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Resistance to Hepatitis C Virus: Potential Genetic and Immunological Determinants

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Resistance to Hepatitis C Virus: Potential Genetic and Immunological Determinants Resistance to hepatitis C virus: potential genetic and immunological determinants Michael Mokhlis Mina A thesis submitted in fulfilment of the requirement for the degree of Doctor of Philosophy The Kirby Institute The University of New South Wales September 2020 GRIS 23/2/21, 6:22 pm Thesis Title and Abstract Declarations Inclusion of Publications Corrected Thesis and Statement Responses Thesis Title Resistance to hepatitis C virus: potential genetic and immunological determinants Thesis Abstract Studies of highly exposed individuals who remain seronegative (HESN) for HIV infection led to the discovery that homozygosity for the d32 mutation in the CCR5 chemokine receptor gene abrogated viral entry into target cells, and was associated with resistance to infection. In addition, evidence for protective immunity has been found in some HESN groups, such as sex workers in the Gambia. Population studies of those at high risk for hepatitis C virus (HCV) infection suggest that a HESN phenotype exists. There is a growing body of evidence for protective immunity, which allows clearance of HCV without seroconversion, and proof-of- principle evidence from in vitro studies that genetic polymorphisms may confer resistance to establishment of infection. This doctoral research project explores evidence for protective immunity, including via genetically programmed variations in host responses and provides evidence that genetic mutations confer resistance against HCV. The data generally strengthens the notion that investigations of naturally occurring polymorphisms within the HCV interactome, and genetic association studies of well-characterised HESN individuals, may identify potential targets for vaccine design and inform novel therapies. https://gris.unsw.edu.au/examinations/thesub/view/92987/responses Page 1 of 1 GRIS 23/2/21, 6:23 pm Thesis Title and Abstract Declarations Inclusion of Publications Corrected Thesis and Statement Responses ORIGINALITY STATEMENT " I hereby declare that this submission is my own work and to the best of my knowledge it contains no materials previously published or written by another person, or substantial proportions of material which have been accepted for the award of any other degree or diploma at UNSW or any other educational institution, except where due acknowledgement is made in the thesis. Any contribution made to the research by others, with whom I have worked at UNSW or elsewhere, is explicitly acknowledged in the thesis. I also declare that the intellectual content of this thesis is the product of my own work, except to the extent that assistance from others in the project's design and conception or in style, presentation and linguistic expression is acknowledged. COPYRIGHT STATEMENT " I hereby grant the University of New South Wales or its agents a non-exclusive licence to archive and to make available (including to members of the public) my thesis or dissertation in whole or part in the University libraries in all forms of media, now or here after known. I acknowledge that I retain all intellectual property rights which subsist in my thesis or dissertation, such as copyright and patent rights, subject to applicable law. I also retain the right to use all or part of my thesis or dissertation in future works (such as articles or books). For any substantial portions of copyright material used in this thesis, written permission for use has been obtained, or the copyright material is removed from the final public version of the thesis. AUTHENTICITY STATEMENT " I certify that the Library deposit digital copy is a direct equivalent of the final officially approved version of my thesis. https://gris.unsw.edu.au/examinations/thesub/view/92987/responses#declarations_view Page 1 of 1 GRIS 23/2/21, 6:24 pm Thesis Title and Abstract Declarations Inclusion of Publications Corrected Thesis and Statement Responses UNSW is supportive of candidates publishing their research results during their candidature as detailed in the UNSW Thesis Examination Procedure. Publications can be used in your thesis in lieu of a Chapter provided: You contributed greater than 50% of the content in the publication and are the "primary author", i.e. you were responsible primarily for the planning, execution and preparation of the work for publication. You have approval to include the publication in their thesis in lieu of a Chapter from your Supervisor and Postgraduate Coordinator. The publication is not subject to any obligations or contractual agreements with a third party that would constrain its inclusion in the thesis. " My thesis has publications - either published or submitted for publication - incorporated into it in lieu of a Chapter/s. Details of these publications are provided below. Publication Details #1 Full Title: Resistance to hepatitis C virus: potential genetic and immunological determinants Authors: Michael M Mina, Fabio Luciani, Barbara Cameron, Rowena A Bull, Michael R Beard, David Booth, Andrew R Lloyd Journal or Book Name: Lancet Infectious Diseases Volume/Page Numbers: 2015;15: 451–60 Date Accepted/Published: Published Online February 19, 2015 Status: published The Candidate's Contribution to Review fully written by Michael Mina the Work: Location of the work in the thesis This paper is chapter 1 of the thesis. It sets the scene for the whole PhD. The paper and/or how the work is provides evidence that an HESN phenotype exists and it introduces the hypothesis of incorporated in the thesis: the PhD and illustrates that studies of individuals who were highly exposed but seronegative (HESN) for HIV infection led to the discovery that homozygosity for the Δ32 deletion mutation in the CCR5 gene prevents viral entry into target cells, and is associated with resistance to infection. Additionally, evidence for protective immunity has been noted in some HESN groups, such as sex workers in The Gambia. Population studies of individuals at high risk for hepatitis C virus infection suggest that an HESN phenotype exists. This Review discusses the possibility that genetic mutations confer resistance against hepatitis C virus, and also explores evidence for protective immunity, including via genetically programmed variations in host responses. Publication Details #2 Full Title: Natural killer cells in highly exposed hepatitis C-seronegative injecting drug users https://gris.unsw.edu.au/examinations/thesub/view/92987/responses#incl_of_pubs_stmt_view Page 1 of 3 GRIS 23/2/21, 6:24 pm Authors: M. M. Mina, B. Cameron, F. Luciani, U. Vollmer-Conna, A. R. Lloyd Journal or Book Name: Journal of Viral Hepatitis Volume/Page Numbers: 2016 Jun;23(6):464-72 Date Accepted/Published: Accepted for publication December 2015 Status: published The Candidate's Contribution to First author and performed experiments the Work: 80% contribution Location of the work in the thesis This is chapter 2 and follows on nicely from the literature review showing evidence that and/or how the work is there is protective immunity in the HESN phenotype. incorporated in the thesis: I describe a very robust algorithm to identify HESN and then use this cohort for immunity analysis. This is the first of 2 chapters that discuss immunity in the HESN phenotype. This chapter discusses innate immunity and chapter 3 provides evidence of adaptive immunity. Publication Details #3 Full Title: Anti-envelope antibody responses in highly exposed seronegative individuals may be associated with protection from HCV infection Authors: Michael Mina, Alexander Underwood, Auda Eltahla, Bing-Ru Wu, Melanie R. Walker, Rowena A. Bull, Andrew R. Lloyd Journal or Book Name: Journal of Viral Hepatitis Volume/Page Numbers: 2020;00:1–10 Date Accepted/Published: 11 May 2020 Status: published The Candidate's Contribution to First author and performed experiments the Work: Write manuscript, identification subjects, perform majority experimental work, data analysis, completing revisions Location of the work in the thesis This is chapter 3 in the thesis and is the second paper to discuss protective immunity. and/or how the work is Chapter 2 focuses on innate immunity whilst chapter 3 studies adaptive immunity. incorporated in the thesis: The chapter describes anti-HCV Envelope (E) antibody responses in the HESN Phenotype. The chapter also provides evidence of neutralization activity and HCV E–specific memory B cells. These findings suggest that HESN subjects may be resistant to HCV infection through humoral immune-mediated mechanisms which flows on nicely from chapters 1 and 2. Publication Details #4 Full Title: Polymorphisms in DOCK2 are associated with protection against hepatitis C infection Authors: Michael M. Mina, Hui Li, Auda Eltahla, Fabio Luciani, Louisa Degenhardt, William D. Rawlinson, Nick Martin, Elliot C. Nelson, David Booth, Andrew R. Lloyd Journal or Book Name: Journal of Infectious Diseases Volume/Page Numbers: Date Accepted/Published: Status: submitted The Candidate's Contribution to First author and performed experiments. >80% contribution. the Work: Location of the work in the thesis This is chapter 4 of the thesis and flows on from the concept introduced in chapter 1 and/or how the work is regarding genetic resistance in the HESN phenotype. incorporated in the thesis: The chapter provides evidence linking polymorphisms in the immunoregulatory https://gris.unsw.edu.au/examinations/thesub/view/92987/responses#incl_of_pubs_stmt_view Page 2 of 3 GRIS 23/2/21, 6:24 pm proteins encoded by DOCK-2 to resistance against HCV infection. CANDIDATE’S DECLARATION " I declare that I have complied
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