Inhibitory effect of the combination of CpG-induced cytokines with lamivudine against hepatitis B virus replication in vitro
| Autor: | Christian Trepo, Fabien Zoulim, Isabelle Chemin, David Durantel, Olivier Hantz, Julie Lucifora, Isabelle Vincent |
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| Rok vydání: | 2009 |
| Předmět: |
Pharmacology
Hepatitis B virus biology Reverse-transcriptase inhibitor medicine.medical_treatment virus diseases Lamivudine biology.organism_classification medicine.disease_cause Virology digestive system diseases Virus Infectious Diseases Cytokine Immune system Orthohepadnavirus Hepadnaviridae Immunology medicine Pharmacology (medical) medicine.drug |
| Zdroj: | Antiviral Therapy. 14:131-135 |
| ISSN: | 2040-2058 1359-6535 |
| DOI: | 10.1177/135965350901400115 |
| Popis: | Background Currently approved antiviral monotherapies against chronic hepatitis B fail to eradicate hepatitis B virus (HBV), to overcome the defects in HBV-specific immune responses and to prevent HBV relapse after cessation of therapy. CpG oligodesoxynucleotides (CpG ODN) are synthetic agonists of Toll-like receptor 9 and potent inducers of innate and acquired immunity. Our aim was to establish the proof of concept of the antiviral benefit of combining a nucleoside analogue with CpG-induced cytokines on HBV replication in vitro. Methods Peripheral blood mononuclear cells from HBV-negative individuals were stimulated with CpG ODN to generate CpG-induced cytokine supernatants. Proliferating HepaRG and HepG2 cells were transduced with recombinant HBV baculovirus and differentiated HepaRG cells were inoculated with HBV virions. Antiviral effects of CpG-induced cytokine with or without lamivudine were evaluated by analysing HBV DNA, HBV RNA and antigen secretion (hepatitis B surface antigen [HBsAg] and hepatitis B e antigen [HBeAg]). Results Following transduction or HBV inoculation, CpG-induced cytokines strongly inhibited HBV viral intermediates of replication, as well as HBsAg and HBeAg secretion from infected cells. Strikingly, in transduced HepaRG cells, the combination of CpG-induced cytokines with lamivudine reduced the 50% effective concentration of lamivudine by 100-fold. Importantly, the treatment of CpG-induced cytokines prior to HBV inoculation conferred a partial protection against infection to hepatocytes. Conclusions CpG-induced cytokines associated with polymerase inhibitors represent a promising combination to suppress HBV replication. Such an immunotherapeutic strategy should be evaluated in vivo to assess restoration and duration of anti-HBV-specific immune responses. |
| Databáze: | OpenAIRE |
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