The hepatitis C virus (HCV) chronically infects an estimated 170 million people worldwide. Following acute HCV infectton, only 15-45% of individuals resolve the virus spontaneously. Clearance of HCV infecfion requires the generation of potent antiviral T cell effectors. Virally encoded proteins are known to induce a dysregulated activation state In peripheral blood monocytes, and cytokines from aberrantly activated monocytes can adversely affect T cell priming by dendritic cells. In preliminary studies, we have shown that polymorphisms of the Killer Immunoglobulin Receptor (KIR) family of NK cell receptors and their human leukocyte antigen (HLA) class I ligands are major host determinants of spontaneous HCV clearance;that acute HCV infection triggers NK cell activation pathways involving the natural cytotoxicity receptor NKG2D;and that stress-inducible cell-surface ligands for NKG2D are expressed on HCVactivated peripheral blood monocytes. We hypothesize that NK cells may promote effective T cell priming by clearing aberrantly-activated monocytes and virally infected cells, or by contribufing to the elaboration of potent antiviral cytokines. Moreover, we propose that effector and cytokine responses of NK cells may be triggered, in part, by NKG2D and modulated by inhibitory and activating KIR, and that NK cells with a
Chronic hepatitts C virus is the leading cause of liver cirrhosis and liver cancer in America, and current treatments are long, arduous, and fail to successfully cure the virus in more than half the cases. This proposal focuses on the mechanisms by which the immune system clears the virus during treatment, and it may identify new ways to predict treatment success. It may also define drug targets for new treatments of chronic hepatitts C virus.
|Nabekura, Tsukasa; Kanaya, Minoru; Shibuya, Akira et al. (2014) Costimulatory molecule DNAM-1 is essential for optimal differentiation of memory natural killer cells during mouse cytomegalovirus infection. Immunity 40:225-34|
|Hartigan-O'Connor, Dennis J; Lin, Din; Ryan, James C et al. (2014) Monocyte activation by interferon ? is associated with failure to achieve a sustained virologic response after treatment for hepatitis C virus infection. J Infect Dis 209:1602-12|
|Price, Jennifer C; Murphy, Rosemary C; Shvachko, Valentina A et al. (2014) Effectiveness of telaprevir and boceprevir triple therapy for patients with hepatitis C virus infection in a large integrated care setting. Dig Dis Sci 59:3043-52|
|Cozen, Myrna L; Ryan, James C; Shen, Hui et al. (2013) Nonresponse to interferon-? based treatment for chronic hepatitis C infection is associated with increased hazard of cirrhosis. PLoS One 8:e61568|