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Evaluation of CD8+ T Cell Responses Towards Conserved HIV-1 Epitopes

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Evaluation of CD8+ T Cell Responses Towards Conserved HIV-1 Epitopes Evaluation of CD8+ T cell responses towards conserved HIV-1 epitopes in naturally infected and vaccinated individuals Ambreen Ashraf Section of Immunology Division of Infectious Diseases Department of Medicine Imperial College London This Thesis was submitted to Imperial College for the Degree of Doctor of Philosophy January 2017 Declaration of Originality I hereby declare that all the work illustrated in this thesis signifies my novel work and was performed in the laboratories of International AIDS Vaccine Initiative, Department of Immunology, Imperial College of Science, Technology and Medicine, London and has not been submitted to any other institution. Furthermore, I have used no other source of information except those which are notified by citations. Ms Ambreen Ashraf 2 Copyright Declaration The copyright of this thesis rests with the author and is made available under a Creative Commons Attribution Non-Commercial No Derivatives licence. Researchers are free to copy, distribute or transmit the thesis on the condition that they attribute it, that they do not use it for commercial purposes and that they do not alter, transform or build upon it. For any reuse or redistributions, researchers must make clear to others the licence terms of this work. 3 Abstract of thesis Human Immunodeficiency Virus (HIV) infection is a global public health priority. An effective HIV- 1 vaccine strategy must overcome the enormous genetic diversity generated by the virus while inducing potent, long lasting immune responses. In this thesis, virus-specific cellular immune responses directed towards HIV conserved regions were evaluated using a validated IFN-γ enzyme- linked immunospot (ELISpot) assay and two sets of peptide panels based upon HIV-1 vaccine candidates. One panel was based on the 14 of the most highly conserved (HIVconsv – 806 amino acids) regions of the HIV-1 proteome and was designed to provide extensive coverage of subtypes A, B, C and D. The second panel represents Gag, Reverse Transcriptase (RT), Integrase (INT), Nef and Envelope sequences derived from a consensus subtype A reference (GRIN/Env). The purpose of this study was to examine the extent of T cell responses to HIV-1 epitopes elicited at different stages of HIV-1 infection and in vaccinees. Individuals infected with HIV-1 subtypes (A, B, C and D) from the UK, Rwanda, Uganda, and Zambia representing a wide range of genetic backgrounds were tested using a HIVconsv peptide matrix and GRIN pools. CD8 responses were identified across Gag, RT and INT and there was no apparent subtype specific bias in terms of recognition of both peptide panels (HIVconsv and GRIN/Env). GRIN appeared to be more antigenic because GRIN incorporated both conserved and variable epitopes compared to HIVconsv panel that only comprised conserved peptide sequences. Furthermore, there was no association between IFN-γ T cell responses and control of viraemia in early infection between viraemic controllers (VC) and viraemic progressors (VP). However, VC appeared to be slightly more polyfunctional than VP. Viral inhibition assay (VIA) employed to assess the vaccine specific responses demonstrated that conserved regions of the HIV-1 proteome could result in an increased ability to inhibit a panel of HIV-1 isolates in vitro. Although detection of a CD8+ T cell response against a particular epitope does not necessarily translate to protection, the conserved nature of HIV-1 epitopes suggests that these domains are immunogenic and might be important for viral function. Thus, these data support the inclusion of conserved sequences in any future vaccine candidate. 4 Acknowledgements First of all, I would like to express my sincere gratitude to all my Ph.D supervisors Dr Jakub Kopycinski Dr Peter Hayes and Professor Frances Gotch for their continuous guidance, support and understanding. Their continuous motivation, encouragement and wealth of knowledge helped me throughout my research years and especially with the writing of my thesis. I could not have accomplished my goals if I did not have mentor and advisor like Dr Jakub Kopycinski. Special thanks to Professor Frances Gotch for her constant support and encouragement during impossible times. My sincere thanks to Dr Jill Gilmour for supporting this project. Many thanks to the whole team of IAVI for their help and support. I would like to say thanks to my fellow colleagues; Francesco Lala, Vanaja Kakarla, Natalia Frenandez and Cynthia Bishop for providing a great and entertaining working atmosphere in the lab. Thanks to Dr Tony Tarragona for all his help, support and time. Very special thanks to Anil Gunesh and Justyna Czyzewska-Khan for their support and time. They always helped me when I needed. Besides this, I would like to express my thanks to my very close and dear friends; Monica Belich, Nabeela Helling, Raunaque Hasnat, Michael Korzinski, Manish Sinha, Aggeliki Spentzou for listening and advising to me when I was in despair. My humble and the most gracious thanks to Simon Beddows for his friendship, help, support, criticism, encouragement, advice and mentorship in all aspects of my life. I could never be where I am in my life without his guidance. I would like to say thanks to all my uncle, aunts who have supported me during very difficult times of my life and also to my brothers. I truly wish my late parents could be here today to see me achieving my goals. In the end, I would like to dedicate my thesis to my late parents Mr M.Ashraf Khan and Mrs Javed Naz Khan and to my precious son Rafaan. This research was completely supported by IAVI. 5 Table of Contents Declaration of Originality ................................................................................................. 2 Copyright Declaration ....................................................................................................... 3 Abstract of thesis ............................................................................................................... 4 Acknowledgements ........................................................................................................... 5 Table of Contents .............................................................................................................. 6 List of Figures ................................................................................................................. 11 List of Tables .................................................................................................................. 13 List of Abbreviation ........................................................................................................ 15 Publication arising from this Thesis................................................................................ 18 Chapter 1: Introduction ................................................................................................. 19 1.1 Discovery of Human Immunodeficiency Virus .............................................. 19 1.2 HIV.................................................................................................................. 19 1.3 Epidemiology .................................................................................................. 19 1.4 HIV testing and diagnosis ............................................................................... 20 1.5 HIV-1 diversity and subtypes ......................................................................... 21 1.6 HIV-1 genome and replication cycle .............................................................. 22 1.7 Immunopathogenesis of HIV-1 infection ....................................................... 23 1.8 Immune response to HIV-1 ............................................................................. 27 1.8.1 Innate Immunity .................................................................................................................. 27 1.8.2 Adaptive Immunity ............................................................................................................. 29 1.9 HIV-1 Vaccine development and strategies .................................................... 39 1.9.1 Use of viruses as vaccine vectors ........................................................................................ 44 1.10 Specific Aims and hypothesis ......................................................................... 46 Chapter 2: Materials and Methods ................................................................................ 47 6 2.1 Study Cohorts .................................................................................................. 47 2.1.1 UK HIV infected cohort ...................................................................................................... 47 2.1.2 African Cohort .................................................................................................................... 47 2.1.3 HIV Negative Cohort .......................................................................................................... 47 2.1.4 B001 (IAVI Sponsored Clinical Trial) Vaccinees .............................................................. 48 2.2 Plasma Viral Load (pVL) and Lymphocyte Count ......................................... 48 2.2.1 UK Cohort .......................................................................................................................... 48 2.2.2 African Cohort .................................................................................................................... 48 2.3 Media for cell culture .....................................................................................
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