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Evaluation of T-Cell and B-Cell Epitopes and Design of Multivalent Vaccines Against Htlv-1 Diseases

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Evaluation of T-Cell and B-Cell Epitopes and Design of Multivalent Vaccines Against Htlv-1 Diseases EVALUATION OF T-CELL AND B-CELL EPITOPES AND DESIGN OF MULTIVALENT VACCINES AGAINST HTLV-1 DISEASES DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Roshni Sundaram, M.S. * * * * * The Ohio State University 2003 Dissertation Committee: Approved by Professor Pravin T.P. Kaumaya, Adviser Professor Christopher M. Walker Adviser Professor Neil R. Baker Department of Microbiology Professor Marshall V. Williams ABSTRACT Human T-cell lymphotropic virus type I (HTLV-1) is a C type retrovirus that is the causative agent of an aggressive T-cell malignancy, adult T-cell leukemia/lymphoma (ATLL). The virus is also implicated in a number of inflammatory disorders, the most prominent among them being HTLV-1 associated myelopathy or tropical spastic paraparesis (HAM/TSP). HTLV-1, like many viruses that cause chronic infection, has adapted to persist in the face of an active immune response in infected individuals. The viral transactivator Tax is the primary target of the cellular immune response and humoral responses are mainly directed against the envelope protein. Vaccination against HTLV-1 is a feasible option as there is very little genetic and antigenic variability. Vaccination regimes against chronic viruses must be aimed at augmenting the immune response to a level that is sufficient to clear the virus. This requires that the vaccine delivers a potent stimulus to the immune system that closely resembles natural infection to activate both the humoral arm and the cellular arm. It is also clear that multicomponent vaccines may be more beneficial in terms of increasing the breadth of the immune response as well as being applicable in an outbred population. As a step in this direction, this dissertation work first describes the identification and evaluation of human T-cell and B-cell epitope based vaccines that are capable of inducing robust immune responses. A novel strategy was designed for delivery of multiple Tax protein derived CTL epitopes into the same antigen presenting cell for the simultaneous ii priming of anigen specific T-cells. This design allowed antigen processing by cellular proteasomes to efficiently liberate the individual minimal epitopes endogenously for presentation via MHC Class I. This type of construct was effective in vivo in HLA-A*0201 transgenic mice in inducing cellular immune responses against all individual epitopes. A statistically significant reduction in viral replication was observed in mice that were immunized with a multiepitope Tax CTL construct and challenged with recombinant Tax vaccinia virus, by the induction of antiviral IFN-γ and cytolysis of infected target cells. This reduction was determined to be the result of immune responses specifically targeting the Tax protein and was dependent on the presence of CD8+ T-cells. Studies were also undertaken to engineer peptides that have a high propensity to fold into native protein like structure for the induction of antibodies that have a high affinity for the complex transient secondary structure adopted by the native protein. A single matrix multicomponent template strategy was applied to design a peptide from the central region of the TM (residues 347-374) that forms a parallel trimeric hairpin structure. Mutational studies have implicated this region to be critical for the fusion process after receptor binding. The template design served to constrain the individual peptide strands at one end and bring them in close proximity to promote hydrophobic interactions to initiate a coiled coil formation. Key mutations in the native peptide sequence were also made to increase hydrophobic interactions. We observed that the mutations combined with the template design resulted in a peptide that had a high helical content in aqueous medium and antibodies raised against the peptide recognized native viral protein with higher affinity compared with the wild type template peptide antibodies. These results suggested the presence of native sequence like conformation. Furthermore, a chimeric peptide incorporating a “promiscuous” T-helper iii epitope derived from the region of chain reversal in the TM subunit (residues 392-415 of gp21) implicated in the fusion process was tested for its ability to induce neutralizing antibodies. This peptide induced high titered antibodies that were capable of inhibiting HTLV-1 infected cell induced syncytia formation. These data, taken together may have implications in the development of multivalent vaccines against HTLV-1. iv Dedicated to my father v ACKNOWLEDGMENTS I express my deepest gratitude to my mentor Dr. Pravin Kaumaya for his patience and support. His enthusiasm and encouragement in pursuing a multitude of novel ideas was the key to the success of this project. I would like to express my sincere thanks to Dr. Christopher Walker for his assistance in overcoming many technical difficulties and for all the useful suggestions and insightful discussions to improve on my results. I extend my appreciation to my committee members Dr. Neil Baker and Dr. Marshall Williams for their time and effort. I also thank Dr. Francois Lemonnier for providing us with the transgenic animal model and cell lines, Dr. Steven Jacobson for reagents necessary to carry out this project and Dr. Don Young for all the statistical analysis. I thank Dr. Valerie Bergdall, Carrie Kraly and the vivarium staff for training me in animal handling and assistance in the maintenance of large breeding colonies. Further thanks are also due to Dr. Sharad Rawale for synthesis of peptides and circular dichroism experiments. Finally, I am indebted to my parents and my family for their unconditional love, support and encouragement. I am also eternally grateful to my husband who helped and stood by me through all the challenging times over the years. vi VITA 1992-1995……………………………………………….B.S. Microbiology University of Bombay, India 1995-1997……………………………………………….M.S. Microbiology University of Bombay, India 1997-2003………………………………………………Graduate Teaching and Research Associate, The Ohio State University ` PUBLICATIONS Sundaram, R., Sun, Y., Walker, C.M., Lemonnier, F.A., Jacobson, S., and Kaumaya, P.T.P (2003) A Novel Multivalent Human CTL Peptide Construct Elicits Robust Cellular Immune Responses in HLA-A*0201 Transgenic Mice: Implications for HTLV-1 Vaccine Design. Vaccine 21(21-22), 2767-2781 Sundaram, R., Dakappagari, N., and Kaumaya P.T.P. (2002). Synthetic Peptides as Cancer Vaccines. Peptide Science. Biopolymers 66(3), 200-16. Sundaram, R., and Kaumaya P.T.P. (2001). Multivalent Vaccine Studies for HTLV-1 Associated Diseases. In Peptides: The Wave of the Future. (Lebl, M., and Houghten, R.A., Eds) Kluwer Academic Publishers, The Netherlands 1006-1007. Sundaram, R., Walker, C.M., and Kaumaya P.T.P. (2001). Evaluation of HTLV-1 Cytotoxic T-Cell Epitopes in HLA-A*0201 Transgenic Mice. In Peptides: The Wave of the Future. (Lebl, M., and Houghten, R.A., Eds) Kluwer Academic Publishers, The Netherlands 1008- 1009. FIELDS OF STUDY Major Field: Microbiology vii TABLE OF CONTENTS Page Abstract .................................................................................................................................ii Dedication.............................................................................................................................v Acknowledgments..............................................................................................................vi Vita .......................................................................................................................................vii List of Tables.......................................................................................................................xi List of Figures ....................................................................................................................xii Chapters: 1. Introduction History and Epidemiology..........................................................................1 Genetic Organization of HTLV-1 ............................................................2 The Tax protein and its role in transformation...............5 Disease Association and Pathogenesis.....................................................6 Adult T-cell Leukemia/Lymphoma (ATLL) ..................8 HTLV-1 Associated Myelopathy .......................................8 Other diseases linked to HTLV-1 infection.....................9 Immune Responses....................................................................................10 Humoral response...............................................................10 The helper T-cell response ................................................11 The cytotoxic T-cell response...........................................11 Current Therapy .........................................................................................11 Vaccine Studies...........................................................................................13 Mapping humoral determinants .......................................15 Mapping T-cell determinants............................................18 viii Animal models and protection studies............................21 Peptide Vaccine Approach................................................25 2. Design and Characterization of a Multiepitope CTL Peptide Construct in HLA-A*0201 Transgenic β2M Db Double Knockout Mice Rationale ......................................................................................................28
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