Inhibitory natural killer cell receptors: role and mechanism of action in hepatitis C virus infection. (360G-Wellcome-076991_B_05_A)

We have recently shown that specific combinations of inhibitory killer cell immunoglobulin-like receptors (KIR) and their HLA class I ligands determine the outcome of hepatitis C virus (HCV) infection. The goal of this project to is to understand how this protection works at a molecular level. There are three specific aims: To determine the role of KIR in the response of chronically infected individuals to interferon-a based therapies and whether the KIR:MHC class I interaction impacts on HCV diversity To determine how expression of the activating and inhibitory receptors on NK are "balanced"; and how specific KIR alleles affect this balance such that some KIR alleles protect against chronic infection with HCV. To investigate the peptide specificity of KIR as a mechanism that underlies their protective effect in HCV infection. This will test the hypothesis that different KIR have different peptide specificities and that diversity in peptide specificity is one reason why only specific KIR alleles are protective in HCV infection. These studies will give novel insights into NK cell receptor biology and can thus inform potential NK cell based therapies for chronic HCV infection.