CD8+ T-Cell Responses in Hepatitis B and C: The (HLA-) A, B, and C of Hepatitis B and C

Abstract

Approximately 500 million people are chronically infected with the hepatitis B virus (HBV) or hepatitis C virus (HCV) worldwide and are thus at high risk of progressive liver disease, leading to liver fibrosis, cirrhosis and ultimately hepatocellular cancer. Virus-specific CD8+ T-cells play a major role in viral clearance in >90% of adult patients who clear HBV and in approximately 30% of patients who clear HCV in acute infection. However, several mechanisms contribute to the failure of the adaptive CD8+ T-cell response in those patients who progress to chronic infection. These include viral mutations leading to escape from the CD8+ T-cell response as well as exhaustion and dysfunction of virus-specific CD8+ T-cells. Antiviral efficacy of the virus-specific CD8+ T-cell response also strongly depends on its restriction by specific human leukocyte antigens (HLA) class I alleles. Our review will summarize the role of HLA-A, B and C-restricted CD8+ T-cells in HBV and HCV infection. Due to the current lack of a comprehensive database of HBV- and HCV-specific CD8+ T-cell epitopes, we also provide a summary of the repertoire of currently well-described HBV- and HCV-specific CD8+ T-cell epitopes. A better understanding of the factors that contribute to the success or failure of virus-specific CD8+ T-cells may help to develop new therapeutic options for HBV eradication in patients with chronic HBV infection (therapeutic vaccination and/or immunomodulation) as well as a prophylactic vaccine against HCV infection.

Differential virus‐specific CD8+ T‐cell epitope repertoire in hepatitis C virus genotype 1 versus 4

“…For HCV genotype 1, it has been demonstrated that certain HLA class I types such as B*15, B*27 and B*57 are associated with viral clearance, implying that epitopes restricted by these HLA class I types may be superior vaccine targets. We demonstrated previously that the protective role of HLA‐B*27 is due to an immunodominant HLA‐B*27‐restricted CD8 + T‐cell epitope; however, protection was limited to HCV genotype 1 due to the variation of the epitope in other HCV genotypes . To date, only relatively small studies analysed the role of HLA class I types in HCV genotype 4 infection and did not show a clear association between a specific HLA class I type and infection outcome .…”

“…Upon antibody‐mediated deletion of CD8 + T cells in chimpanzees, HCV viremia persists until CD8 + T‐cell counts recover and HCV‐specific CD8 + T cells become detectable . In addition, the association of specific HLA class I alleles and spontaneous HCV clearance further supports the dominant role of HCV‐specific CD8 + T cells in viral clearance . Thus, virus‐specific CD8 + T cells are an important target for prophylactic vaccination strategies.…”

Influence of HLA‐B18 on liver fibrosis progression in a cohort of HIV/HCV coinfected individuals

“…The highly variable set of genes inside human genome produces different HLA haplotypes, each of them able to present a variety of antigens, allowing the immune cells to mount an effective response against the pathogen. A less efficient host response hampers the viral clearance, thus resulting in an incessant liver inflammation that leads to hepatic fibrosis over time . Some studies suggest that this mechanism can interfere with the achievement of a sustained virological response in course of treatment, at least with the interferon‐based therapies …”

Overcoming CD8+ T-Cell Exhaustion in Viral Hepatitis: Lessons from the Mouse Model and Clinical Perspectives

“…One reason for CD8+ T-cell failure is the emergence of viral sequence mutations that can lead to loss of recognition by antiviral CD8+ T cells. In HBV infection, such viral escape seems to play a minor role [9][10][11][12] . In contrast, viral escape can be observed in about half the number of HCV-infected patients [9,13,14] .…”

“…In HBV infection, such viral escape seems to play a minor role [9][10][11][12] . In contrast, viral escape can be observed in about half the number of HCV-infected patients [9,13,14] . A further key determinant for the failure of virus-specific CD8+ T-cell responses is a phenomenon called T-cell exhaustion in which chronic antigen stimulation of virus-specific CD8+ T cells leads to a gradual loss of antiviral effector functions [15][16][17][18][19][20] .…”