Targets of small interfering RNA restriction during human immunodeficiency virus type 1 replication

Journal of Virology
Yong GaoEric J Arts

Abstract

Small interfering RNAs (siRNAs) have been shown to effectively inhibit human immunodeficiency virus type 1 (HIV-1) replication in vitro. The mechanism(s) for this inhibition is poorly understood, as siRNAs may interact with multiple HIV-1 RNA species during different steps of the retroviral life cycle. To define susceptible HIV-1 RNA species, siRNAs were first designed to specifically inhibit two divergent primary HIV-1 isolates via env and gag gene targets. A self-inactivating lentiviral vector harboring these target sequences confirmed that siRNA cannot degrade incoming genomic RNA. Disruption of the incoming core structure by rhesus macaque TRIM5alpha did, however, provide siRNA-RNA-induced silencing complex access to HIV-1 genomic RNA and promoted degradation. In the absence of accelerated core disruption, only newly transcribed HIV-1 mRNA in the cytoplasm is sensitive to siRNA degradation. Inhibitors of HIV-1 mRNA nuclear export, such as leptomycin B and camptothecin, blocked siRNA restriction. All HIV-1 RNA regions and transcripts found 5' of the target sequence, including multiply spliced HIV-1 RNA, were degraded by unidirectional 3'-to-5' siRNA amplification and spreading. In contrast, HIV-1 RNA 3' of the target sequenc...Continue Reading

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Citations

Feb 12, 2013·Nucleic Acids Research·Leszek LisowskiMark A Kay
Feb 15, 2014·Infectious Diseases in Obstetrics and Gynecology·Lee Adam Wheeler
Feb 25, 2009·Expert Opinion on Biological Therapy·Ben Berkhout, Olivier ter Brake
Oct 3, 2009·Annals of the New York Academy of Sciences·Ben Berkhout

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