Targeting ribosome assembly on the HCV RNA using a small RNA molecule

Abstract

Translation initiation of hepatitis C virus (HC V) RNA is the initial obligatory step of the viral life cycle, mediated through the internal ribosome entry site (IRES ) present in the 5′-untranslated region (UTR). Initiation on the HC V IRES is mediated by multiple structure-specific interactions between IRES RNA and host 40S ribosomal subunit. In the present study we demonstrate that the SLIIIef domain, in isolation from other structural elements of HC V IRES , retain the ability to interact with 40S ribosome subunit. A small RNA SLRef, mimicking the SLIIIef domain was found to interact specifically with human La protein and the ribosomal protein S5 and selectively inhibit HC V RNA translation. More importantly, SLRef RNA showed significant suppression of replication in HC V monocistronic replicon and decrease of negative strand synthesis in HC V cell culture system. Finally, using Sendai virus based virosome, the targeted delivery of SLRef RNA into mice liver succeeded in selectively inhibiting HC V IRES mediated translation in vivo. © 2012 Landes Bioscience.