Adaptive immune response during hepatitis C virus infection

Abstract

Hepatitis C virus (HCV) infection affects about 170 million people worldwide and it is a major cause of liver cirrhosis and hepatocellular carcinoma. HCV is a hepatotropic non-cytopathic virus able to persist in a great percentage of infected hosts due to its ability to escape from the immune control. Liver damage and disease progression during HCV infection are driven by both viral and host factors. Specifically, adaptive immune response carries out an essential task in controlling non-cytopathic viruses because of its ability to recognize infected cells and to destroy them by cytopathic mechanisms and to eliminate the virus by non-cytolytic machinery. HCV is able to impair this response by several means such as developing escape mutations in neutralizing antibodies and in T cell receptor viral epitope recognition sites and inducing HCV-specific cytotoxic T cell anergy and deletion. To impair HCV-specific T cell reactivity, HCV affects effector T cell regulation by modulating T helper and Treg response and by impairing the balance between positive and negative co-stimulatory molecules and between pro- and anti-apoptotic proteins. In this review, the role of adaptive immune response in controlling HCV infection and the HCV mechanisms to evade this response are reviewed.

Keywords: Adaptive immune response; Anergy; Apoptosis; Chemotaxis; Hepatitis C; Hepatitis C virus escape mutations; Hepatitis C virus-specific T helper cells; Hepatitis C virus-specific cytotoxic T cells; T regs.

Figure 1

Hepatitis C virus-specific immune response activation. Graph showing the priming of naïve T cells by professional antigen-presenting cells in the lymph nodes after antigen up-take in the liver. After specific-T cell activation, these cells become effector T helper (Th) and cytotoxic T cells (CTL) and they migrate into the liver. Th2 response regulates B cells while Th1 response controls CTLs effector function. Specifc-CTLs are able to destroy hepatitis C virus (HCV) by cytolytic and non-cytolytic mechanisms.

Figure 2

Cytolytic and non-cytolytic mechanisms to eliminate hepatitis C virus by specific cytotoxic T cells. Scheme showing the hepatitis C virus (HCV) viral load and alanine-amminotransferase (ALT) dynamics after acute HCV infection in relation to appearance of HCV-specific cytotoxic T cells and gamma-interferon secretion. Once HCV-specific cytotoxic T cells are detectable an ALT peak is observed, while when gamma interferon is secreted HCV titers decreased and ALT value becomes normal. CTL: Cytotoxic T lymphocyte.

Figure 3

Scheme showing the hepatitis C virus strategies to escape from hepatitis C virus-specific cytotoxic T cells control. Hepatitis C virus (HCV) modulates the balance between positive and negative co-stimulatory molecules, between pro- and anti-apoptotic molecules, and between Th and Treg cells and develops escape mutations at TCR recognition site. PD-1: Programmed cell death protein 1; CTLA-4: Cytotoxic T-lymphocyte antigen 4; BTLA: B- and T-lymphocyte attenuator; Tim-3: T-cell immunoglobulin domain and mucin domain 3; ICOS: Inducible T-cell Costimulator; GITR: Glucocorticoid induced tumor necrosis factor receptor family related gene; Bim: Bcl-2-interacting mediator; Mcl-1: Myeloid leukemia cell differentiation protein; (-) inhibition; (+) induction.

Figure 4

FACS^® dot-plots and histograms of hepatitis C virus-specific CD8⁺ cells from hepatitis C virus patients with different viral control. Hepatitis C virus (HCV)-specific CD8⁺ cells were stained with Abs anti γ-IFN, anti-PD-1, anti-CD127, anti-Mcl-1, anti-Bim, anti-CD8 plus pentameric HLA-A2/NS3₁₄₀₆ peptide complexes. PD1, γ-IFN and CD127 was analyzed directly ex vivo. Antigen specific proliferation was assessed after blocking or not apoptosis. After expansion Bim and Mcl-1 expression was analyzed. HCV-specific CTLs controlling HCV infection expressed a CD127^high, PD-1^low, Mcl-1^high and Bim^low phenotype while CTLs not controlling HCV displayed the opposite phenotype. MFI: mean fluorescence intensity, Pent: Pe-HLA-A2/NS3₁₄₀₆ pentameric complexes. PBMC: Peripheral blood mononuclear cells. PD-1: Programmed cell death protein 1; IFN: Interferon; Bim: Bcl-2-interacting mediator; Mcl-1: Myeloid leukemia cell differentiation protein.

Figure 5

Chemokine receptor expression of liver infiltrating CD8 T cells according to liver damage. Immunohistochemical CD8 staining of liver samples from patients with different degree of liver inflammation. CCR5 and CXCR3 expression on CD8 T cells from those samples was studied by FACS^® analysis after staining with the appropriate mAbs. A positive correlation between CCR5 and CXCR3 expression on intrahepatic total CD8⁺ T cells and liver inflammation was observed. LA: Lobular activity; PPA: Peri-portal activity according to Metavir Index.

Figure 6

Scheme showing the role of T cell intrahepatic recruitment according to the degree of liver damage and viral control. In resolved hepatitis C virus (HCV) infection an adequate effector T cell response is attracted to the liver to clear the virus. After that, a memory T cell population is continuously patrolling the liver to keep under control viral traces. Nevertheless, in persistent infection, after HCV-specific T cell failure to control infection, a non-specific inflammatory infiltrate is sequestered into the liver, responsible of the persistent liver damage. CTL: Cytotoxic T lymphocytes.