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

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 l...

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Bibliographic Details
Published in:Journal of biochemistry (Tokyo) 2009-10, Vol.146 (4), p.481-489
Main Authors: Sugiyama, Ryuichi, Habu, Yuichiro, Ohnari, Aki, Miyano-Kurosaki, Naoko, Takaku, Hiroshi
Format: Article
Language:English
Subjects:
Anti-HIV Agents - pharmacology
Cell Line
combination therapy
Conserved Sequence - genetics
Dimerization
HIV-1
HIV-1 - drug effects
HIV-1 - genetics
lentiviral vector
Mutagenesis - drug effects
Mutagenesis - genetics
Mutation - genetics
Nucleic Acid Conformation
RNA Interference
RNA, Small Interfering - genetics
RNA, Small Interfering - pharmacology
virus escape mutation
Virus Replication - drug effects
well-conserved dimerization initiation site (DIS)
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Summary: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.
ISSN:0021-924X
1756-2651
DOI:10.1093/jb/mvp093