Potent immune activation in chronic hepatitis C patients upon administration of an oral inducer of endogenous interferons that acts via Toll-like receptor 7

Andre Boonstra, Bisheng Liu, Anthonie Groothuismink, Jilling Bergmann, Joep Bruijne, Daphne Hotho, Bettina Hansen, AA van Vliet, JJV de Rooij, SP Fletcher, LA Bauman, M Rahimy, JR Appleman, JL Freddo, HW Reesink, Rob de Knegt, HLA Janssen

Research output: Contribution to journalArticleAcademicpeer-review

24 Citations (Scopus)

Abstract

Background: ANA773, an oral prodrug of a small-molecule Toll-like receptor (TLR)7 agonist, induces a dose-related decrease in serum HCV RNA levels in chronic hepatitis C patients. Methods: The prodrug ANA773 was administered to healthy individuals and chronic hepatitis C patients. At different time points during the course of treatment, modulation of the phenotype and function of peripheral leukocytes were evaluated to determine the role of distinct immune cells on the clinical outcome of therapy. Results: Early after administration of the TLR7 agonist, a mild transient reduction of the number of lymphocytes was observed in both healthy individuals and chronic hepatitis C patients. Moreover, repeated administration of ANA773 resulted in transiently reduced numbers of myeloid and plasmacytoid dendritic cells (DC) in blood. Interestingly, reduced plasmacytoid DC numbers as well as increased serum interferon (IFN)-alpha and IFN-gamma inducible protein (IP)-10 levels were observed only in vir Conclusions: These findings indicate that the viral load decline in chronic hepatitis C patients treated with the TLR7 agonist ANA773 is likely due to intrinsic differences in the induction of endogenous IFNs and IFN-stimulated gene products (IFN-alpha and IP-10) upon TLR7 ligation.
Original languageEnglish
Pages (from-to)657-667
Number of pages11
JournalAntiviral Therapy
Volume17
Issue number4
DOIs
Publication statusPublished - 2012

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