Nucleic Acids Research Advance Access originally published online on December 8, 2006
Nucleic Acids Research 2007 35(1):247-255; doi:10.1093/nar/gkl1022
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Nucleic Acids Research, 2007, Vol. 35, No. 1 247-255
© 2006 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
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Use of modified U1 snRNAs to inhibit HIV-1 replication
Department of Medical Genetics and Microbiology Toronto, Ontario, Canada 1 Department of Medicine, University of Toronto Toronto, Ontario, Canada 2 Department of Biochemistry and Microbiology, University of Victoria Victoria, BC, Canada
*To whom correspondence should be addressed at Department of Medical Genetics and Microbiology, University of Toronto, 1 King's College Circle, Toronto, Ontario, M5S-1A8. Tel: +416 978 2500; Fax: +416 978-6885; Email: alan.cochrane{at}utoronto.ca
Received August 10, 2006. Revised November 13, 2006. Accepted November 14, 2006.
Control of RNA processing plays a central role in regulating the replication of HIV-1, in particular the 3' polyadenylation of viral RNA. Based on the demonstration that polyadenylation of mRNAs can be disrupted by the targeted binding of modified U1 snRNA, we examined whether binding of U1 snRNAs to conserved 10 nt regions within the terminal exon of HIV-1 was able to inhibit viral structural protein expression. In this report, we demonstrate that U1 snRNAs complementary to 5 of the 15 regions targeted result in significant suppression of HIV-1 protein expression and viral replication coincident with loss of viral RNA. Suppression of viral gene expression is dependent upon appropriate assembly of a U1 snRNP particle as mutations of U1 snRNA that affect binding of U1 70K or Sm proteins significantly reduced efficacy. However, constructs lacking U1A binding sites retained significant anti-viral activity. This finding suggests a role for these mutants in situations where the wild-type constructs cause toxic effects. The conserved nature of the sequences targeted and the high efficacy of the constructs suggests that this strategy has significant potential as an HIV therapeutic.
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