No abstract

Hepatitis C virus (HCV) sets up persistent infection in the majority of those exposed. It is likely that, as with other persistent viral infections, the efficacy of T-lymphocyte responses influences long-term outcome. However, little is known about the functional capacity of HCV-specific T-lymphocyte responses induced after acute infection. We investigated this by using major histocompatibility complex class I-peptide tetrameric complexes (tetramers), which allow direct detection of specific CD8؉ T lymphocytes ex vivo, independently of function. Here we show that, early after infection, virus-specific CD8؉ T lymphocytes detected with a panel of four such tetramers are abnormal in terms of their synthesis of antiviral cytokines and lytic activity. Furthermore, this phenotype is commonly maintained long term, since large sustained populations of HCV-specific CD8 ؉ T lymphocytes were identified, which consistently had very poor antiviral cytokine responses as measured in vitro. Overall, HCV-specific CD8 ؉ T lymphocytes show reduced synthesis of tumor necrosis factor alpha (TNF-␣) and gamma interferon (IFN-␥) after stimulation with either mitogens or peptides, compared to responses to Epstein-Barr virus and/or cytomegalovirus. This behavior of antiviral CD8 ؉ T lymphocytes induced after HCV infection may contribute to viral persistence through failure to effectively suppress viral replication.

CD8+ T lymphocytes play a major role in antiviral immune defense. Their significance for acute hepatitis C is unclear. Our aim was to correlate the CD8+ T cell response with the outcome of infection. Eighteen patients with acute hepatitis C and 19 normal donors were studied. Hepatitis C virus (HCV)-specific CD8+ T cells were identified in the enzyme-linked immunospot assay by their interferon-gamma (IFN-gamma) production after specific stimulation. The highest numbers of IFN-gamma-producing HCV-specific CD8+ T cells were found in patients with acute hepatitis C and a self-limited course of disease during the first 6 months after onset of disease, but these numbers dropped thereafter to undetectable levels. The differences in responsiveness between patients with self-limited disease versus patients with a chronic course were statistically significant (P<.001). Our data show that the number of IFN-gamma-producing HCV-specific CD8+ T cells during the first 6 months after onset of disease is associated with eradication of the HCV infection.

Multiple inhibitory receptors may play a role in the weak or absent CD81 T-cell response in chronic hepatitis B virus (HBV) infection. Yet few receptors have been characterized in detail and little is known about their complex regulation. In the present study, we investigated the role of the signaling lymphocyte activation molecule (SLAM)-related receptor CD244 and of programmed death 1 (PD-1) in HBV infection in 15 acutely and 66 chronically infected patients as well as 9 resolvers and 21 healthy controls. The expression of CD244, PD-1, and T-cell immunoglobulin domain and mucin domain 3 (TIM-3) was analyzed in virus-specific CD81 T-cells derived from peripheral blood or liver using major histocompatibility complex class I pentamers targeting immunodominant epitopes of HBV, Epstein-Barr-virus (EBV), or influenza virus (Flu). In chronic HBV infection, virusspecific CD81 T-cells expressed higher levels of CD244 both in the peripheral blood and liver in comparison to the acute phase of infection or following resolution. CD244 was expressed at similarly high levels in EBV infection, but was low on Flu-specific CD81 Tcells. In chronic HBV infection, high-level CD244 expression coincided with an increased expression of PD-1. The inhibition of the CD244 signaling pathway by antibodies directed against either CD244 or its ligand CD48 resulted in an increased virus-specific proliferation and cytotoxicity as measured by the expression of CD107a, interferon-c, and tumor necrosis factor-a in CD81 T-cells. Conclusion: CD244 and PD-1 are highly coexpressed on virus-specific CD81 T-cells in chronic HBV infection and blocking CD244 or its ligand CD48 may restore T-cell function independent of the PD-1 pathway. CD244 may thus be another potential target for immunotherapy in chronic viral infections.