Impaired Effector Function of Hepatitis C Virus-Specific CD8+ T Cells in Chronic Hepatitis C Virus Infection

Abstract

The cellular immune response contributes to clearance of hepatitis C virus (HCV) and persists for decades after recovery from infection. The immunological basis for the inefficiency of the cellular immune response in chronically infected persons is not known. Here, we used four HLA-A2 tetramers, specific for two HCV core and two HCV NS3 epitopes, to investigate at the single-cell level effector function and phenotype of HCV-specific CD8+ T cells in 20 chronically infected and 12 long-term recovered patients. Overall, HCV-specific, tetramer+ T cells were more frequently found in PBMCs of chronically infected patients than in those of recovered patients. However, when compared with HCV-tetramer+ T cells of recovered patients, they displayed an impaired proliferative capacity. As a result of the impaired proliferative capacity, HCV-specific T cell lines derived from chronically infected patients displayed less peptide-specific cytotoxicity than those from recovered patients. In addition, proliferation and ex vivo IFN-γ production of HCV-tetramer+ cells, but not influenza-virus-specific T cells, were defective in chronically infected patients and could not be restored by in vitro stimulation with peptide and IL-2. At least three distinct phenotypes of HCV-specific CD8+ T cells were identified and associated with certain functional characteristics. In addition, impairment of proliferative, cytokine, and cytotoxic effector functions of tetramer+ T cells in viremic patients was associated with weak ex vivo HCV-specific CD4+ T cell responses. Thus, the defective functions of HCV-specific CD8+ T cells might contribute to viral persistence in chronically infected patients, and knowledge on their reversibility may facilitate the development of immunotherapeutic vaccines.

Subversion of effector CD8+ T cell differentiation in acute hepatitis C virus infection: exploring the immunological mechanisms

“…On the other hand, under conditions of chronic infection, it is possible that memory CTL ultimately undergo exhaustion or deletion [47]. Altogether these data suggest that central memory HCV-specific CCR7 + /CD8 + T cells are potentially functional in patients with acute HCV infection, accounting for the high generation of semi-effector CCR7 -cells shown in patients in the ex vivo analyses.…”

Increased natural cytotoxicity receptor expression and relevant IL‐10 production in NK cells from chronically infected viremic HCV patients

“…Chronic persistent HCV replication was recently shown to be the result of a focused, monospecific CD8 + CTL antiviral immune response with failure to generate or sustain a detectable virus-specific CD4 + T cell response [9]. This has been advocated as one of the potential mechanisms that could prevent the generation of new variant-specific CD8 + CTL responses upon the emergence of escape virus variants in the context of acute HCV replication.…”

“…Spontaneous resolution of HCV infection has been linked to vigorous and multi-specific T cell responses, while attenuated CD4 + and CD8 + T cell responses have been observed during the chronic phase of viral persistence [3][4][5][6]. Failure to control HCV replication has also been associated with functional defects of virus-specific CD8 + cytotoxic T lymphocytes (CTL) [7][8][9][10] and, most recently, to the appearance of viral escape mutations in immunodominant CD8 + CTL epitopes associated with a lack of or relative defects in HCV-specific CD4 + T cell responses [11][12][13]. Adaptive immune defects during HCV infection are not limited to HCV-specific immune responses and may reflect the broader effects of HCV on the editing of T cell responses also on other antigen specificities [14].…”

Enhancement of CD4 and CD8 immunity by anti-CD137 (4-1BB) monoclonal antibodies during hepatitis C vaccination with recombinant adenovirus

“…In fact, the frequency of CTL precursors against HCV proteins found in patients with chronic hepatitis C is very low, in comparison to that found in HIV or CMV infections [46][47][48]. It has been described that HCV can infect DC and that expression of HCV proteins inside DC induces an impairment of its stimulatory functions [20] and this impairment might lead an inefficient priming of anti-HCV T cell responses [19,29,49]. Thus, there is a need for the development of strategies able to induce potent immune responses against HCV proteins that could be effective in the treatment and prevention of HCV infection.…”