In acute infection with hepatitis C virus (HCV), 15-30% clear the virus and more than 70% progress to chronic infection. HCV resolution is influenced by host polymorphisms of killer immunoglobulin-like receptors (KIR) and their human leukocyte antigen (HLA) class I ligands. Published genomic analyses suggest that weak inhibitory combinations of KIR and HLA (and hence stronger immunity) are associated with increasing rates of HCV resolution, while strong inhibitory KIR/ligand genotypes are associated with HCV chronicity. Genomic typing alone fails to examine critically important features of KIR biology, however. First, there is marked variability in the size of KIR-defined NK cell subsets among different individuals. Second, allelic polymorphisms in individual KIR genes can markedly affect receptor density and function. Third, the combined inhibitory effects of multiple KIR, as well as confounding effects of activating KIR, can dilute effects of discrete inhibitory KIR/ligand pairs. In the current proposal, we employ flow cytometry combined with genomic analyses to examine the effects of NK cell KIR expression and compound KIR/HLA types on HCV resolution. Data from our preliminary studies show that spontaneous HCV resolution is associated with the robust NK cell expression of weakly inhibitory receptors such as KIR2DL3 in the context of their cognate HLA-C ligands. In addition, we demonstrate that inhibitory KIR3DL receptors and their HLA-A and -B ligands are strongly associated with HCV chronicity. The highest resolution rates are in compound phenotypes with weak inhibitory KIR2DL/HLA-C pairs in the absence of confounding inhibitory KIR3DL1/HLA-A or -B pairs. Patients with these weak inhibitory KIR/HLA types resolve HCV at rates exceeding 50- 70%, compared with an overall clearance rate of 16% in our study population. Further, we find that activating KIR correlate with viral clearance in selected HLA types, with HCV resolution rates nearly twice those of the overall cohort. Finally, our preliminary data show that KIR/HLA types associated with spontaneous HCV resolution may predispose to cirrhosis among patients who fail to clear the virus. Based upon these compelling preliminary data, we propose a broader study to test the fundamental hypothesis that differential NK cell activation underlies diverse outcomes of HCV infection. We will (i) define KIR/HLA genotypic and phenotypic correlates of HCV resolution in a large cohort of HCV patients; (ii) define KIR/HLA types correlated with treatment induced HCV eradication among chronically infected patients; (iii) define KIR/HLA correlates of HCV cirrhosis among chronically infected patients; and (iv) define the functional effects of selected KIR/HLA interactions on NK cell activation and NK cell memory in response to in vitro stimuli, and in response to acute and chronic HCV infection in vivo. The studies outlined in this proposal test the hypothesis that KIR/HLA interactions have profound, rather than modest effects on HCV immunity, and that polymorphisms of KIR and HLA underlie host responses to selected infectious agents. These studies also will help to identify KIR as attractive drug targets for pharmacologic antiviral therapies.