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Permanent link (DOI): https://doi.org/10.7939/R3139M

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MODULATION OF IMMUNE RESPONSE BY HCV-DERIVED F, CORE AND NS3 PROTEINS Open Access

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Other title
Subject/Keyword
HCV
Immunology
DCs modulation
Type of item
Thesis
Degree grantor
University of Alberta
Author or creator
Samrat, Subodh Kr
Supervisor and department
Agrawal, Babita (Department of Surgery)
Examining committee member and department
Tyrrell, Lorne (Li ka Shing Institute of Virology and Medical Microbiology and Immunology)
Agrawal, Babita (Department of Surgery)
Walker, Christopher (The Research Institute at Nationwide Children's Hospital, Columbus , Ohio)
Rayat, Gina (Department of Surgery
Burshtyn, Debby (Medical Microbiology and Immunology)
Department
Department of Surgery
Specialization
Experimental Surgery
Date accepted
2013-09-30T09:01:48Z
Graduation date
2013-11
Degree
Doctor of Philosophy
Degree level
Doctoral
Abstract
The hepatitis C virus leads to chronic infection in the majority of infected individuals; however, in a minority of patients, acute infection is followed by viral clearance. The immune correlates of viral clearance are not yet clear, but have been extensively investigated, suggesting the role of multispecific and multifunctional cellular immunity. In the current studies, we demonstrated that endogenous expression of the F protein in human DCs leads to contrasting effects on activation and apoptosis of DCs, allowing the activated DCs to efficiently internalize apoptotic DCs. These in turn result in the efficient ability of DCs to process and present antigen, and prime and stimulate antigen-specific T cells from HCV-naive individuals. Our in vivo studies show that mice immunized with F- or core-containing adenovector induce dysfunctional T cells with reduced granzyme B (GrB) expression which are unable to kill peptide-loaded target cells. Exogenous addition of IL-2 in in vitro cultures, as well as immunization with the toll-like receptor (TLR) agonist poly I:C restores the GrB expression in T cells. Thus, we have discovered a new mechanism of T cell modulation by HCV-derived antigens and we have also delineated strategies to overcome this dysfunction. Further, we have analyzed the early immune events in the mice immunized with recombinant adenovector containing core and NS3 in a time-course manner. Our results demonstrate that despite efficient expression of both antigens at the site of immunization, T cell proliferation and IL-2, IL-6 and IL-12 production were significantly higher in NS3-immunized mice at 12-48 hours after immunization compared to the core-immunized mice. These studies have implied that early events in antigen encounters imprint the subsequent immunity and the final outcome; two distinct patterns of early events in immunity can be demonstrated for the antigens core and NS3. Over all, my studies have discovered a new mechanism of immune modulation by HCV-derived antigens that could help in designing both prophylactic and therapeutic vaccine candidates against the HCV.
Language
English
DOI
doi:10.7939/R3139M
Rights
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. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of these terms. 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.
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