Initiation of Protein Synthesis by Hepatitis C Virus Is Refractory to Reduced eIF2 · GTP · Met-tRNAiMetTernary Complex Availability

Abstract

A cornerstone of the antiviral interferon response is phosphorylation of eukaryotic initiation factor (eIF)2α. This limits the availability of eIF2·GTP·Met-tRNAiMetternary complexes, reduces formation of 43S preinitiation complexes, and blocks viral (and most cellular) mRNA translation. However, many viruses have developed counterstrategies that circumvent this cellular response. Herein, we characterize a novel class of translation initiation inhibitors that block ternary complex formation and prevent the assembly of 43S preinitiation complexes. We find that translation driven by the HCV IRES is refractory to inhibition by these compounds at concentrations that effectively block cap-dependent translation in vitro and in vivo. Analysis of initiation complexes formed on the HCV IRES in the presence of inhibitor indicates that eIF2α and Met-tRNAiMetare present, defining a tactic used by HCV to evade part of the antiviral interferon response.