1873The Antiviral Response to the Toll-Like Receptor 7 Agonist GS-9620 in Preclinical Models of Chronic Hepatitis B is Associated with an Intrahepatic Cytotoxic T Cell Transcriptional SignatureLi Li1, Peng Yue1, Robert E. Lanford2, Stephan Menne3, Congrong Niu1, Stephane Daffis1, Daniel Tumas1, Abigail Fosdick1, William E. Delaney1, Simon P. Fletcher1;1Gilead Sceinces, Foster City, CA; 2Department of Virology and Immunology, Texas Biomedical Research Institute, San Antonio, TX; 3Department of Microbiology & Immunology, Georgetown University Medical Center, Washington DC, DC
Background & Aims: GS-9620, an oral agonist of toll-like receptor 7 (TLR7), is in phase 2 studies for the treatment of chronic hepatitis B (CHB). In earlier preclinical studies, GS-9620 induced prolonged suppression of serum viral DNA and antigens in the chimpanzee and woodchuck models of CHB. Here we present a follow-up transcriptional analysis of liver biopsy samples from these animal model studies in order to define the intrahepatic cellular and molecular characteristics of the antiviral response to GS-9620 in vivo.
Methods: Whole transcriptome analysis of liver biopsies taken from chronically infected chimpanzees (n=3) and woodchucks (n=7) during treatment with GS-9620 or placebo (woodchuck study only, n=7) was performed by RNA-Seq. Intrahepatic transcriptional responses 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 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, 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 作者: StephenW 时间: 2014-10-16 10:42
