title: Therapeutic Antiviral Effect of the Nucleic Acid Polymer REP 2055 against Persistent Duck Hepatitis B Virus Infection.
abstract: Previous studies have demonstrated that nucleic acid polymers (NAPs) have both entry and post-entry inhibitory activity against duck hepatitis B virus (DHBV) infection. The inhibitory activity exhibited by NAPs prevented DHBV infection of primary duck hepatocytes in vitro and protected ducks from DHBV infection in vivo and did not result from direct activation of the immune response. In the current study treatment of primary human hepatocytes with NAP REP 2055 did not induce expression of the TNF, IL6, IL10, IFNA4 or IFNB1 genes, confirming the lack of direct immunostimulation by REP 2055. Ducks with persistent DHBV infection were treated with NAP 2055 to determine if the post-entry inhibitory activity exhibited by NAPs could provide a therapeutic effect against established DHBV infection in vivo. In all REP 2055-treated ducks, 28 days of treatment lead to initial rapid reductions in serum DHBsAg and DHBV DNA and increases in anti-DHBs antibodies. After treatment, 6/11 ducks experienced a sustained virologic response: DHBsAg and DHBV DNA remained at low or undetectable levels in the serum and no DHBsAg or DHBV core antigen positive hepatocytes and only trace amounts of DHBV total and covalently closed circular DNA (cccDNA) were detected in the liver at 9 or 16 weeks of follow-up. In the remaining 5/11 REP 2055-treated ducks, all markers of DHBV infection rapidly rebounded after treatment withdrawal: At 9 and 16 weeks of follow-up, levels of DHBsAg and DHBcAg and DHBV total and cccDNA in the liver had rebounded and matched levels observed in the control ducks treated with normal saline which remained persistently infected with DHBV. These data demonstrate that treatment with the NAP REP 2055 can lead to sustained control of persistent DHBV infection. These effects may be related to the unique ability of REP 2055 to block release of DHBsAg from infected hepatocytes.
authors.affiliation: Department of Molecular and Cellular Biology, School of Biological Sciences, University of Adelaide, Adelaide, SA, Australia.|Department of Microbiology, Faculty of Medicine, University of Peradeniya, Peradeniya, Sri Lanka.
authors.forename: Faseeha
authors.initials: F
authors.lastname: Noordeen
authors.affiliation: Department of Molecular and Cellular Biology, School of Biological Sciences, University of Adelaide, Adelaide, SA, Australia.
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Scougall
authors.affiliation: Department of Molecular and Cellular Biology, School of Biological Sciences, University of Adelaide, Adelaide, SA, Australia.
authors.forename: Arend
authors.initials: A
authors.lastname: Grosse
authors.affiliation: Department of Molecular and Cellular Biology, School of Biological Sciences, University of Adelaide, Adelaide, SA, Australia.
authors.forename: Qiao
authors.initials: Q
authors.lastname: Qiao
authors.affiliation: Department of Molecular and Cellular Biology, School of Biological Sciences, University of Adelaide, Adelaide, SA, Australia.
authors.forename: Behzad B
authors.initials: BB
authors.lastname: Ajilian
authors.affiliation: Department of Molecular and Cellular Biology, School of Biological Sciences, University of Adelaide, Adelaide, SA, Australia.
authors.forename: Georget
authors.initials: G
authors.lastname: Reaiche-Miller
authors.affiliation: SA Pathology, Hanson Institute, Centre For Neurological Diseases, Adelaide, SA, Australia.
authors.forename: John
authors.initials: J
authors.lastname: Finnie
authors.affiliation: Department of Gastroenterology and Hepatology, University Hospital, University of Duisburg-Essen, Essen, Germany.
authors.forename: Melanie
authors.initials: M
authors.lastname: Werner
authors.affiliation: Department of Gastroenterology and Hepatology, University Hospital, University of Duisburg-Essen, Essen, Germany.
authors.forename: Ruth
authors.initials: R
authors.lastname: Broering
authors.affiliation: Department of Gastroenterology and Hepatology, University Hospital, University of Duisburg-Essen, Essen, Germany.
authors.forename: Joerg F
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 Molecular and Cellular Biology, School of Biological Sciences, University of Adelaide, Adelaide, SA, Australia.
authors.forename: Allison R
authors.initials: AR
authors.lastname: Jilbert
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000627:therapeutic use*; D016207:Cytokines / Q000096:biosynthesis; D004372:Ducks; D004371:Hepatitis Virus, Duck / Q000302:isolation & purification*; D006524:Hepatitis, Viral, Animal / Q000188:drug therapy* / Q000473:pathology / Q000821:virology; D009838:Oligodeoxyribonucleotides / Q000627:therapeutic use*; D010850:Picornaviridae Infections / Q000188:drug therapy* / Q000473:pathology / Q000821:virology
chemical_list: D000998:Antiviral Agents; D016207:Cytokines; D009838:Oligodeoxyribonucleotides; C000608433:REP 2055