Journal of RNAi and Gene Silencing (October 2005), 1(2), 56-65

Review

A novel approach for inhibition of HIV-1 by RNA interference: counteracting viral escape with a second generation of siRNAs

Olivier ter Brake and Ben Berkhout*

ABSTRACT

RNA interference (RNAi) is an evolutionary conserved gene silencing mechanism in which small interfering RNA (siRNA) mediates the sequence specific degradation of mRNA. The recent discovery that exogenously delivered siRNA can trigger RNAi in mammalian cells raises the possibility to use this technology as a therapeutic tool against pathogenic viruses. Indeed, it has been shown that siRNAs can be used effectively to inhibit virus replication. The focus of this review is on RNA interference strategies against HIV-1 and how this new technology may be developed into a new successful therapy. One of the hallmarks of RNAi, its sequence specificity, also presents a way out for the virus, as single nucleotide substitutions in the target region can abolish the suppression. Strategies to prevent the emergence of resistant viruses have been suggested and involve the targeting of conserved sequences and the simultaneous use of multiple siRNAs, similar to current highly active antiretroviral therapy. We present an additional strategy aimed at preventing viral escape by using a second generation of siRNAs that recognize the mutated target sites.

KEYWORDS: HIV-1, RNA interference, gene therapy, siRNA, shRNA, multiple, lentiviral vector

Department of Human Retrovirology, University of Amsterdam, Academic Medical Center (AMC), Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands.

*Correspondence to: Ben Berkhout, Email: b.berkhout@amc.uva.nl, Tel: + 31-20-5664853, Fax: + 31-20-6916531

© Copyright Ter Brake and Berkhout

(Received 02 September 2005; Revised 06 October 2005; Accepted 06 October 2005)