title: Initiation of protein synthesis by hepatitis C virus is refractory to reduced eIF2.GTP.Met-tRNA(i)(Met) ternary complex availability.
abstract: A cornerstone of the antiviral interferon response is phosphorylation of eukaryotic initiation factor (eIF)2alpha. This limits the availability of eIF2.GTP.Met-tRNA(i)(Met) ternary 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 eIF2alpha and Met-tRNA(i)(Met) are present, defining a tactic used by HCV to evade part of the antiviral interferon response.
authors.affiliation: Department of Biochemistry and McGill Cancer Center, McGill University, Montreal, Quebec, Canada.
authors.forename: Francis
authors.initials: F
authors.lastname: Robert
authors.forename: Lee D
authors.initials: LD
authors.lastname: Kapp
authors.forename: Shakila N
authors.initials: SN
authors.lastname: Khan
authors.forename: Michael G
authors.initials: MG
authors.lastname: Acker
authors.forename: Sarah
authors.initials: S
authors.lastname: Kolitz
authors.forename: Shirin
authors.initials: S
authors.lastname: Kazemi
authors.forename: Randal J
authors.initials: RJ
authors.lastname: Kaufman
authors.forename: William C
authors.initials: WC
authors.lastname: Merrick
authors.forename: Antonis E
authors.initials: AE
authors.lastname: Koromilas
authors.forename: Jon R
authors.initials: JR
authors.lastname: Lorsch
authors.forename: Jerry
authors.initials: J
authors.lastname: Pelletier
mesh_terms: D000818:Animals; D001312:Aurintricarboxylic Acid / Q000737:chemistry / Q000494:pharmacology; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism*; D006160:Guanosine Triphosphate / Q000378:metabolism*; D016174:Hepacivirus / Q000187:drug effects / Q000235:genetics*; D051379:Mice; D008957:Models, Genetic; D014176:Protein Biosynthesis / Q000187:drug effects / Q000235:genetics*; D011500:Protein Synthesis Inhibitors / Q000737:chemistry / Q000494:pharmacology; D012358:RNA, Transfer, Met / Q000378:metabolism*; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics; D012270:Ribosomes / Q000187:drug effects / Q000378:metabolism
chemical_list: D015852:Eukaryotic Initiation Factor-2; D011500:Protein Synthesis Inhibitors; D012358:RNA, Transfer, Met; D001312:Aurintricarboxylic Acid; D006160:Guanosine Triphosphate