Toll-like receptor 7 agonist GS-9620 induces prolonged inhibition of HBV via a type I interferon-dependent mechanism

JOURNAL OF HEPATOLOGY

卷:68

Article

Niu, Congrong¹  Li, Li¹  Daffis, Stephane¹  Lucifora, Julie²  Bonnin, Marc²  Maadadi, Sarah²  Salas, Eduardo¹  Chu, Ruth¹  Ramos, Hilario¹  Livingston, Christine M.¹  Beran, Rudolf K.¹  Garg, Abhishek V.¹  Balsitis, Scott¹  Durantel, David²  Zoulim, Fabien^2,3,4  Delaney, William E.¹  Fletcher, Simon P.¹ 

[1] Gilead Sci Inc, 333 Lakeside Dr, Foster City, CA 94404 USA

[2] Univ Claude Bernard Lyon 1, Ctr Leon Berard, Ctr Rech Cancerol Lyon, INSERM 1052,CNRS 5286, F-69003 Lyon, France

[3] HCl, F-69002 Lyon, France

[4] IUF, F-75005 Paris, France

关键词: TLR7;    GS-9620;    Hepatitis B virus;    Interferon-alpha;    cccDNA;    Interferon-stimulated gene;    MHC;    Immunoproteasome;    APOBEC;    Smc5/6;   

DOI  :  10.1016/j.jhep.2017.12.007

来源: Elsevier

【 摘 要 】

Background & Aims: GS-9620, an oral agonist of toll-like receptor 7 (TLR7), is in clinical development for the treatment of chronic hepatitis B (CHB). GS-9620 was previously shown to induce prolonged suppression of serum viral DNA and antigens in the woodchuck and chimpanzee models of CHB. Herein, we investigated the molecular mechanisms that contribute to the antiviral response to GS-9620 using in vitro models of hepatitis B virus (HBV) infection. Methods: Cryopreserved primary human hepatocytes (PHH) and differentiated HepaRG (dHepaRG) cells were infected with HBV and treated with GS-9620, conditioned media from human peripheral blood mononuclear cells treated with GS-9620 (GS-9620 conditioned media [GS-9620-CM]), or other innate immune stimuli. The antiviral and transcriptional response to these agents was determined. Results: GS-9620 had no antiviral activity in HBV-infected PHH, consistent with low level TLR7 mRNA expression in human hepatocytes. In contrast, GS-9620-CM induced prolonged reduction of HBV DNA, RNA, and antigen levels in PHH and dHepaRG cells via a type I interferon (IFN)-dependent mechanism. GS-9620CM did not reduce covalently closed circular DNA (cccDNA) levels in either cell type. Transcriptional profiling demonstrated that GS-9620-CM strongly induced various HBV restriction factors-although not APOBEC3A or the Smc5/6 complex - and indicated that established HBV infection does not modulate innate immune sensing or signaling in cryopreserved PHH. GS-9620-CM also induced expression of immunoproteasome subunits and enhanced presentation of an immunodominant viral peptide in HBV-infected PHH. Conclusions: Type I IFN induced by GS-9620 durably suppressed HBV in human hepatocytes without reducing cccDNA levels. Moreover, HBV antigen presentation was enhanced, suggesting additional components of the TLR7-induced immune response played a role in the antiviral response to GS-9620 in animal models of CHB. (C) 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

【 授权许可】

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