Suppression of hepatitis B virus through therapeutic activation of RIG-I and IRF3 signaling in hepatocytes
Sooyoung Lee 1 , Ashish Goyal 2 , Alan S Perelson 2 , Yuji Ishida 3 4 , Takeshi Saito 3 , Michael Gale Jr 1
Affiliations
Affiliations
1
Center for Innate Immunity and Immune Disease, Department of Immunology, University of Washington, Seattle, WA 98109, USA.
2
Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, NM, USA.
3
Division of Gastrointestinal and Liver Diseases, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
4
PhoenixBio Co., Ltd., Research and Development Unit, Higashi-Hiroshima, Japan.
Hepatitis B virus (HBV) mediates persistent infection, chronic hepatitis, and liver disease. HBV covalently closed circular (ccc)DNA is central to viral persistence such that its elimination is considered the cornerstone for HBV cure. Inefficient detection by pathogen recognition receptors (PRRs) in the infected hepatocyte facilitates HBV persistence via avoidance of innate immune activation and interferon regulatory factor (IRF)3 induction of antiviral gene expression. We evaluated a small molecule compound, F7, and 5'-triphosphate-poly-U/UC pathogen-associated-molecular-pattern (PAMP) RNA agonists of RIG-I, a PRR that signals innate immunity, for ability to suppress cccDNA. F7 and poly-U/UC PAMP treatment of HBV-infected cells induced RIG-I signaling of IRF3 activation to induce antiviral genes for suppression of cccDNA formation and accelerated decay of established cccDNA, and were additive to the actions of entecavir. Our study shows that activation of the RIG-I pathway and IRF3 to induce innate immune actions offers therapeutic benefit toward elimination of cccDNA.