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.

Polarization of granulocytic myeloid‐derived suppressor cells by hepatitis C core protein is mediated via IL‐10/STAT3 signalling

“…Furthermore, HCVc activates a signal transducer that is critical for the development of regulatory APCs . Because the induction of HCVc‐specific T‐cell responses is inversely correlated with the serum HCVc concentration, we hypothesized that the high concentration of circulating HCVc found during HCV infection may facilitate the development of MDSCs and be responsible for the attenuation of HCV‐specific T‐cell responses, leading to HCV persistence . Therefore, this study aimed to examine the possible involvement and mechanism of HCVc in MDSC expansion and T‐cell suppression in patients with CHC.…”

Hepatitis C virus alternative reading frame protein (ARFP): Production, features, and pathogenesis

“…Other cytokines are affected by F protein as well, F protein stimulates peripheral blood mononuclear cells (PBMCs) by modifying the Th2 cytokine profile in which interferon‐gamma (IFN‐γ) and IL‐2 are decreased and IL‐4 and IL‐5 are increased significantly 35 . High levels of IL‐10, IL‐2, and very low levels of IFN‐γ were also reported by a more recent study 36 . Also the presence of F protein actively suppresses the type I and III interferon induction through retinoic‐acid‐inducible gene‐I pathways.…”

“…35 High levels of IL-10, IL-2, and very low levels of IFN-γ were also reported by a more recent study. 36 Also the presence of F protein actively suppresses the type I and III interferon induction through retinoic-acid-inducible gene-I pathways. As a result, TNF-α, IFN-λ1, and IFN-λ2/3 which are stimulated by interferon would suppress as well.…”

“…In this regard, F and core antigens induce poor T cell responses and lead to the generation of CD8+ and CD4+ cells with low expression of granzyme B which makes them unable to kill infected cells. 36 Also, F protein can induce apoptosis in DCs by increasing the expression of CD-95 and CD-95L molecules involved in apoptosis. 37 Furthermore, F protein can contribute to a bias in Th1/Th2 responses and help hepatic cells become carcinogenic.…”

Heterologous Immunity between Adenoviruses and Hepatitis C Virus (HCV): Recombinant Adenovirus Vaccine Vectors Containing Antigens from Unrelated Pathogens Induce Cross-Reactive Immunity Against HCV Antigens

“…We have been studying recombinant adenovirus vectors (rAds) that express various HCV antigens as a way to understand the generation of protective immune responses against HCV antigens in both humans (ex vivo) and mice (in vivo) for vaccine purposes [23,24,25,26,27]. During these studies, we started to observe unusual cellular and humoral immunity against various HCV antigens even when we used replication-deficient, non-recombinant adenovirus vector (hu Ad5) not containing an HCV transgene, as controls for our recombinant Ads.…”