Hepatitis C virus internal ribosome entry site (HCV IRES)

The Hepatitis C virus internal ribosome entry site (HCV IRES) is a highly structured RNA element located within the 5' untranslated region (5' UTR) of the HCV genome [1, 6]. It is essential for the viral life cycle as it mediates cap-independent translation initiation, allowing the virus to synthesize its polyprotein by directly recruiting the host's 40S ribosomal subunit and eukaryotic initiation factor 3 (eIF3) [7, 13]. Because the IRES sequence is exceptionally conserved among clinical isolates and its unique structural domains—such as the subdomain IIa which acts as a conformational switch—are critical for function, it is a prominent target for direct-acting antiviral drug development [5, 9]. Therapeutic strategies targeting the IRES include small molecule inhibitors like benzimidazoles that arrest the RNA in an inactive state, as well as antisense oligonucleotides and RNA interference (shRNA/siRNA) agents that block ribosome assembly or promote viral RNA degradation [1, 3, 5]. Clinical candidates such as ISIS 14803 have explored this pathway in human trials, though challenges remain regarding potency and the delivery of nucleic acid-based therapeutics [4, 7]. Additionally, host-targeting agents like Miravirsen interfere with IRES stability by sequestering miR-122, a host microRNA that binds directly to the IRES region to facilitate viral replication [2, 8].

Other names

IRES_HCVHCV 5' UTRHCV 5' untranslated regionHepatitis C virus 5' untranslated regionHepatitis C virus 5' UTR

Inhibits viral translation initiation by binding to highly conserved RNA structural subdomains (e.g., subdomain IIa, III, or IV) and locking the RNA element into an inactive conformation, competing with host initiation factors, or sterically blocking the recruitment and assembly of the 40S ribosomal subunit and eukaryotic initiation factor 3 (eIF3) [1, 5, 13].