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Viruses 2015, 7(7), 3345-3360;

RNase P Ribozymes Inhibit the Replication of Human Cytomegalovirus by Targeting Essential Viral Capsid Proteins

Institute of Virology, School of Life Sciences, Nanjing University, Nanjing 210093, China
Taizhou Institute of Virology, Taizhou 225300, China
Jiangsu Affynigen Biotechnologies, Inc., Taizhou 225300, China
School of Public Health, University of California, Berkeley, CA 94720, USA
The People's Hospital of Taizhou, Taizhou 225300, China
Program in Comparative Biochemistry, University of California, Berkeley, CA 94720, USA
State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan 430072, China
These authors contributed equally to this work.
Author to whom correspondence should be addressed.
Academic Editor: Kenneth Lundstrom
Received: 25 March 2015 / Revised: 8 May 2015 / Accepted: 18 June 2015 / Published: 24 June 2015
(This article belongs to the Special Issue Gene Therapy with Emphasis on RNA Interference)
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An engineered RNase P-based ribozyme variant, which was generated using the in vitro selection procedure, was used to target the overlapping mRNA region of two proteins essential for human cytomegalovirus (HCMV) replication: capsid assembly protein (AP) and protease (PR). In vitro studies showed that the generated variant, V718-A, cleaved the target AP mRNA sequence efficiently and its activity was about 60-fold higher than that of wild type ribozyme M1-A. Furthermore, we observed a reduction of 98%–99% in AP/PR expression and an inhibition of 50,000 fold in viral growth in cells with V718-A, while a 75% reduction in AP/PR expression and a 500-fold inhibition in viral growth was found in cells with M1-A. Examination of the antiviral effects of the generated ribozyme on the HCMV replication cycle suggested that viral DNA encapsidation was inhibited and as a consequence, viral capsid assembly was blocked when the expression of AP and PR was inhibited by the ribozyme. Thus, our study indicates that the generated ribozyme variant is highly effective in inhibiting HCMV gene expression and blocking viral replication, and suggests that engineered RNase P ribozyme can be potentially developed as a promising gene-targeting agent for anti-HCMV therapy. View Full-Text
Keywords: gene therapy; ribozyme; RNase P; cytomegalovirus; gene targeting gene therapy; ribozyme; RNase P; cytomegalovirus; gene targeting

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Yang, Z.; Reeves, M.; Ye, J.; Trang, P.; Zhu, L.; Sheng, J.; Wang, Y.; Zen, K.; Wu, J.; Liu, F. RNase P Ribozymes Inhibit the Replication of Human Cytomegalovirus by Targeting Essential Viral Capsid Proteins. Viruses 2015, 7, 3345-3360.

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