Hepatitis C virus-specific cytotoxic T cell response restoration after treatment-induced hepatitis C virus control

Abstract

Hepatitis C virus (HCV)-specific cytotoxic T cell (CTL) response plays a major role in viral control during spontaneous infection resolution. These cells develop an exhausted and pro-apoptotic status during chronic onset, being unable to get rid of HCV. The role of this response in contributing to sustained viral response (SVR) after anti-HCV is controversial. Recent studies show that after successful interferon-based anti-HCV treatment, HCV traces are still detectable and this correlates with a peak of HCV-specific CTL response activation, probably responsible for maintaining SVR by subsequent complete HCV clearing. Moreover, SVR patients' serum is still able to induce HCV infection in naïve chimpanzees, suggesting that the infection could be under the control of the immune system after a successful treatment, being transmissible in absence of this adaptive response. At least theoretically, treatment-induced viral load decrease could allow an effective HCV-specific CTL response reestablishment. This effect has been recently described with anti-HCV interferon-free regimes, based on direct-acting antivirals. Nevertheless, this is to some extent controversial with interferon-based therapies, due to the detrimental immunoregulatory α-interferon effect on T cells. Moreover, HCV-specific CTL response features during anti-HCV treatment could be a predictive factor of SVR that could have clinical implications in patient management. In this review, the recent knowledge about the role of HCV-specific CTL response in the development of SVR after anti-HCV treatment is discussed.

Keywords: Apoptosis; Chronic hepatitis; Direct-acting antivirals; Exhaustion; Hepatitis C virus; Hepatitis C virus-specific cytotoxic T cell response; Interferon-alpha; Ribavirin; Treatment.

Figure 1

Hepatitis C virus-specific cytotoxic T lymphocyte effector abilities by either direct infected hepatocyte killing through release of perforin and granizyme-B or non-cytopathic hepatitis C virus deletion through γ-interferon and tumor necrosis factors-α secretion. HCV: Hepatitis C virus; TNF: Tumor necrosis factors.

Figure 2

Theoretical hepatitis C virus viral load, hepatitis C virus-specific cytotoxic T lymphocyte frequency and activated natural Killer cell frequency kinetics during anti-hepatitis C virus treatment with interferon-free and interferon-containing regimes, according to the different types of response. PegIFN: Pegylated-a2-interferon; RBV: Ribavirin; DAA: Direct acting antiviral; NK: Natural Killer cell; CTL: Cytotoxic T lymphocyte; HCV: Hepatitis C virus; RVR: Rapid viral response; EVR: Early viral response; ETR: End of treatment response; SVR: Sustained viral response.

Figure 3

Representative FACS^® dot-plots of peripheral blood mononuclear cells from a sustained viral responder (A) and a null responder (B) after treatment with pegylated-α2-interferon plus ribavirin. The dot-plots show the frequency of hepatitis C virus (HCV)-specific cytotoxic T lymphocyte (CTLs) directly ex-vivo and after specific in-vitro challenge, besides the PD-1 phenotype pre- and after treatment. PBL: Peripheral blood lymphocytes; MFI: Mean fluorescence intensity; tx: Treatment; NA: Not available; PentNS3₁₄₀₆: Multimeric complexes HLA-A2/NS3₁₄₀₆ phycoerithryn labelled; PentNS3₁₀₇₃: Multimeric complexes HLA-A2/NS3₁₀₇₃ phycoerithryn labelled.