The 341-nucleotide 5' non-translated region is the most conserved part of t
he hepatitis C virus (HCV) genome, It contains a highly structured internal
ribosomal entry site (IRES) that mediates cap-independent initiation of tr
anslation of the viral polyprotein by a mechanism that is unprecedented in
eukaryotes. The first step in translation initiation is assembly of eukaryo
tic initiation factor (eIF) 3, eIF2, GTP, initiator tRNA and a 40S ribosoma
l subunit into a 43S preinitiation complex, The HCV IRES recruits this comp
lex and directs its precise attachment at the initiation codon to form a 48
S complex in a process that does not involve eIFs 4A, 4B or 4F. The IRES co
ntains sites that bind independently with the eIF3 and 40S subunit componen
ts of 43S complexes, and structural determinants that ensure the correct sp
atial orientation of these binding sites so that the 48S complex assembles
precisely at the initiation codon.