title: Nucleic acid-based polymers effective against hepatitis B Virus infection in patients don't harbor immunostimulatory properties in primary isolated liver cells.
abstract: Nucleic acid polymers (NAPs) block the release of subviral particles from hepatocytes, a mechanism consistent with their antiviral activity against hepatitis B virus (HBV) in patients. Analysis of immunostimulatory properties of NAPs were conducted with several NAP species: REP 2006, the prototypic degenerate NAP [dN]40, containing TLR9-stimulatory CpG; REP 2055 a clinically active NAP with a sequence [dAdC]20devoid of CpG content; REP 2139 (also clinically active) and REP 2165 (REP 2055 analogues further rendered immunologically inactive by replacing cytidine with 5-methylcytidine and incorporating 2'-O methylation of riboses). These analyses revealed pro-inflammatory responses in human peripheral blood mononuclear cells with REP 2006 and with REP 2139 and REP 2165 only at high dose but displayed no significant antiviral activity. In primary isolated human hepatocytes and liver sinusoidal endothelial cells no significant inflammatory or antiviral responses were detected for any NAPs. In human Kupffer cells pro-inflammatory activity was observed with REP 2006 and REP 2055, whereas a weak but significant induction of interferon genes was only observed with REP 2006 at the highest concentration. We therefore hypothesize that the antiviral activity of NAPs optimized to treat HBV infection in patients cannot be explained by direct induction of innate antiviral responses.
authors.affiliation: Department of Gastroenterology and Hepatology, University Hospital at the University Duisburg-Essen, Essen, Germany.|Department of General-, Visceral- and Transplantation Surgery, University Hospital at the University Duisburg-Essen, Essen, Germany.
authors.forename: Catherine Isabell
authors.initials: CI
authors.lastname: Real
authors.affiliation: Department of Gastroenterology and Hepatology, University Hospital at the University Duisburg-Essen, Essen, Germany.
authors.forename: Melanie
authors.initials: M
authors.lastname: Werner
authors.affiliation: Department of General-, Visceral- and Transplantation Surgery, University Hospital at the University Duisburg-Essen, Essen, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Paul
authors.affiliation: Department of Gastroenterology and Hepatology, University Hospital at the University Duisburg-Essen, Essen, Germany.
authors.forename: Guido
authors.initials: G
authors.lastname: Gerken
authors.affiliation: Department of Gastroenterology and Hepatology, University Hospital at the University Duisburg-Essen, Essen, Germany.|Evangelisches Klinikum Niederrhein GmbH, Duisburg, Germany.
authors.forename: Joerg Friedrich
authors.initials: JF
authors.lastname: Schlaak
authors.affiliation: Replicor Inc., Montreal, Quebec, Canada.
authors.forename: Andrew
authors.initials: A
authors.lastname: Vaillant
authors.affiliation: Department of Gastroenterology and Hepatology, University Hospital at the University Duisburg-Essen, Essen, Germany.
authors.forename: Ruth
authors.initials: R
authors.lastname: Broering
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology; D002478:Cells, Cultured; D006509:Hepatitis B / Q000517:prevention & control* / Q000821:virology; D006515:Hepatitis B virus / Q000187:drug effects* / Q000502:physiology; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007728:Kupffer Cells / Q000187:drug effects / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D009696:Nucleic Acids / Q000737:chemistry* / Q000494:pharmacology; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology; D011108:Polymers / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000998:Antiviral Agents; D009696:Nucleic Acids; D009838:Oligodeoxyribonucleotides; D011108:Polymers; C000608433:REP 2055; C000628017:REP 2139