Background: Natural Killer (NK) cells constitute a first line of defense against viral infections; their function is governed by the integration of signals from multiple activating and inhibitory cell surface receptors. We hypothesized that since NK cells become rapidly activated by cytokines, response to anti-HCV therapy would be predicted by the phenotype and function of NKs. Methods: We used a cohort of 101 patients (56 African-, 45 Caucasian-American) who received Pegylated-IFN and Ribavirin for 48 weeks. Multiparameter FACS analysis was used to examine relative expression of 14 different inhibitory/activating receptors in pretreatment samples. IL-128B genotyping (rs12979860) was also performed. Results: Pretreatment levels of inhibitory receptors CD158a, CD158b and CD158e were higher in patients who demonstrated poor viral decline within the first 28 days of therapy. Higher expression levels of inhibitory receptors NKG2A, CD158b and CD158e were demonstrable in patients who failed to achieve SVR. Conversely, pre-treatment expression levels of activating receptors NKRp44, CD161, tumor necrosis factor-related apoptosisinducing ligand (TRAIL) were higher on NK cell populations in those who subsequently experienced SVR. Patients carrying the IL-28B T allele had higher NKG2A expression. We created a mathematical regression model incorporating race, viral level, and two inhibitory receptors. The ROC area-under-the curve was 0.88 which is highly predictive of SVR. Moreover, the model performed complementarily with IL-28B across the CC, CT, and TT genotypes. For example, among CC patients with NK-SVR model scores below the 50th percentile, none experienced SVR, whereas in those with model scores above the 50th percentile, 90% achieved SVR. Purified NKG2A-negative NKs treated with pegylated-IFN-alpha for 4 hours demonstrated higher levels of IP-10 and TRAIL compared to their NKG2A-positive counterparts. Conclusions: These results provide novel insights into the associations of NK phenotype with IL-28B genotype and gene expression patterns, as well as the role of NKs in mediating IFN-induced viral clearance of chronic HCV infection.
L., G.-M., K., B., L., C., C.D., H., M.W., T., P.J., C., … H.R., R. (2011). NK inhibitory receptor expression associated with treatment failure and IL-28B genotype in patients with chronic hepatitis C. Hepatology. L. Golden-Mason, I/Hepatology, Hepatitis C Center, University of Colorado Denver, Aurora, CO, United States: John Wiley and Sons Inc. Retrieved from http://ovidsp.ovid.com/ovidweb.cgi?T=JS&PAGE=reference&D=emed10&NEWS=N&AN=70592765