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本帖最后由 StephenW 于 2015-4-12 05:38 编辑
RS-3064
Viral hepatitis
Hepatitis B & D - Experimental
ANTIVIRAL EFFECTS OF NUCLEIC ACID POLYMERS ON HEPATITIS B VIRUS INFECTION
Clément Guillot* 1, Olivier Hantz1, Andrew Vaillant2, Isabelle Chemin1
1Cancer Research Center of Lyon UMR Inserm 1052 CNRS 5286, Lyon, France, 2REPLICor Inc., Montreal, Canada
Corresponding author’s email: [email protected]
Background and Aims:
Hepatitis B virus (HBV) infection remains a major public health problem worldwide and current therapies are rarely able to cure HBV infection. Nucleic acid polymers (NAPs) have been shown to inhibit duck HBV infection in vitro and in vivo (Noordeen et al., 2013). NAPs have been shown to eliminate the hepatitis B surface antigen (HBsAg) from the blood (in ducks infected with the duck hepatitis B virus) but the mechanism whereby NAPs achieve the removal of surface antigen from the blood has yet to be clearly elucidated. Due to their phosphorothioate oligonucleotide structure, NAPs are chemically analogous to sulfated polyglycans such as heparin which are known to block entry of hepatitis B virus. In this study we investigated the in vitro antiviral activity of NAPs in HBV infected HepaRG cells and primary human hepatocytes.
Methods:
NAP uptake into cells was assessed using Cy3 labeled NAPs. In order to evaluate potent effects of NAPs on HBV entry as well as post-entry, HBV infected differentiated HepaRG cells and primary human hepatocytes were treated with NAPs every two days starting at the time of infection or starting two days post-infection. The Elecsys HBsAg II quant automated system was used to quantitatively measure the secreted HBsAg. PreS1 containing particles were also assessed by ELISA and extracellular HBV DNA was measured by real-time PCR.
Results:
Fluorescent NAPs were observed to enter into differentiated HepaRG cells and in primary cultures more particularly in hepatocytes rather than biliary cells. 5µM and 1µM NAPs significantly reduced extracellular HBsAg by 80% and 40% respectively as well as PreS1 containing particles when added at the time of infection. Interestingly, 5µM NAPs seems also to decrease extracellular HBsAg by 25% as well as PreS1 containing particles when added two days post-infection, suggesting NAPs exert a post-entry antiviral effect.
Conclusions:
In this study, we showed a strong antiviral activity of nucleic acid polymers against HBV infection in HepaRG cells and primary human hepatocytes. Our results suggest that NAPs are able to block entry of HBV but also to have an effect on the replication cycle following entry of the virus which results in a reduction of HBsAg released into the supernatant. These antiviral activities both on virus entry and within the cells promise a strong potential of NAPs alone or in combination with already existing antiviral treatments.
Disclosure of Interest: C. Guillot: : None Declared, O. Hantz: : None Declared, A. Vaillant: Stockholder: REPLICor, Employee: REPLICor (VP, CSO), I. Chemin: : None Declared
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发表于 2015-4-12 05:38
