................................................... 50 3.5.2 Integration of input genes in transgenic maize plants ............................ 53 3.5.3 Immunoglobulin-specific ELISA and native western blot demonstrate that 2F5 is correctly assembled in maize endosperm ..................... 54 3.5.4 2F5 expression in maize endosperm ....................................................... 58 3.6 Discussion ......................................................................................................... 59 3.7 Conclusions ...................................................................................................... 63 3.8 References ........................................................................................................ 65 CHAPTER 4: NEXT GENERATION COMBINATION MICROBICIDES TO COMBAT HIV THROUGH MULTI-GENE ENGINEERING 4.1 Abstract ............................................................................................................. 75 4.2 Introduction ...................................................................................................... 76 4.2.1 Antiviral lectins ..................................................................................... 77 4.2.1.1 Cyanovirin-N ................................................................................... 80 4.2.1.2 Griffithsin ........................................................................................ 83 4.2.2 Human monoclonal HIV-neutralizing antibody 4E10 ........................... 86 4.2.3 Combination microbicide candidate containing CV-N, GRFT and 4E10 ................................................................... 88 4.3 Aim ................................................................................................................... 90 4.4 Materials and methods ...................................................................................... 90 4.4.1 Transformation vectors .......................................................................... 90 4.4.2 Transient expression of CV-N and GRFT individually, together, and combined with 4E10, in N. benthamiana leaves ......................... 93 4.4.3 Transformation, selection and regeneration of putative transgenic plants ......................................................... 94 4.4.4 Enzyme-linked immunosorbent assay (ELISA) ...................................
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