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

  • Author / Creator
    Samrat, Subodh Kr
  • 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.

  • Subjects / Keywords
  • Graduation date
    2013-11
  • Type of Item
    Thesis
  • Degree
    Doctor of Philosophy
  • DOI
    https://doi.org/10.7939/R3139M
  • License
    This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.
  • Language
    English
  • Institution
    University of Alberta
  • Degree level
    Doctoral
  • Department
    • Department of Surgery
  • Specialization
    • Experimental Surgery
  • Supervisor / co-supervisor and their department(s)
    • Agrawal, Babita (Department of Surgery)
  • Examining committee members and their departments
    • Burshtyn, Debby (Medical Microbiology and Immunology)
    • Agrawal, Babita (Department of Surgery)
    • Tyrrell, Lorne (Li ka Shing Institute of Virology and Medical Microbiology and Immunology)
    • Rayat, Gina (Department of Surgery
    • Walker, Christopher (The Research Institute at Nationwide Children's Hospital, Columbus , Ohio)