Natural killer (NK) cells are large granular lymphocytes that play an important role in the control of viral infections. NK cells do have direct antiviral effects, mediated by cytolytic (eg, TNF-related apoptosis inducing ligand (TRAIL) or perforin mediated) or non-cytolytic (eg, IFN-γ mediated) effector functions as well as regulatory effects.1––3 The latter may be mediated by lysing of virus-infected antigen-presenting cells, activated CD4 T cells or virus-specific CD8 T cells.4

Several lines of evidence support an important role of NK cells in hepatitis C virus (HCV) infection. First, genetic studies have demonstrated that genes encoding the inhibitory NK cell receptor KIR2DL3 and its human leukocyte antigen C group 1 (HLA-C1) ligand directly influence resolution of HCV infection.5 Second, an activated multifunctional NK cell response (cytotoxicity and IFN-γ production) is detectable early after HCV exposure in healthcare workers and injecting drug users who do not develop acute infection suggesting an important contribution to the prevention of high-level viremia.6 ,7 Third, highly activated NK cells with increased degranulation and significant cytokine production are present during acute HCV infection although irrespective of the outcome of infection.8 ,9 Fourth, NK cells can inhibit HCV replication in vitro by IFN-γ mediated non-cytoytic and by perforin/granzyme and TRAIL-mediated cytotoxic mechanisms.1 In this context, it is interesting to note that HCV-infected hepatocytes upregulate expression of TRAIL receptors.10 Fifth, in chronic HCV infection, NK cells are activated and may display alterations in phenotype and function.1 ,2 Finally, upon initiation of antiviral IFN-based therapy, NK cells are further activated and may contribute to HCV clearance by primarily cytotoxic TRAIL-mediated effector functions.11 Interestingly, …