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Open Access
Peer-reviewed
Research Article
Therapeutic Antiviral Effect of the Nucleic Acid Polymer REP 2055 against Persistent Duck Hepatitis B Virus Infection
Faseeha Noordeen,
Catherine A. Scougall,
Arend Grosse,
Qiao Qiao,
Behzad B. Ajilian,
Georget Reaiche-Miller,
John Finnie,
Melanie Werner,
Ruth Broering,
Joerg F. Schlaak,
Andrew Vaillant ,
Allison R. Jilbert
PLOS
Published: November 11, 2015
DOI: 10.1371/journal.pone.0140909
Allison R. Jilbert
Department of Molecular and Cellular Biology, School of Biological Sciences, University of Adelaide, Adelaide, SA, Australia
Faseeha Noordeen
Department of Microbiology, Faculty of Medicine, University of Peradeniya, Peradeniya, Sri Lanka
John Finnie
SA Pathology, Hanson Institute, Centre For Neurological Diseases, Adelaide, SA, Australia
Melanie Werner, Ruth Broering, Joerg F. Schlaak
Department of Gastroenterology and Hepatology, University Hospital, University of Duisburg-Essen, Essen, Germany
Andrew Vaillant
Replicor Inc., Montreal, Quebec, Canada
Corresponding Authors
Email: [email protected] (AJ)
Email: [email protected] (AV)
Competing Interests
This study was funded by Replicor Inc. Dr. Andrew Vaillant is employed by Replicor Inc. NAPs are protected by patents wholly owned by Replicor Inc and are currently in development for the treatment of hepatitis B / hepatitis D infection. Relevant patents are: US 8,067,385 Antiviral oligonucleotides targeting HBV US 8,008,270 Antiviral oligonucleotides targeting viral families US 7,358,068 Antiviral oligonucleotides, US 8,008,269 Antiviral oligonucleotides. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials, as detailed online in the guide for authors.
Author Contributions
Conceived and designed the experiments: FN RB AV ARJ. Performed the experiments: FN CAS AG QQ BBA GR-M MW. Analyzed the data: FN CAS QQ GR-M JF RB JFS AV ARJ. Wrote the paper: FN CAS AV ARJ.
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. |
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发表于 2015-11-12 12:24
