The authors acknowledge the support of the Italian Ministry of Health, Fondazione Cariplo (Vaccine Program to P.D. and S.A.), Associazione Italiana Ricerca Cancro (AIRC IG-11523 to G.C.; AIRC Special Selleck 3-Methyladenine Program Molecular Clinical Oncology 5 per mille no. 9965 to P.D.), and an ERC Advanced Grant to S.A. (no. 269022). The authors declare no financial or commercial conflict of interest. ""Natural killer (NK) cells are critical to the immune response to viral infections. Their functions are controlled by receptors for major histocompatibility complex (MHC) class I, including NKG2A and killer-cell immunoglobulin-like receptors (KIR). In order to evaluate the role of MHC class I receptors in the immune response to hepatitis C virus infection we have studied patients with Chronic Hcv Infection by multi-parameter flow cytometry directly ex vivo. This has permitted evaluation of combinatorial expression of activating and inhibitory receptors on single NK cells. Individuals with chronic HCV infection had fewer CD56dim NK cells than healthy controls (4��9?��?3��4% versus 9��0?��?5��9%, P?0��05). Expression levels of the inhibitory receptor NKG2A was up-regulated on NK cells from individuals with chronic hepatitis C virus (HCV) (NKG2A mean fluorescence intensity 5692?��?2032 versus 4525?��?1646, P?0��05). Twelve individuals were treated with pegylated interferon and ribavirin. This resulted in a down-regulation of NKG2A expression on CD56dim NK cells. Individuals with a sustained virological response (SVR) had greater numbers of NKG2A-positive, KIR-negative NK cells VE822 than those without SVR (27��6?��?9��6% NK cells versus 17��6?��?5��7, P?0��02). Our data show that NKG2A expression is dysregulated in chronic HCV infection and that NKG2A-positive NK cells are associated with a beneficial response to pegylated interferon and ribavirin therapy. Hepatitis C is a common chronic viral infection. The virus poses a significant challenge to the immune system, as the majority of individuals exposed to hepatitis C virus (HCV) are unable to clear HCV spontaneously, develop a chronic infection and are predisposed to cirrhosis and hepatocellular carcinoma. This failure to mount a successful immune response is multi-factorial in nature and includes abnormalities in T, B and dendritic cell responses. Natural killer (NK) cells are lymphocytes that can interact directly with virus-infected host cells, activate dendritic cells Ibrutinib and also secrete T helper type 1 (Th1) cytokines to augment cytotoxic T cell responses [1]. Their functions are controlled by multiple activating and inhibitory receptors, and they integrate signals derived from these receptors to determine whether or not they become activated. NK cells are enriched in the liver in comparison to peripheral blood [2] and a number of studies have documented abnormalities of NK cells in chronic HCV infection. These include changes in NK cell frequency, activity and subpopulation [3�C8].