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Journal of Biochemistry Advance Access published online on June 24, 2009
Journal of Biochemistry, 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 Sugiyama1,4, Yuichiro Habu1,3, Aki Ohnari1,4, Naoko Miyano-Kurosaki1 and Hiroshi Takaku1,2

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

To whom correspondence should be addressed: Prof. Hiroshi Takaku: 1Department of Life and Environmental Science and the 2High Technology Research Center, Chiba Institute of Technology, 2-17-1 Tsudanuma, Narashino, Chiba 275-0016, Japan, Tel: 047-478-0407, Fax: 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 antiviral 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: HIV-1, RNA interference, shRNA, well-conserved dimerization initiation site (DIS), virus escape mutation, combination therapy, lentiviral vector.

5These authors contributed equally to this work.


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