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Immune Responses against Hepatitis C Virus Open Access


Other title
Hepatitis C Virus
Adaptive Immunity
Heterologous Immunity
Immune Responses
Dose and route
Type of item
Degree grantor
University of Alberta
Author or creator
Singh, Shakti
Supervisor and department
Agrawal, Babita (Surgery)
Examining committee member and department
Rayat, Gina (Department of Surgery, University of Alberta)
Madrenas, Quim (Department of Microbiology and Immunology, Mcgill University)
Agrawal, Babita (Department of Surgery, University of Alberta)
Tyrell, Lorne (Department of Medical Microbiology and Immunology, University of Alberta)
Mason, Andrew (Department of Medicine, University of Alberta)
Department of Surgery
Experimental Surgery
Date accepted
Graduation date
Doctor of Philosophy
Degree level
Hepatitis C virus (HCV) leads to chronic infection in the majority of infected patients presumably due to failure or inefficiency of the immune responses generated. Both antibody and cellular immune responses have been suggested to be important in viral clearance. Non-replicative adenoviral vectors expressing antigens of interest are considered as attractive vaccine vectors for a number of pathogens. In this study, we sought to evaluate cellular and humoral immune responses against HCV NS4 protein using recombinant adenovirus as a vaccine vector expressing NS4 antigen. We have also measured the effect of antigen doses and routes of immunization on the quality and extent of the immune responses, especially their role in viral load reduction, in a recombinant Vaccinia-HCV (Vac-HCV) infection mouse model. Our results show that an optimum dose of adenovirus vector (2×107 pfu/mouse) administered intramuscularly (i.m.) induces high T cell proliferation, granzyme B-expressing CD8+ T cells, pro-inflammatory cytokines such as IFN-γ, TNF-α, IL-2 and IL-6, and antibody responses that can significantly reduce the Vac-HCV viral load in the ovaries of female C57BL/6 mice. Our results demonstrate that recombinant adenovirus vector can induce both humoral and cellular protective immunity against HCV-NS4 antigen, and that immunity is intricately controlled by route and dose of immunizing vector. Adenoviruses (Ad) are commonly used as vectors for gene therapy and/or vaccine delivery. Recombinant Ad vectors are being tested as vaccines for many pathogens. Here, we have made a surprising observation that peptides derived from various hepatitis C virus (HCV) antigens contain extensive regions of homology with multiple adenovirus proteins, and conclusively demonstrate that adenovirus vector can induce robust, heterologous cellular and humoral immune responses against multiple HCV antigens. Intriguingly, the induction of this cross-reactive immunity leads to significant reduction of viral loads in a recombinant vaccinia-HCV virus infected mouse model, supporting their role in antiviral immunity against HCV. Healthy human subjects with Ad-specific pre-existing immunity demonstrated cross-reactive cellular and humoral immune responses against multiple HCV antigens. These findings reveal the potential of a previously uncharacterized property of natural human adenovirus infection to dictate, modulate and/or alter the course of HCV infection upon exposure. This intrinsic property of adenovirus vectors to cross-prime HCV immunity can also be exploited to develop a prophylactic and/or therapeutic vaccine against HCV.
Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. The author reserves all other publication and other rights in association with the copyright in the thesis and, except as herein before provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.
Citation for previous publication
Singh S, Vedi S, Li W, Samrat SK, Kumar R, Agrawal B. Recombinant Adenoviral Vector expressing HCV NS4 Induce Protective Immune Responses in A Mouse Model of Vaccinia-HCV Virus Infection: A Dose and Route Conundrum. Vaccine. ePub 2014 March 11. PMID: 24631092.Singh S, Vedi S, Samrat SK, Li W, Kumar R and Agrawal B. Heterologous Immunity between Adenoviruses and Hepatitis C Virus: A New Paradigm in HCV Immunity and Vaccines. Plos One (Under review).

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