Intrahepatic transcriptional responses Selleck HKI272 were characterized by gene set enrichment analysis (GSEA), Ingenuity Pathway Analysis (IPA) and a gene module approach. Results: GS-9620 induced a broad intrahepatic immune response in HBV-infected chimpanzees, with type I interferon (IFN), T cell and B cell gene signatures prominently up-regulated. Notably, the transcriptional signature induced by GS-9620

was significantly enriched with genes induced during HBV clearance in acutely infected chimpanzees (Wieland et al. (2004) PNAS 101: 6669-74). Underscoring the parallels with natural clearance of acute infection, the HBsAg reduction by GS-9620 in HBV-infected chimpanzees was associated with up-regulation of intrahepatic CD8+ T cell and cytotoxic cell gene signatures, as well as B cell and plasma cell tran-scriptional profiles. Notably, the elevated expression of cyto-toxic cell-associated genes (e.g. perforin, granzyme B and Fas ligand) was accompanied by significant induction AZD6244 in vivo of transcrip-tional signatures consistent with hepatocyte apoptosis (e.g. caspase 3 and caspase 7), as well as hepatocyte regeneration and

proliferation (e.g. cell cycle regulatory genes). Importantly, GS-9620 also induced an intrahepatic cytotoxic T cell gene signature in chronically infected woodchucks, suggesting this is a key mechanism of antiviral response to GS-9620 in both chimpanzee and woodchuck models of CHB. Likewise, the induction of intrahepatic interferon-stimulated gene (ISG) expression suggests that antiviral ISGs may also play a role in GS-9620 treatment response in these animal models. Conclusion: These data indicate that the antiviral response induced by GS-9620 in preclinical models of CHB was likely mediated, at least in part, 上海皓元 by the cytolytic activity of CD8+ T cells. Induction of a strong intrahepatic B cell response may also have played an important role in HBsAg antigen seroconversion. Disclosures: Li Li – Employment: Gilead Sciences Peng Yue – Employment: Gilead Sciences

Robert E. Lanford – Grant/Research Support: Arrowhead Research Stephan Menne – Advisory Committees or Review Panels: Hoffman-La Roche; Consulting: Northeastern Wildlife Inc.; Grant/Research Support: Hoffmann-La Roche Congrong Niu – Employment: Gilead Science Stephane Daffis – Employment: Gilead Sciences Daniel Tumas – Employment: Gilead Sciences, Inc Abigail Fosdick – Employment: Gilead Sciences William E. Delaney – Employment: Gilead Sciences; Patent Held/Filed: Gilead Sciences; Stock Shareholder: Gilead Sciences Simon P. Fletcher – Employment: Gilead Sciences; Stock Shareholder: Gilead Sciences Background: As hepatitis D is the result of a double infection of HDV with HBV, therapeutic goals are in relation with both viral infections. The definitive end-point of HDV therapy appears the clearance of HBsAg.