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Journal of Biochemistry Advance Access originally published online on June 24, 2009
Journal of Biochemistry 2009 146(4):481-489; doi:10.1093/jb/mvp093
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© The Authors 2009. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved

RNA Interference Targeted to the Conserved Dimerization Initiation Site (DIS) of HIV-1 Restricts Virus Escape Mutation

Ryuichi Sugiyama1,*, Yuichiro Habu1,3, Aki Ohnari1,*, Naoko Miyano-Kurosaki1 and Hiroshi Takaku1,2,{dagger}

1Department of Life and Environmental Science; 2High Technology Research Center, Chiba Institute of Technology, 2-17-1 Tsudanuma, Narashino-shi, Chiba 275-0016, Japan; and 3Department of Microbiology, Immunology and Pathology 1619 Campus Delivery, Colorado State University, Fort Collins, CO 80523-1619, USA

{dagger}To whom correspondence should be addressed. Tel: +81-047-478-0407, Fax: +81-047-471-8764, E-mail: hiroshi.takaku{at}it-chiba.ac.jp

Received April 14, 2009; Accepted June 10, 2009


  Abstract

Short hairpin RNAs (shRNA) targeting viral or cellular genes can effectively inhibit human immunodeficiency virus type 1 (HIV-1) replication. This inhibition, however, may induce mutations in the targeted gene, leading to rapid escape from the shRNA-induced inhibition. We generated a lymphoid cell line that stably expressed a 19-bp shRNA targeting a well-conserved dimerization initiation site (DIS) of HIV-1, which strongly inhibited viral replication, thereby delaying virus escape. Furthermore, treatment of HIV-1 infection with DIS- and vif-shRNA combination therapy resulted in superior anti-viral responses compared to vif-shRNA monotherapy. Continuous challenge with HIV-1, however, generated virus mutants that could overcome the RNA interference restriction. Such anti-genes may be promising tools for HIV-1 gene therapy for HIV/acquired immunodeficiency syndrome.

Key Words: combination therapy, lentiviral vector, HIV-1, RNA interference, well-conserved dimerization initiation site (DIS), virus escape mutation

Abbreviations: HIV-1, human immunodeficiency virus type1; DIS, dimerization initiation site; vif, HIV-1 virion infectivity factor; RNAi, RNA interference; shRNA, short hairpin RNA; EGFP, enhanced green fluorescent protein

*These authors contributed equally to this work.


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