Here we extend our study to examine if HCV infection

elevates TRAIL-DR4/DR5-mediated apoptosis via caspase-8 activation. Methods: Using HCV JFH-1 cell-culture system (HCVcc), the expression level of DR4 and DR5 in HCV-infected Huh7.5.1 cells was analyzed by qRT-PCR and Western blotting. Caspase activity assay and Western blotting were conducted for analysis of TRAIL-DR4/DR5-mediated caspase activation cascade in infected cells by using recombinant TRAIL, caspase inhibitors, and siRNAs specific to DR4 and DR5. Results: Dasatinib HCV infection stimulates DR4 and DR5 gene expression at both levels of transcription and translation. HCV-induced apoptosis via DR4/DR5 was evidenced by the reduction of caspase-3/7 activity by both DR4 and DR5 silencing and the increase of cleavage of cas-pases including caspase-8, caspase-9, and caspase-3 by TRAIL treatment. Treatment of infected cells with caspase-8 specific inhibitor resulted in the decline of HCV-induced cleavage of PARP and Bid, a pro-apoptotic protein. Conclusions: Our data identify that HCV infection elevatesTRAIL-DR4/DR5-mediated apoptosis MAPK inhibitor of human hepatoma cells via caspase-8 activation. Given the importance of apoptosis in promoting hepatic fibro-genesis, these results suggest potential utility for TRAIL inhibition in chronic hepatitis C. Disclosures: Raymond T. Chung – Advisory Committees or Review Panels: Idenix; Consulting: Enanta; Grant/Research Support: Gilead, Merck, Mass Biologic,

Gilead The following people have nothing to disclose: Jae Young Jang, Seong-Jun Kim, Eun Kyung Cho, Soung Won Jeong, Yun Nah Lee, Sae Hwan Lee, Sang Gyune Kim, Sang-Woo Cha, Young Seok Kim, Young Deok Cho, Hong Soo Kim, Boo Sung Kim, Wenyu Lin Background: CD16pos monocytes have been implicated in the pathogenesis of chronic liver disease and HIV infection. The non-classical CD14negCD1 6pos monocyte subset is thought to promote inflammatory responses to viral infection. The role played by non-classical monocytes in immunity to hepatitis C viral (HCV) infection is unknown. Methods: Extensive multipa-rameter flow cytometric analysis was used to determine the phe-notype and function of CD16pos

monocytes. Non-classical CD16pos monocytes were distinguished medchemexpress by negativity for CD 14 and high levels of CD1 1c, within a low forward-side scatter gate from which CD56pos NK cells were excluded. Cytokine gene expression was detected using RT-PCR. Antigen presentation was assessed in vitro using autologous HCV-specific CD8pos T cells and T cell clones. Results: These non-classical CD16p°sCD11chigh monocytes express high levels of HLA-DR and CD86, are negative for classical mDC (BDCA-1) and pDC (BDCA-2/4) antigens and for the neutrophil marker CD66b. However, the mDC2 antigen BDCA-3 was detected on 13.6% – 47% of these non-classical monocytes in chronic HCV infection. Compared to normal control subjects, their expression of co-inhibitory molecules is increased in chronic HCV infection, galectin-9 (mean 12.