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Antimicrobial Agents and Chemotherapy, August 2009, p. 3226-3235, Vol. 53, No. 8
0066-4804/09/$08.00+0     doi:10.1128/AAC.00189-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Cyclosporine Inhibits Flavivirus Replication through Blocking the Interaction between Host Cyclophilins and Viral NS5 Protein{triangledown}

Min Qing,1,2 Feng Yang,3 Bo Zhang,2 Gang Zou,1,2 John M. Robida,3 Zhiming Yuan,1 Hengli Tang,3* and Pei-Yong Shi2,4*

State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China,1 Wadsworth Center, New York State Department of Health, Albany, New York 12201,2 Department of Biological Science, Florida State University, Tallahassee, Florida 32306,3 Department of Biomedical Sciences, University at Albany, State University of New York, Albany, New York 122084

Received 11 February 2009/ Returned for modification 27 March 2009/ Accepted 12 May 2009

Although flaviviruses cause significant human diseases, no effective therapy is currently available. Host factors essential for viral replication are potential targets for antiviral development. Here we report that cyclophilins (CyPs), a family of cellular peptidyl-prolyl isomerases (PPIases), play a role in flavivirus replication. Huh-7.5 cells with knockdown of different isoforms of CyP were less efficient than parental cells in supporting flavivirus replication, including West Nile virus (WNV), dengue virus, and yellow fever virus. The low viral replication in CyP A (CyPA) knockdown cells could be rescued by trans supplying of a wild-type CyPA but not by trans supplying of a mutant CyPA (defective in the PPIase activity), indicating that the isomerase activity of CyPA is critical for viral replication. Immunoprecipitation and biochemical pulldown analyses showed that CyPA interacts with WNV genomic RNA and viral NS5 protein in the replication complex. Furthermore, antiviral experiments demonstrated that cyclosporine (Cs; an 11-amino-acid cyclic peptide known to block the PPIase activity of CyPA) inhibits flavivirus replication in cell culture at nontoxic concentrations. Time-of-addition and transient replicon results indicated that Cs inhibits flavivirus at the step of viral RNA synthesis. Biochemical analysis showed that Cs directly blocks the interaction between CyPA and WNV NS5 protein. Our results suggest that host CyPA is a component of flavivirus replication complex and could be targeted for potential antiviral development.

* Corresponding authors. Mailing address for P.-Y. Shi: 10 Biopolis Road, #05-01 Chromos, Singapore 138670. Phone: (65) 67222909. Fax: (65) 67222916. E-mail: pei_yong.shi{at}novartis.com. Mailing address for H. Tang: King Building, Stadium Dr., Department of Biological Science, Florida State University, Tallahassee, FL 32306-4370. Phone: (850) 645-2402. Fax: (850) 645-8447. E-mail: tang{at}bio.fsu.edu

{triangledown} Published ahead of print on 18 May 2009.

Antimicrobial Agents and Chemotherapy, August 2009, p. 3226-3235, Vol. 53, No. 8
0066-4804/09/$08.00+0     doi:10.1128/AAC.00189-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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