title: Immunization with Recombinant Adenoviral Vectors Expressing HCV Core or F Proteins Leads to T Cells with Reduced Effector Molecules Granzyme B and IFN-γ: A Potential New Strategy for Immune Evasion in HCV Infection.
abstract: Multispecific, broad, and potent T cell responses have been correlated with viral clearance in hepatitis C virus (HCV) infection. However, the majority of infected patients develop chronic infection, suggesting that natural infection mostly leads to development of inefficient T cell immunity. Multiple mechanisms of immune modulation and evasion have been shown in HCV infection through various investigations. This study examined the generation and modulation of T cell responses against core and frameshift (F) proteins of HCV. A single immunization of mice with replication incompetent recombinant adenovirus vectors encoding for F or core antigens induces poor T cell responses and leads to generation of CD4+ and CD8+ T cells with low granzyme B (GrB) expression. These T cells have impaired GrB enzyme activity and are unable to kill peptide loaded target cells. The low intracellular expression of GrB is not due to degranulation of cytotoxic granules containing cytotoxic T cells. Addition of exogenous IL-2 in in vitro cultures leads to partial recovery of GrB production, whereas immunization with the Toll-like receptor (TLR) agonist poly I:C leads to complete restoration of GrB expression in both CD4+ and CD8+ T cells. Thus, a possible new strategy of T cell modulation is recognized wherein effector T cells are caused to be dysfunctional by HCV-derived antigens F or core, and strategies are also delineated to overcome this dysfunction. These studies are important in the investigation of prophylactic vaccine and immunotherapy strategies for HCV infection.
authors.affiliation: 1 Department of Surgery, University of Alberta , Edmonton, Canada .
authors.forename: Subodh Kumar
authors.initials: SK
authors.lastname: Samrat
authors.affiliation: 1 Department of Surgery, University of Alberta , Edmonton, Canada .|2 Department of Laboratory Medicine and Pathology, Faculty of Medicine and Dentistry, University of Alberta , Edmonton, Canada .
authors.forename: Satish
authors.initials: S
authors.lastname: Vedi
authors.affiliation: 1 Department of Surgery, University of Alberta , Edmonton, Canada .
authors.forename: Shakti
authors.initials: S
authors.lastname: Singh
authors.affiliation: 1 Department of Surgery, University of Alberta , Edmonton, Canada .
authors.forename: Wen
authors.initials: W
authors.lastname: Li
authors.affiliation: 2 Department of Laboratory Medicine and Pathology, Faculty of Medicine and Dentistry, University of Alberta , Edmonton, Canada .
authors.forename: Rakesh
authors.initials: R
authors.lastname: Kumar
authors.affiliation: 1 Department of Surgery, University of Alberta , Edmonton, Canada .
authors.forename: Babita
authors.initials: B
authors.lastname: Agrawal
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D004337:Drug Carriers; D053804:Granzymes / Q000378:metabolism*; D057131:Immune Evasion; D007371:Interferon-gamma / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D013601:T-Lymphocytes / Q000276:immunology*; D014614:Vaccines, Synthetic / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D014758:Viral Core Proteins / Q000235:genetics / Q000276:immunology*; D014765:Viral Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*
chemical_list: D004337:Drug Carriers; D014614:Vaccines, Synthetic; D014758:Viral Core Proteins; D014765:Viral Vaccines; C433031:hepatitis C protein F, Hepatitis C virus; C069130:nucleocapsid protein, Hepatitis C virus; D007371:Interferon-gamma; D053804:Granzymes