The novel TLR7 agonist GS-9620 induces a diverse set of interferon stimulated genes

Abstract

Event Abstract Back to Event The novel TLR7 agonist GS-9620 induces a diverse set of interferon stimulated genes Christian R. Frey1*, Adam Palazzo1, Joseph Hesselgesser1, Tomas Cihlar1 and Stefan Pflanz1 1 Gilead Sciences, Inc., United States Efficient innate and adaptive immunity is necessary for initial containment and subsequent clearance of viral infections, including hepatitis viruses B (HBV) and C (HCV). Part of the initial anti-viral immune response is the interaction of single stranded viral RNA with Toll-like receptor 7 (TLR7) within the endolysosomal compartment leading to activation of plasmacytoid dendritic cells and B lymphocytes. We demonstrated that the novel TLR7-selective agonist GS 9620 induces IFN- and other cytokines and chemokines in human PBMC in vitro cultures in a dose-dependent manner. Moreover, we showed that GS-9620-dependent activation networks include the upregulated expression of lymph node retention marker CD69 on lymphocytes such as B cells and T cells. Profiling the GS-9620-dependent induction of gene expression in PBMC on a whole-genome level using the Illumina bead chip revealed a gene signature consistent with an anti-viral response including the upregulation of interferon-stimulated genes (ISGs). For a select panel of ISGs (MX1, OAS1, ISG15, IFIT1 and IFIT2) and other genes (CCL8, CCL19, CD38, IL-1RN), the time- and concentration-dependent induction after the stimulation with GS-9620 was confirmed using quantitative PCR. In addition, we showed a similar pattern of TLR7 agonist-dependent ISG induction in ex vivo experiments using fresh whole human blood. In conclusion, the TLR7 agonist GS-9620 broadly activates anti-viral genes including ISGs. These observations confirm the antiviral potential of GS-9620 and may facilitate the identification of sensitive pharmacodynamic markers to inform the clinical development of GS-9620. Keywords: GS-9620, TLR7, Interferon-stimulated genes, PBMC, antiviral immunity Conference: 15th International Congress of Immunology (ICI), Milan, Italy, 22 Aug - 27 Aug, 2013. Presentation Type: Abstract Topic: Innate immunity Citation: Frey CR, Palazzo A, Hesselgesser J, Cihlar T and Pflanz S (2013). The novel TLR7 agonist GS-9620 induces a diverse set of interferon stimulated genes. Front. Immunol. Conference Abstract: 15th International Congress of Immunology (ICI). doi: 10.3389/conf.fimmu.2013.02.00820 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 21 Jun 2013; Published Online: 22 Aug 2013. * Correspondence: Dr. Christian R Frey, Gilead Sciences, Inc., Foster City, CA, 94404, United States, christian.frey@gilead.com Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Christian R Frey Adam Palazzo Joseph Hesselgesser Tomas Cihlar Stefan Pflanz Google Christian R Frey Adam Palazzo Joseph Hesselgesser Tomas Cihlar Stefan Pflanz Google Scholar Christian R Frey Adam Palazzo Joseph Hesselgesser Tomas Cihlar Stefan Pflanz PubMed Christian R Frey Adam Palazzo Joseph Hesselgesser Tomas Cihlar Stefan Pflanz Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.