Combination of soluble coxsackievirus-adenovirus receptor and anti-coxsackievirus siRNAs exerts synergistic antiviral activity against coxsackievirus B3
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 cytoplasmati...
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| Veröffentlicht in: | Antiviral research 2009-09, Vol.83 (3), p.298-306 |
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| creator | Werk, Denise Pinkert, Sandra Heim, Albert Zeichhardt, Heinz Grunert, Hans-Peter Poller, Wolfgang Erdmann, Volker A. Fechner, Henry Kurreck, Jens |
| description | 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. |
| doi_str_mv | 10.1016/j.antiviral.2009.07.002 |
| format | Article |
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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.</description><identifier>ISSN: 0166-3542</identifier><identifier>EISSN: 1872-9096</identifier><identifier>DOI: 10.1016/j.antiviral.2009.07.002</identifier><identifier>PMID: 19591879</identifier><identifier>CODEN: ARSRDR</identifier><language>eng</language><publisher>Kidlington: Elsevier B.V</publisher><subject>Antibiotics. Antiinfectious agents. Antiparasitic agents ; Antiviral agents ; Antiviral Agents - pharmacology ; Antiviral therapy ; Biological and medical sciences ; Cardiology. Vascular system ; Cells, Cultured ; Coxsackie and Adenovirus Receptor-Like Membrane Protein ; Coxsackievirus ; Coxsackievirus B3 ; Coxsackievirus-adenovirus receptor ; Enterovirus B, Human - drug effects ; Fibroblasts - virology ; General pharmacology ; Heart ; Humans ; Medical sciences ; Myocarditis. Cardiomyopathies ; Pharmaceutical technology. Pharmaceutical industry ; Pharmacology. 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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.</description><subject>Antibiotics. Antiinfectious agents. Antiparasitic agents</subject><subject>Antiviral agents</subject><subject>Antiviral Agents - pharmacology</subject><subject>Antiviral therapy</subject><subject>Biological and medical sciences</subject><subject>Cardiology. Vascular system</subject><subject>Cells, Cultured</subject><subject>Coxsackie and Adenovirus Receptor-Like Membrane Protein</subject><subject>Coxsackievirus</subject><subject>Coxsackievirus B3</subject><subject>Coxsackievirus-adenovirus receptor</subject><subject>Enterovirus B, Human - drug effects</subject><subject>Fibroblasts - virology</subject><subject>General pharmacology</subject><subject>Heart</subject><subject>Humans</subject><subject>Medical sciences</subject><subject>Myocarditis. Cardiomyopathies</subject><subject>Pharmaceutical technology. Pharmaceutical industry</subject><subject>Pharmacology. Drug treatments</subject><subject>Receptors, Virus - metabolism</subject><subject>RNA interference</subject><subject>RNA, Small Interfering - pharmacology</subject><subject>Small interfering RNA</subject><subject>Virus Attachment - drug effects</subject><subject>Virus Replication - drug effects</subject><issn>0166-3542</issn><issn>1872-9096</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2009</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkc9uEzEQxi0EomnhFcAXuO3iP9n1-hgiKEgVSAjOlmOPK4eNHWxv1bwJj4u3iYLg0pPH0m9mvvk-hF5T0lJC-3fbVofi73zSY8sIkS0RLSHsCVrQQbBGEtk_RYtK9g3vluwCXea8JYT0Qg7P0QWVnaygXKDf67jb-KCLjwFHh3Mcp80I2MT7rM1PD3XHlBttIcSHEicwsC8xYR0snlU0_7I4-29fVhnDPaRSf4cA6dbn4g0-a8bazFU5YH2rfcjlv334PX-Bnjk9Znh5eq_Qj48fvq8_NTdfrz-vVzeNWXJSGqoFs4MTA6HUglsyw4HzTWdBLmW913R2MEZaGISb73dgHSOCcdYRN_QDv0Jvj3P3Kf6aIBe189nAOOoAccqqF52Y7XwUZITxjlJSQXEETYo5J3Bqn_xOp4OiRM3pqa06O6Hm9BQRqqZXO1-dVkybHdi_fae4KvDmBOhs9OiSDsbnM8foIAV_GLQ6clCdu_OQVDYeggHra3xF2egfFfMHvy7BzQ</recordid><startdate>20090901</startdate><enddate>20090901</enddate><creator>Werk, Denise</creator><creator>Pinkert, Sandra</creator><creator>Heim, Albert</creator><creator>Zeichhardt, Heinz</creator><creator>Grunert, Hans-Peter</creator><creator>Poller, Wolfgang</creator><creator>Erdmann, Volker A.</creator><creator>Fechner, Henry</creator><creator>Kurreck, Jens</creator><general>Elsevier B.V</general><general>Elsevier</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QO</scope><scope>7T7</scope><scope>7TM</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>P64</scope><scope>7X8</scope></search><sort><creationdate>20090901</creationdate><title>Combination of soluble coxsackievirus-adenovirus receptor and anti-coxsackievirus siRNAs exerts synergistic antiviral activity against coxsackievirus B3</title><author>Werk, Denise ; Pinkert, Sandra ; Heim, Albert ; Zeichhardt, Heinz ; Grunert, Hans-Peter ; Poller, Wolfgang ; Erdmann, Volker A. ; Fechner, Henry ; Kurreck, Jens</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c430t-1a72d8f78011def42c3e33b5de949006c5d8cc9de87f0006fedf20723250f8683</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2009</creationdate><topic>Antibiotics. Antiinfectious agents. Antiparasitic agents</topic><topic>Antiviral agents</topic><topic>Antiviral Agents - pharmacology</topic><topic>Antiviral therapy</topic><topic>Biological and medical sciences</topic><topic>Cardiology. Vascular system</topic><topic>Cells, Cultured</topic><topic>Coxsackie and Adenovirus Receptor-Like Membrane Protein</topic><topic>Coxsackievirus</topic><topic>Coxsackievirus B3</topic><topic>Coxsackievirus-adenovirus receptor</topic><topic>Enterovirus B, Human - drug effects</topic><topic>Fibroblasts - virology</topic><topic>General pharmacology</topic><topic>Heart</topic><topic>Humans</topic><topic>Medical sciences</topic><topic>Myocarditis. Cardiomyopathies</topic><topic>Pharmaceutical technology. Pharmaceutical industry</topic><topic>Pharmacology. Drug treatments</topic><topic>Receptors, Virus - metabolism</topic><topic>RNA interference</topic><topic>RNA, Small Interfering - pharmacology</topic><topic>Small interfering RNA</topic><topic>Virus Attachment - drug effects</topic><topic>Virus Replication - drug effects</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Werk, Denise</creatorcontrib><creatorcontrib>Pinkert, Sandra</creatorcontrib><creatorcontrib>Heim, Albert</creatorcontrib><creatorcontrib>Zeichhardt, Heinz</creatorcontrib><creatorcontrib>Grunert, Hans-Peter</creatorcontrib><creatorcontrib>Poller, Wolfgang</creatorcontrib><creatorcontrib>Erdmann, Volker A.</creatorcontrib><creatorcontrib>Fechner, Henry</creatorcontrib><creatorcontrib>Kurreck, Jens</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Biotechnology Research Abstracts</collection><collection>Industrial and Applied Microbiology Abstracts (Microbiology A)</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Antiviral research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Werk, Denise</au><au>Pinkert, Sandra</au><au>Heim, Albert</au><au>Zeichhardt, Heinz</au><au>Grunert, Hans-Peter</au><au>Poller, Wolfgang</au><au>Erdmann, Volker A.</au><au>Fechner, Henry</au><au>Kurreck, Jens</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Combination of soluble coxsackievirus-adenovirus receptor and anti-coxsackievirus siRNAs exerts synergistic antiviral activity against coxsackievirus B3</atitle><jtitle>Antiviral research</jtitle><addtitle>Antiviral Res</addtitle><date>2009-09-01</date><risdate>2009</risdate><volume>83</volume><issue>3</issue><spage>298</spage><epage>306</epage><pages>298-306</pages><issn>0166-3542</issn><eissn>1872-9096</eissn><coden>ARSRDR</coden><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.</abstract><cop>Kidlington</cop><pub>Elsevier B.V</pub><pmid>19591879</pmid><doi>10.1016/j.antiviral.2009.07.002</doi><tpages>9</tpages></addata></record> |
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| ispartof | Antiviral research, 2009-09, Vol.83 (3), p.298-306 |
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| subjects | Antibiotics. Antiinfectious agents. Antiparasitic agents Antiviral agents Antiviral Agents - pharmacology Antiviral therapy Biological and medical sciences Cardiology. Vascular system Cells, Cultured Coxsackie and Adenovirus Receptor-Like Membrane Protein Coxsackievirus Coxsackievirus B3 Coxsackievirus-adenovirus receptor Enterovirus B, Human - drug effects Fibroblasts - virology General pharmacology Heart Humans Medical sciences Myocarditis. Cardiomyopathies Pharmaceutical technology. Pharmaceutical industry Pharmacology. Drug treatments Receptors, Virus - metabolism RNA interference RNA, Small Interfering - pharmacology Small interfering RNA Virus Attachment - drug effects Virus Replication - drug effects |
| title | Combination of soluble coxsackievirus-adenovirus receptor and anti-coxsackievirus siRNAs exerts synergistic antiviral activity against coxsackievirus B3 |
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