GS-9620, an oral agonist of toll-like receptor-7, induces prolonged suppression of hepatitis B virus in chronically infected chimpanzees

Robert E. Lanford, Bernadette Guerra, Deborah Chavez, Luis Giavedoni, Vida L. Hodara, Kathleen M. Brasky, Abigail Fosdick, Christian R. Frey, Jim Zheng, Grushenka Wolfgang, Randall L. Halcomb, Daniel B. Tumas

    Research output: Contribution to journalArticlepeer-review

    227 Scopus citations

    Abstract

    Background & Aims: Direct-acting antiviral agents suppress hepatitis B virus (HBV) load, but they require life-long use. Stimulation of the innate immune system could increase its ability to control the virus and have long-lasting effects after a finite regimen. We investigated the effects of immune activation with GS-9620 - a potent and selective orally active small molecule agonist of Toll-like receptor 7 - in chimpanzees with chronic HBV infection. Methods: GS-9620 was administered to chimpanzees every other day (3 times each week) for 4 weeks at 1 mg/kg and, after a 1-week rest, for 4 weeks at 2 mg/kg. We measured viral load in plasma and liver samples, the pharmacokinetics of GS-9620, and the following pharmacodynamics parameters: interferon-stimulated gene expression, cytokine and chemokine levels, lymphocyte and natural killer cell activation, and viral antigen expression. Clinical pathology parameters were monitored to determine the safety and tolerability of GS-9620. Results: Short-term oral administration of GS-9620 provided long-term suppression of serum and liver HBV DNA. The mean maximum reduction of viral DNA was 2.2 logs, which occurred within 1 week of the end of GS-9620 administration; reductions of >1 log persisted for months. Serum levels of HBV surface antigen and HBV e antigen, and numbers of HBV antigen-positive hepatocytes, were reduced as hepatocyte apoptosis increased. GS-9620 administration induced production of interferon-α and other cytokines and chemokines, and activated interferon-stimulated genes, natural killer cells, and lymphocyte subsets. Conclusions: The small molecule GS-9620 activates Toll-like receptor 7 signaling in immune cells of chimpanzees to induce clearance of HBV-infected cells. This reagent might be developed for treatment of patients with chronic HBV infection.

    Original languageEnglish (US)
    Pages (from-to)1508-1517.e10
    JournalGastroenterology
    Volume144
    Issue number7
    DOIs
    StatePublished - Jun 2013

    Keywords

    • Antiviral
    • Innate Immunity
    • Interferon-α
    • Pathogen Recognition
    • TLR-7

    ASJC Scopus subject areas

    • Hepatology
    • Gastroenterology

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