title: Combination therapy including CpG oligodeoxynucleotides and entecavir induces early viral response and enhanced inhibition of viral replication in a woodchuck model of chronic hepadnaviral infection.
abstract: CpG oligodeoxynucleotides (ODNs) stimulate immune cells via TLR9 and are potentially useful immunomodulators for the treatment of chronic viral infections. In the present study, different classes of CpGs were tested for their capacities for innate immune activation and antiviral activities in the woodchuck model. A class P CpG ODN was found to stimulate interferon (IFN) production in woodchuck peripheral blood mononuclear cells (PBMCs) in vitro, and following subcutaneous administration in vivo, it was observed to induce IFN and MxA expression in woodchuck PBMCs. Combination treatment with CpG ODN and entecavir (ETV) led to effective suppression of the woodchuck hepatitis virus (WHV) load in the woodchucks, with early viral responses and inhibition of replication. The woodchuck hepatitis surface antigen (WHsAg) serum concentrations were strongly decreased by CpG and ETV together but not by either agent alone, indicating synergistic effects. However, viral control post-treatment was still transient, similar to that observed with ETV alone. Significantly elevated levels of serum aspartate aminotransferase (AST) but not of alanine aminotransferase (ALT) in some of the woodchucks receiving CpG ODN were noted, but these increases were resolved before the completion of treatment and were not associated with an elevated serum bilirubin level or coagulation disorders, suggesting the absence of a significant safety concern.
authors.affiliation: Institute of Virology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany; Department of Infectious Diseases, Taihe Hospital, Hubei University of Medicine, Shiyan, China.
authors.forename: Zhongji
authors.initials: Z
authors.lastname: Meng
authors.affiliation: Institute of Virology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Xiaoyong
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Institute of Virology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Rongjuan
authors.initials: R
authors.lastname: Pei
authors.affiliation: Institute of Virology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Ejuan
authors.initials: E
authors.lastname: Zhang
authors.affiliation: Institute of Virology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Thekla
authors.initials: T
authors.lastname: Kemper
authors.affiliation: Pfizer Oligonucleotides Therapeutics Unit, Düsseldorf, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Vollmer
authors.affiliation: Pfizer Vaccine Immunotherapeutics, Ottawa, Canada.
authors.forename: Heather L
authors.initials: HL
authors.lastname: Davis
authors.affiliation: Institute of Medical Virology, Justus-Liebig University Giessen, Giessen, Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Glebe
authors.affiliation: Institute of Medical Virology, Justus-Liebig University Giessen, Giessen, Germany.
authors.forename: Wolfram
authors.initials: W
authors.lastname: Gerlich
authors.affiliation: Institute of Virology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Roggendorf
authors.affiliation: Institute of Virology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany. Electronic address: Mengji.lu@uni-due.de.
authors.forename: Mengji
authors.initials: M
authors.lastname: Lu
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D004279:DNA, Viral / Q000097:blood; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D006147:Guanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006510:Hepatitis B Antibodies / Q000097:blood; D017919:Hepatitis B Virus, Woodchuck / Q000187:drug effects*; D019694:Hepatitis B, Chronic / Q000097:blood / Q000188:drug therapy* / Q000821:virology; D016898:Interferon-alpha / Q000096:biosynthesis / Q000097:blood; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000378:metabolism; D008392:Marmota; D009838:Oligodeoxyribonucleotides / Q000235:genetics / Q000494:pharmacology*; D011897:Random Allocation; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; C408982:CPG-oligonucleotide; D004279:DNA, Viral; D006510:Hepatitis B Antibodies; D016898:Interferon-alpha; D009838:Oligodeoxyribonucleotides; C413685:entecavir; D006147:Guanine
keywords: CpG oligodeoxynucleotides; Hepatitis B virus; Immunotherapy; Toll-like receptor; Woodchuck hepatitis virus