title: Combination of soluble coxsackievirus-adenovirus receptor and anti-coxsackievirus siRNAs exerts synergistic antiviral activity against coxsackievirus B3.
abstract: Coxsackievirus B3 (CVB-3) is a major causative agent of chronic heart muscle infections. The present study describes a cell culture system with an ongoing virus infection to evaluate two novel inhibitory strategies, either individually or combined: (1) RNA interference (RNAi) to degrade cytoplasmatic CVB-3 RNA and (2) a vector-delivered soluble variant of the coxsackievirus-adenovirus receptor fused to a human immunoglobulin (sCAR-Fc), which inhibits cellular uptake of CVB-3. Both approaches were capable of inhibiting CVB-3 in persistently infected human myocardial fibroblasts. The antiviral effect of a single treatment lasted for up to one week and could be extended by repeated applications. Each of the single treatments initially reduced the virus titer by approximately 1-log, whereas the combination of both approaches resulted in 4-log inhibition and retained substantial antiviral activity at later time points, when the effect of sCAR-Fc or siRNAs alone had already disappeared. Further analysis revealed that sCAR-Fc protects cells from virus-induced lysis but does not diminish the virus load. Reduction of the virus titer was only achieved with additional destruction of viral RNA by RNAi. Taken together, combination of RNAi and a protein-based antiviral strategy was found to result in a strong synergistic inhibition of an ongoing virus infection.
authors: Free University Berlin, Institute for Chemistry and Biochemistry, Thielallee 63, 14195 Berlin, Germany.
authors: Denise
authors: D
authors: Werk
authors: Sandra
authors: S
authors: Pinkert
authors: Albert
authors: A
authors: Heim
authors: Heinz
authors: H
authors: Zeichhardt
authors: Hans-Peter
authors: HP
authors: Grunert
authors: Wolfgang
authors: W
authors: Poller
authors: Volker A
authors: VA
authors: Erdmann
authors: Henry
authors: H
authors: Fechner
authors: Jens
authors: J
authors: Kurreck
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D029822:Enterovirus B, Human / Q000187:drug effects*; D005347:Fibroblasts / Q000821:virology; D006801:Humans; D034741:RNA, Small Interfering / Q000494:pharmacology*; D011991:Receptors, Virus / Q000378:metabolism*; D053585:Virus Attachment / Q000187:drug effects*; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; C568771:CLMP protein, human; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D034741:RNA, Small Interfering; D011991:Receptors, Virus